Topical compositions and uses of pai-1 inhibitors

Abstract

This disclosure provides new technologies (e.g., compositions) and methods of using them. In particular, this disclosure provides the insight that improved compositions, for example, plasminogen activator inhibitor-1 (PAI-1) inhibitors, may be suitable for the treatment and / or prevention of certain diseases, symptoms, and / or conditions.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 583,467, filed September 18, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Topical compositions are commonly used to treat and / or prevent dermatological conditions. This disclosure provides new technologies (e.g., compositions, methods, kits, etc.) for incorporating or delivering active agents (e.g., PAI-1 inhibitors), their production, and uses (including in the treatment and / or prevention of a variety of diseases, symptoms, and / or conditions). Summary of the Invention

[0003] This disclosure recognizes the need for improved topical compositions for treating diseases, conditions, and / or illnesses. In some embodiments, this disclosure particularly provides improved compositions that include and / or deliver an active agent (e.g., a PAI-1 inhibitor). This disclosure particularly provides compositions for formulation of topical applications that include and / or deliver an active agent (e.g., a PAI-1 inhibitor). In some embodiments, such compositions can be used, for example, in various cosmetic and medical applications.

[0004] Compositions containing or delivering an active agent (e.g., a PAI-1 inhibitor) (e.g., the original compositions described herein), such as PCT patent application number PCT US2019 / 050849 filed on September 12, 2019, entitled "PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) Inhibitors and Uses Therefor", published on March 19, 2020, entitled "USES OF PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) Inhibitors and Uses Therefor", and / or PCT patent application number PCT US2019 / 050849 filed on March 19, 2020, entitled "USES OF PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) Inhibitors and Uses Therefor". Those described in PCT patent application number PCT / US2019 / 050890, filed September 19, 2019, for “INHIBITORS”, have been successfully used for the topical application of active agents (e.g., PAI-1 inhibitors).

[0005] For example, in some embodiments, a primary composition containing and / or delivering an active agent (e.g., a PAI-1 inhibitor) is formulated as an ethanol-based composition. As is known to those skilled in the art, alcohol-based compositions can be used to deliver the active agent more effectively topically than other compositions (e.g., water-based compositions) because ethanol is a known permeation enhancer for topical use. However, insights from this disclosure, particularly, indicate that the active agent in an ethanol-based composition (i.e., an ethanol-based composition containing and / or delivering the active agent (e.g., a PAI-1 inhibitor)) can settle to the bottom of the container over time. That is, this disclosure identifies the source of the problem with such ethanol-based compositions. This disclosure particularly provides compositions, for example, with reduced ethanol content relative to a suitable reference composition (e.g., a primary composition as described herein). In some embodiments, the improved compositions as described herein contain more water relative to such reference (e.g., primary) compositions containing and / or delivering the relevant active agent. In some embodiments, this disclosure provides surprising insights into how water-based compositions deliver (e.g., locally) the active agent more effectively than reference compositions containing a localized penetration enhancer (e.g., the original composition, e.g., an alcohol-based composition). The inventors have conducted extensive research on such compositions and, as described in the examples, have made important and surprising findings that define certain embodiments and / or categories of such compositions as particularly and unexpectedly useful and / or advantageous.

[0006] In some embodiments, this disclosure particularly provides compositions comprising or delivering a PAI-1 inhibitor (e.g., improved compositions as described herein). In some embodiments, the compositions as described herein are formulated for topical application to a subject's site. In some embodiments, the compositions as described herein are substantially free of ETOH.

[0007] In some embodiments, the site is skin. In some embodiments, the site contains or actually contains multiple hair follicles. In some embodiments, each hair follicle optionally contains a hair disposed therein.

[0008] In some embodiments, the composition (e.g., the improved composition) is substantially free of all alcohols. In some embodiments, the composition is substantially free of sorbitol.

[0009] In some embodiments, no more than 35% by weight of the composition (e.g., the improved composition) contains a penetration enhancer.

[0010] In some embodiments, the penetration enhancer is one or more of glycerol, isopropyl myristate, and / or propylene glycol. In some embodiments, the composition (e.g., the improved composition) comprises more than 1% but not more than 15% of glycerol by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises 10% of glycerol by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises less than 15% of isopropyl myristate by weight of the composition as described herein. In some embodiments, the composition comprises more than 1% but not more than 15% of isopropyl myristate by weight of the composition as described herein. In some embodiments, the composition comprises 10% of isopropyl myristate by weight of the composition as described herein. In some embodiments, the composition (e.g., the improved composition) comprises more than 1% but not more than 15% of propylene glycol by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises 10% of propylene glycol by weight of the composition.

[0011] In some embodiments, the composition (e.g., the improved composition) comprises more than 1% but not more than 3% of steareth 20 by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises 2% of steareth 20 by weight of the composition.

[0012] In some embodiments, the composition (e.g., the improved composition) comprises more than 1% but not more than 6% of Tween 80 by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises 3.5% of Tween 80 by weight of the composition.

[0013] In some embodiments, the composition (e.g., the improved composition) comprises propylparaben in an amount greater than 0.05% but not more than 0.15% by weight of the composition. In some embodiments, the composition (e.g., the improved composition) comprises propylparaben in an amount of 0.10% by weight of the composition.

[0014] In some embodiments, the composition (e.g., the improved composition) comprises more than 0.05% but not more than 0.15% by weight of the composition of butylated hydroxytoluene. In some embodiments, the composition (e.g., the improved composition) comprises 0.10% by weight of the composition of butylated hydroxytoluene.

[0015] In some embodiments, the composition (e.g., the improved composition) comprises water in an amount greater than 15% but not more than 70% by weight of the composition as described herein. In some embodiments, the composition comprises water in an amount not exceeding 54% by weight of the composition as described herein.

[0016] In some embodiments, the composition (e.g., the improved composition) comprises xanthan gum. In some embodiments, the composition comprises more than 0.1% but not more than 0.3% xanthan gum by weight of the composition as described herein. In some embodiments, the composition comprises 0.2% xanthan gum by weight of the composition as described herein.

[0017] In some embodiments, the composition (e.g., the improved composition) comprises methylparaben in an amount greater than 0.1% but not more than 0.3% by weight of the composition as described herein. In some embodiments, the composition comprises methylparaben in an amount of 0.2% by weight of the composition as described herein.

[0018] In some embodiments, the composition (e.g., the improved composition) comprises disodium edetate. In some embodiments, the composition comprises more than 0.01% but not more than 0.1% of disodium edetate by weight of the composition as described herein. In some embodiments, the composition comprises 0.05% of disodium edetate by weight of the composition as described herein.

[0019] In some embodiments, the PAI-1 inhibitor is selected from the group consisting of peptides, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, fragments of therapeutic antibodies, and / or combinations thereof. In some embodiments, the PAI-1 inhibitor is a 2-aminobenzoic acid analog. In some embodiments, the PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.

[0020] In some implementations, the PAI-1 inhibitor is a compound of formula (1). Equation (1) In some embodiments, R1 and R2 may be the same or different. In some embodiments, each of R1 and R2 represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocycloalkyl, heterocycloalkoxy, aryl group optionally having one or two substituents, 5- to 6-membered cycloheteroaryl group optionally having one or two substituents, or benzofused heteroaryl, amino, or carbamoyl group optionally having one or two substituents, each of which is optionally substituted with one or two substituents, or cyano, carboxyl, or alkoxycarbonyl. In some embodiments, R1 and R2 are optionally linked to each other to form a ring. In some embodiments, R3 is hydrogen, alkyl, cycloalkyl, or aryl group optionally having one or two substituents. In some embodiments, X is -C(R5)=C(R6)-, -C(R7)N-, or -N=C(R8)-. In some embodiments, R5, R6, R7, and R8 each represent hydrogen, halogen, alkyl optionally having one or two substituents, or alkoxy. In some embodiments, L is alkylene (some carbon atoms in the alkylene optionally form a cycloalkyl ring), alkenyl, ynylene, cycloalkylene, alkyloxyalkylene, alkylthioalkylene, alkylene-SO-alkylene, or alkylene-SO2-alkylene, each optionally substituted with one or two substituents, or alkylene-N(R9)-alkylene optionally substituted with one or two substituents. In some embodiments, R9 represents hydrogen or alkyl optionally having one or two substituents. In some embodiments, p represents an integer of 0 or 1. In some embodiments, A is a group represented by any of the following formulas (2), (3), or (4): Equation (2) In some implementation schemes, R 10 and R 11 Same or different. In some implementations, R 10 and R 11 Each of these represents hydrogen or a straight-chain or branched alkyl group. In some embodiments, m represents an integer from 0 to 10.

[0021] Equation (3) In some implementation schemes, R 12 and R 13 Same or different. In some implementations, R 12 and R 13Each of these represents hydrogen, a halogen, or an alkyl group optionally having one or two substituents, a cycloalkyl group optionally having one or two substituents, or an alkoxy group optionally having one or two substituents. In some embodiments, Y represents CH or nitrogen. In some embodiments, Z represents CH2, oxygen, or N-alkyl. In some embodiments, n represents an integer from 0 to 3. In some embodiments, U represents an alkylene group. In some embodiments, t represents an integer of 0 or 1. Equation (4) In some implementation schemes, R 14 and R 15 Same or different. In some implementations, R 14 and R 15 Each of these represents hydrogen, a halogen, or an alkyl group optionally having one or two substituents, a cycloalkyl group optionally having one or two substituents, or an alkoxy group optionally having one or two substituents. In some embodiments, V is an alkylene group, an alkyleneoxyalkylene group, an oxyalkylene group, an alkyleneoxy group, or an oxygen group. In some embodiments, q represents an integer of 0 or 1. In some embodiments, U and t are as defined above. In some embodiments, Ar represents an aryl group having one or two substituents (one or two substituents optionally forming a ring with a portion of the carbon atoms in the aryl group), a 5- to 6-membered cycloaryl group having one or two identical or different heteroatoms optionally having one or two substituents, or a benzofused heteroaryl group optionally having one to three substituents. In some embodiments, B represents COOR. 16 In some implementations, R 16 To indicate hydrogen, alkyl, aryl, or aralkyl, it is formed by CH(R) 17 )O----COR 18 Or ----CH(R) 17 )---O---CO---OR 18 The group represented, where R 17 It is hydrogen or alkyl, and R 18 It is an alkyl or cycloalkyl group, represented by the (5-alkyl-2-oxo-1,3-dioxapentane-4-yl)methyl group of the following formula (5): Equation (5) In some embodiments, R' represents an alkyl group. In some embodiments, R' represents an alkyl or heterocyclic group: a 1H-tetrazole-5-yl group, a 4,5-dihydro-5-oxo-4H-1,2,4-oxadiazole-3-yl group, a 4,5-dihydro-5-thio-4H-1,2,4-oxadiazole-3-yl group, or a 4,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl group represented by formulas (6), (7), (8) (from left to right) and / or (9) (bottom). Equations (6), (7), (8) (from left to right) and (9) (bottom) In some implementations, the PAI-1 inhibitor is a compound of formula (10). Equation (10) In some embodiments, R1 and R2 may be the same or different. In some embodiments, each of R1 and R2 represents hydrogen, halogen, alkyl, or optionally an aryl group having one or two substituents. In some embodiments, R3 is hydrogen or alkyl. In some embodiments, R... 14 and R 15 Same or different. In some implementations, R 14 and R 15 Each of these represents hydrogen, alkyl, or halogen. In some embodiments, V is an alkylene, oxyalkylene, or oxygen. In some embodiments, Ar is an aryl group optionally having one or two substituents, an aryl group optionally having one or two substituents having one or two identical or different heteroatoms, or a benzo-fused heteroaryl group optionally having one or three substituents. In some embodiments, L is an alkylene, alkyloxyalkylene, alkylthioalkylene, alkylene-SO-alkylene, or alkylene-SO2-alkylene. In some embodiments, the PAI-1 inhibitor is selected from the group consisting of: 5-chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, benzopyran compounds, butadiene, spironolactone, imidapril, angiotensin-converting enzyme inhibitors (ACEIs, captopril, or enalapril), angiotensin II receptor antagonists (AIIRA), defibrinogen polynucleotides (polydeoxyribonucleotides), and any combination thereof. In some embodiments, the PAI-1 inhibitor is 5-chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

[0022] In some implementations, the PAI-1 inhibitor is delivered in an amount sufficient to reduce the graying of one or more hairs.

[0023] In some implementations, PAI-1 inhibitors are delivered in amounts sufficient to treat dermatological conditions.

[0024] In some implementations, the PAI-1 inhibitor is delivered in an amount sufficient to treat non-dermatological conditions. In some implementations, non-dermatological conditions include pulmonary fibrosis, lung cancer, chronic myeloid leukemia, metabolic syndrome, diabetes, thrombosis, obesity, renal fibrosis, liver fibrosis, cardiac fibrosis, or atherosclerosis.

[0025] In some embodiments, the composition (e.g., the improved composition) is characterized in that, when applied to an animal containing one or more gray-white hairs, it achieves at least one of the following: (i) reducing the number of gray-white hairs; (ii) restoring the color of one or more gray-white hairs; (iii) preventing one or more non-gray-white hairs from turning gray; and (iv) delaying the onset of graying of one or more non-gray-white hairs. In some embodiments, the composition is characterized in that, when applied to an animal containing one or more hairs, it achieves at least one of the following: (i) reducing hair loss; (ii) preventing hair loss; (iii) delaying the onset of hair loss of one or more hairs; and (iv) increasing the number of hairs on the affected area.

[0026] In some implementation methods, this article provides, in particular, methods for treating or preventing hair from turning gray.

[0027] In some implementation methods, this article provides, in particular, methods for treating or preventing hair loss.

[0028] In some implementation methods, this article provides, in particular, methods for treating or preventing dermatological conditions.

[0029] In some embodiments, the methods described herein include (i) providing the composition described herein (e.g., an improved composition) and (ii) applying the composition to a site of a subject. In some embodiments, the site contains or actually contains a plurality of hair follicles, each follicle having a hair disposed therein, such that the PAI-1 inhibitor is delivered to the subject. In some embodiments, the hair is gray-white. In some embodiments, the hair is not gray-white.

[0030] In some embodiments, the provided composition (e.g., an improved composition) is applied in combination with site-specific microneedle skin conditioning (MSC). In some embodiments, site-specific MSC is performed prior to the application of the composition described herein. In some embodiments, site-specific MSC is performed after the application of the composition described herein. In some embodiments, site-specific MSC and the application of the composition described herein occur substantially simultaneously. In some embodiments, the application also includes administering multiple doses of the composition described herein according to a dosing regimen, wherein at least two consecutive doses are spaced at least 12 hours apart from each other.

[0031] In some embodiments, the dermatological condition is keloid or scleroderma. In some embodiments, the methods described herein also include the application of one or more other active agents selected from the group comprising: pressure therapy, silicone gel sheeting, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high-dose oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy, surgical excision, topical agents, and combinations thereof.

[0032] In some embodiments, the dermatological condition is scleroderma. In some embodiments, the dermatological condition is systemic scleroderma. In some embodiments, the dermatological condition is cutaneous scleroderma. In some embodiments, the method described herein further includes the administration of one or more other active agents selected from the group comprising: 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.

[0033] In some embodiments, the dermatological condition is Raynaud's phenomenon. In some embodiments, the method described herein also includes the administration of one or more other active agents selected from the group consisting of: calcium channel blockers, alpha-blockers, nitroglycerin, angiotensin II receptor antagonists, selective serotonin reuptake inhibitors, trinitroglycerin, tadalafil, ginkgo biloba (…).Ginkgo biloba Extracts, SLx-2101, St. John's Wort, fasudil, cilostazol, iloprost, relaxin, treprostacyclin diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostacyclin diethanolamine, and combinations thereof.

[0034] In some embodiments, the dermatological condition is or includes graying of hair. In some embodiments, the method described herein also includes the application of one or more other active agents selected from the group consisting of: cinnamamidopropyltrimethylammonium chloride, solid lipid nanoparticles, L-cysteine, L-methionine, melatonin, and combinations thereof.

[0035] In some embodiments, the application of the method described herein includes maintaining the composition (e.g., an improved composition) on a skin surface for a certain period of time. In some embodiments, the method described herein further includes removing any remaining composition from the site after the specified period of time. In some embodiments, the step of applying the composition includes massaging the composition into the site. In some embodiments, the specified period of time is at least 1 minute. In some embodiments, the specified period of time is at least 1 hour. In some embodiments, the specified period of time ranges from 1 minute to 10 minutes.

[0036] In some embodiments, the composition (e.g., the improved composition) is or comprises a suspension. In some embodiments, the composition is or comprises a foaming agent. In some embodiments, the composition comprises an emulsion. In some embodiments, the emulsion is a nanoemulsion.

[0037] In some embodiments, the method described herein further includes the step of applying an infiltration treatment. In some embodiments, the infiltration treatment is or includes a non-irritating chemical agent. In some embodiments, the infiltration treatment is or includes the application of an electric or magnetic field. In some embodiments, the infiltration treatment is or includes microneedles. In some embodiments, the infiltration treatment is or includes laser treatment.

[0038] In some embodiments, the PAI-1 inhibitor is administered at the internal osmosis site at approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes. In some embodiments, the PAI-1 inhibitor is administered at the internal osmosis site at approximately 5 minutes to approximately 60 minutes, approximately 5 minutes to approximately 12 minutes, approximately 5 minutes to approximately 15 minutes, or approximately 15 minutes to approximately 30 minutes. In some embodiments, the PAI-1 inhibitor is administered at the internal osmosis site at approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or 24 hours. In some embodiments, the PAI-1 inhibitor is administered at the internal osmosis site at approximately 1 hour to approximately 12 hours, approximately 8 hours to approximately 12 hours, or 12 hours to approximately 24 hours.

[0039] In some embodiments, the methods described herein include administering the composition (e.g., an improved composition) more than once over time. In some embodiments, the interval between each administration of the PAI-1 inhibitor is specified as a time period.

[0040] In some embodiments, this disclosure provides, in particular, compositions (e.g., improved compositions) for treating dermatological conditions.

[0041] In some embodiments, this disclosure provides, in particular, compositions (e.g., improved compositions) for treating or preventing graying of hair.

[0042] In some embodiments, this disclosure particularly provides compositions (e.g., improved compositions) for treating or preventing hair loss. In some embodiments, hair loss is androgenetic alopecia, alopecia areata, frontal fibrosis, and age-related hair loss.

[0043] In some embodiments, the provided composition (e.g., the improved composition) is used in the manufacture of a medicament for treating graying hair.

[0044] In some embodiments, the provided composition (e.g., an improved composition) is used in the manufacture of a medicament for treating hair loss.

[0045] In some embodiments, the provided composition (e.g., an improved composition) is used in the manufacture of a medicament for treating dermatological conditions. In some embodiments, the dermatological condition is selected from scleroderma, keloids, Raynaud's phenomenon, or graying of hair.

[0046] In some embodiments, this disclosure provides, in particular, a kit comprising the composition described herein (e.g., an improved composition) and instructions for applying the composition to the site. In some embodiments, the kit also includes gloves. In some embodiments, the provided kit also includes a patch for covering the composition after application to the site.

[0047] In some embodiments, the provided kit also includes a device for facilitating the penetration of the composition (e.g., an improved composition) into the site of the subject, and instructions for applying the composition to the site. In some embodiments, the device includes multiple needles. In some embodiments, the device is a patch, roller, impression, or pen.

[0048] In some embodiments, the provided composition (e.g., the improved composition) is formulated as a lotion, serum, suspension, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

[0049] These and other aspects covered by this disclosure are described in more detail below and in the claims.

[0050] definition In this application, unless the context otherwise clearly indicates, (i) the term “a / an” may be understood to mean “at least one / at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and “including” may be understood to cover the listed components or steps, whether they are presented on their own or together with one or more other components or steps; (iv) as will be understood by one of ordinary skill in the art, the terms “about” and “approximately” may be understood to allow for standard variations; and (v) where a scope is provided, endpoints are included.

[0051] about: The term "about" as used herein when referring to a value means a value similar to the value mentioned. Generally, those skilled in the art will understand the degree of difference covered by "about" in that context. For example, in some embodiments, the term "about" may cover a range of values ​​up to 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lower of the mentioned value.

[0052] Application:As used herein, the term "administration" generally refers to administering a composition to a subject or system to achieve the delivery of a pharmaceutical agent, which is in or contained in the composition. Those skilled in the art will recognize the many routes of administration that may be used to administer to a subject (e.g., a person) where appropriate. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., via bronchial infusion), buccal, dermal (which may be or include one or more of, for example, local dermal, intradermal, interdermal, transdermal, etc.), intraenteral, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrasheath, intravenous, intravenous, intracardiac, intra-organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., via intratracheal infusion), vaginal, vitreous, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administering a fixed number of doses. In some embodiments, administration may involve intermittent (e.g., multiple doses spaced apart in time) and / or periodic (e.g., individual doses spaced apart by the same time intervals) administration. In some embodiments, administration may involve continuous administration (e.g., infusion) for at least a selected period of time.

[0053] Agent Generally, as used herein, the term "agent" can be used to refer to any chemical class of compound or entity, including, for example, polypeptides, nucleic acids, sugars, lipids, small molecules, metals, or combinations or complexes thereof. Where appropriate, as will be clear from the context to a person skilled in the art, the term can be used to refer to an entity that is or comprises a cell or organism or its fractions, extracts, or components. Alternatively or additionally, as will be clear from the context, the term can be used to refer to a natural product found in and / or obtained from nature. In some cases, also as will be clear from the context, the term can be used to refer to one or more man-made entities because it is designed, engineered, and / or produced by human hand and / or is not found in nature. In some embodiments, the agent can be utilized in isolated or pure form; in some embodiments, the agent can be utilized in crude form. In some embodiments, potential agents can be provided as collections or libraries, for example, collections or libraries that can be screened to identify or characterize active agents therein. In some cases, the term "agent" can refer to a compound or entity that is or comprises a polymer; in some cases, the term can refer to a compound or entity comprising one or more polymeric moieties. In some embodiments, the term "agent" may refer to a compound or entity that is not a polymer and / or substantially free of any polymer and / or substantially free of one or more specific polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or substantially free of any polymeric moieties.

[0054] agonists Those skilled in the art will understand that the term "agonist" can be used to refer to a pharmaceutical condition or event in which the presence, level, extent, type, or form of an agent is associated with an increase in the level or activity of another agent (i.e., the agonized agent). Generally, an agonist can be or includes agents of any chemical class, including, for example, small molecules, peptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity exhibiting the associated activating activity. In some embodiments, an agonist can be direct (in which case it directly affects its target); in some embodiments, an agonist can be indirect (in which case it exerts its effect through means other than binding to its target; for example, by interacting with a modulator of the target, causing a change in the level or activity of the target).

[0055] Antagonists: Those skilled in the art will understand that the term "antagonist," as used herein, can be used to refer to a pharmaceutical condition or event in which the presence, level, extent, type, or form of an agent is associated with a reduction in the level or activity of another agent (i.e., the inhibited agent or target). Generally, antagonists can be or include agents of any chemical class, including, for example, small molecules, peptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity exhibiting associated inhibitory activity. In some embodiments, the antagonist can be direct (in which case it directly exerts its effect on its target); in some embodiments, the antagonist can be indirect (in which case it exerts its effect by means other than binding to its target; for example, by interacting with a modulator of the target, thereby altering the level or activity of the target).

[0056] animal: As used herein, it refers to any member of the animal kingdom. In some implementations, " animal "" refers to a person of any sex and at any developmental stage. In some implementations, " animal "Animal" refers to a non-human animal at any developmental stage. In some embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and / or pigs). In some embodiments, the animal includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0057] Bioactive agents As used herein, the phrase "bioactive agent" refers to any substance that is active in a biological system and / or organism. For example, a substance that has a biological effect on an organism when applied to that organism is considered bioactive. In some embodiments, substances (e.g., peptides, nucleic acids, antibodies) are considered bioactive. wait In the case of biological activity, a portion of a substance that shares at least one biological activity with the whole substance is generally referred to as the "biologically active portion".

[0058] Carrier: As used herein, "carrier" refers to a diluent, adjuvant, excipient, and / or medium applied together with the composition. In some exemplary embodiments, the carrier may include sterile liquids, such as, for example, water and oils, including petroleum, animal, plant, or synthetic oils, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid components.

[0059] Cosmetic ingredients: The term "cosmetic formulation" is used herein to refer to a topically applied composition containing one or more agents with cosmetic properties. To name just a few examples, cosmetic formulations can be skin softeners, nourishing lotions, cleansing lotions, cleansing creams, skin lotions, moisturizing lotions, massage creams, moisturizing creams, cosmetic bases, lipsticks, face masks or facial gels, cleansing formulations (such as shampoos, rinses, body cleansers, hair growth products, or soaps) and / or dermatological compositions (such as lotions, ointments, gels, creams, patches, emollients, balms, pastes, deodorants, antiperspirants, and / or sprays).

[0060] Composition: Those skilled in the art will understand that, as used herein, the term "composition" may be used to refer to a discrete physical entity comprising one or more specified components. Generally, unless otherwise stated, a composition can be in any form—e.g., gas, gel, liquid, solid, etc.

[0061] Include:The description of a composition or method herein as “comprising” one or more specified elements or steps is open-ended, meaning that the specified elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid verbosity, it should also be understood that any composition or method described as “comprising” (or “comprises”) one or more specified elements or steps also describes a corresponding, more limited composition or method that “consisting essentially of” (or “consists essentially of”), meaning that the composition or method includes the specified essential elements or steps and may also include additional elements or steps that do not materially affect the essential and novel characteristics of the composition or method. It should also be understood that any composition or method herein described as “comprising” one or more specified elements or steps or “essentially constitutes” also describes a corresponding, more limited, and closed composition or method that “consisting of” (or “consists of”) to exclude any other unspecified elements or steps. In any composition or method disclosed herein, any known or disclosed equivalent of a specified essential element or step may be substituted for that element or step.

[0062] Cream: The term "cream" refers to a topical composition typically formulated for application to the skin. Creams generally contain an oil- and / or fatty acid-based matrix. Creams formulated according to this disclosure may contain nanoparticles and may be able to penetrate substantially completely (e.g., such nanoparticles) through the skin upon topical application. Such creams may also serve as carriers for incorporated materials (e.g., bioactive agents for one or more known therapeutic agents and / or independent activities).

[0063] 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 bioactive agents) are dispersed. Generally, dispersions are formed when at least two immiscible materials are combined. An "oil-in-water" dispersion is one in which oily particles are dispersed in an aqueous dispersion medium. An "oil-in-water" dispersion is one in which aqueous particles are dispersed in an oily dispersion medium. Those skilled in the art will understand that dispersions can be formed from any two immiscible media and are not strictly limited to combinations of aqueous and oily media. Therefore, the term "dispersion medium" is broadly applicable. any Dispersion media, although usually referring to the "water-based" and "oil-based" categories.

[0064] Dosage form or Unit dosage form: Those skilled in the art will understand 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) intended for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen determined to be relevant to the desired or beneficial outcome when administered to the relevant population (i.e., in relation to a therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0065] Dosage regimen: Those skilled in the art will understand that the term "dosing regimen" can be used to refer to a collection (usually more than one) of individual unit doses administered to a subject, typically spaced apart by time intervals. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each time separate from the other doses. In some embodiments, the individual doses are spaced apart by the same length of time interval; in some embodiments, the dosing regimen includes multiple doses, and the individual doses are spaced apart by at least two different time intervals. In some embodiments, all doses within the dosing regimen have the same unit dose amount. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, the dosing regimen includes a first administration of a first dose amount, followed by one or more additional doses of a second dose amount identical to the first dose amount. In some embodiments, when administered across relevant populations, the dosing regimen is associated with a desired or beneficial outcome (i.e., it is a therapeutic dosing regimen).

[0066] excipient: As used herein, "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. In some embodiments, suitable pharmaceutical excipients may include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc.

[0067] in vitro As used herein, the term “in vitro” refers to events that occur in an artificial environment (e.g., in a test tube or reaction vessel, in a cell culture, etc.) rather than in a multicellular organism.

[0068] in vivo As used herein, "intracellular" refers to events occurring in multicellular organisms such as humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events occurring within living cells (as opposed to, for example, in vitro systems).

[0069] Crude emulsion: As used herein, the term "crude emulsion" refers to an emulsion in which at least some droplets have diameters ranging from several hundred nanometers to micrometers. As will be understood by those skilled in the art, a crude emulsion is characterized by droplets with diameters greater than 300 nm. In some embodiments, the crude emulsion composition utilized according to this disclosure comprises one or more macro-agents or one or more bioactive agents. In some embodiments, the macro-agent included in the crude emulsion composition may be a bioactive agent. Those skilled in the art will understand that the crude emulsion compositions used according to this disclosure can be prepared by any available means, including, for example, chemical or mechanical means. In some embodiments, the droplets in the crude emulsion have a size ranging from about 301 nm to about 1000 μm. In some embodiments, the crude emulsion has droplets with a size distribution between about 301 nm and about 1000 μm. In some embodiments, the droplets in the crude emulsion have a size ranging from about 500 nm to about 5000 μm. In some embodiments, the crude emulsion has droplets with a size distribution between about 500 nm and about 5000 μm.

[0070] Nanoemulsion: As used herein, the term "nanoemulsion" refers to an emulsion in which at least some droplets have diameters in the nanoscale range. As will be understood by those skilled in the art, a nanoemulsion is characterized by droplets with a diameter of 300 nm or less. In some embodiments, the nanoemulsion composition utilized according to this disclosure comprises one or more macroreagents or one or more bioactive agents. In some embodiments, the macroreagent contained in the nanoemulsion composition may be a bioactive agent. Those skilled in the art will understand that the nanoemulsion compositions used according to this disclosure can be prepared by any available means, including, for example, chemical or mechanical means. In some embodiments, the droplets in the nanoemulsion have a size in the range of about 1 nm to about 300 nm. In some embodiments, the nanoemulsion has droplets with a size distribution between about 1 nm and about 300 nm.

[0071] Nanoparticles: As used herein, the term "nanoparticle" refers to solid particles with a diameter of less than 300 nm, as defined by the National Science Foundation. In some embodiments, nanoparticles have a diameter of less than 100 nm, as defined by the National Institutes of Health.

[0072] Nanoparticle composition: As used herein, the term "nanoparticle composition" refers to any substance containing at least one nanoparticle. In some embodiments, the nanoparticle composition is a homogeneous aggregate of nanoparticles. In some embodiments, the nanoparticle composition is a dispersion or emulsion. Typically, dispersions or emulsions are formed when at least two immiscible materials are combined. A "water-in-oil" dispersion is a dispersion in which oily particles (or hydrophobic or nonpolar) are dispersed in an aqueous dispersion medium. A "water-in-oil" dispersion is a dispersion in which aqueous (or hydrophilic or polar) particles are dispersed in an oily dispersion medium. Those skilled in the art will understand that dispersions can be formed from any two immiscible media and are not strictly limited to combinations of aqueous and oily media. Therefore, the term "dispersion medium" is broadly applicable to any dispersion medium, although it generally refers to the "aqueous" and "oily" categories. In some embodiments, the nanoparticle composition is a nanoemulsion. In some embodiments, the nanoparticle composition comprises micelles. In some embodiments, the nanoparticle composition is stable. In some embodiments, the nanoparticle composition comprises one or more bioactive agents to be bound and delivered with the nanoparticles. In some embodiments, the nanoparticle composition is an empty nanoparticle composition (e.g., they do not contain any known therapeutic agents and / or independently active bioactive agents).

[0073] Pharmaceutical Composition As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present at a unit dose suitable for administration in a treatment regimen that, when administered to the relevant population, shows a statistically significant probability of achieving the intended therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in a solid or liquid form, including solid or liquid forms suitable for: oral administration, such as drenching (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets targeted for absorption via the buccal, sublingual, and systemic routes), pills, powders, granules, or pastes for application to the tongue; parenteral administration, such as subcutaneous, intramuscular, intravenous, or epidural injection in the form of, for example, sterile solutions or suspensions or sustained-release formulations; local administration, such as in the form of creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as in the form of pessaries, creams, or foams; sublingual; ocular; transdermal; or via the nose, lungs, and other mucosal surfaces.

[0074] Penetration enhancer or Osmotic therapy:As used herein, the term "penetration enhancer" or "penetration therapy" refers to an agent whose presence or level is associated with an increase in the penetration of the agent of interest through the skin compared to its observed absence. In some embodiments, the penetration enhancer is characterized by its degradation and / or disruption of skin structure. In some embodiments, the penetration enhancer is or comprises a chemical agent (e.g., a chemical or an enzyme). For example, a chemical agent that may damage, disrupt, and / or degrade one or more components of the stratum corneum may include, for example, alcohols, such as short-chain alcohols, long-chain alcohols, or polyols; amines and amides, such as ureas, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, pyrrolidone, or derivatives of pyrrolidone; terpenes and terpene derivatives; fatty acids and their esters; macrocyclic compounds; surfactants (tensides); or sulfoxides (e.g., dimethyl sulfoxide (DMSO), decylmethyl sulfoxide, etc.); surfactants, such as anionic, cationic, and nonionic surfactants; polyols; essential oils; and / or hyaluronidase. In some embodiments, the penetration enhancer may be an irritant because an inflammatory and / or allergic reaction occurs when the agent is applied to the skin. In some embodiments, the penetration enhancer is not an irritant. In some embodiments, the penetration enhancer may be or comprise a chemical agent that does not damage, disrupt, or degrade skin structure, but whose presence or level is still associated with increased penetration of the agent of interest across the skin compared to its absence. In some embodiments, conopeptides, carrier molecules, and carrier peptides may be penetration enhancers that do not damage, disrupt, and / or degrade skin structure. In some embodiments, conopeptides, carrier molecules, and carrier peptides may be penetration enhancers that do not irritate the skin. The term "penetration enhancer" does not cover mechanical devices (e.g., needles, scalpels, etc.) or their equivalents (e.g., other destructive treatments). Furthermore, those skilled in the art will understand that structures such as nanoparticles or emulsions are not chemical agents and therefore not chemical penetration enhancers, even if their presence is associated with increased skin penetration of the agent of interest that may be associated with that structure.

[0075] Pharmaceutically acceptable carriers:As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, or solvent encapsulation material, used to carry or transport the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and will not cause harm to the patient. Some examples of materials that can be used 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients, such as 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 glycerol, 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; ethanol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0076] Prevention / prevention) As used herein, when used in conjunction with the occurrence of a disease, condition, and / or illness, it refers to reducing the risk of developing a disease, condition, and / or illness, and / or delaying the onset of one or more features or symptoms of a disease, condition, or illness. Prevention is considered complete when the onset of a disease, condition, or illness has been delayed for a predetermined period of time.

[0077] Self-application: As used herein, the term "self-application" refers to a situation where a subject is able to apply the composition to himself or her without medical supervision. In some embodiments of the invention, self-application can be performed outside of a clinical setting. To cite just one example, in some embodiments of the invention, a subject can apply a facial beauty cream at home.

[0078] Serum: Those skilled in the art will understand that, as used herein, the term "serum" can refer to a liquid composition. In some embodiments, a serum may contain a concentrated amount of an active agent. In some embodiments, a serum may be used for topical delivery of an active agent. In some embodiments, a serum may refer to a spreadable composition.

[0079] Small molecules:As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Typically, a "small molecule" is a molecule smaller than about 5 kilodaltons (kD). In some embodiments, a small molecule is smaller than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, a small molecule is smaller than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is smaller 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 contain a polymeric moiety. In some embodiments, a small molecule is not and / or does not contain a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not contain a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the small molecule is not and / or does not contain polysaccharides; for example, in some embodiments, the small molecule is not a glycoprotein, proteoglycan, or glycolipid. wait In some embodiments, the small molecule is not a lipid. In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., containing at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent. Those skilled in the art will understand upon reading this disclosure that certain small molecule compounds described herein can 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, isomer forms (e.g., optical and / or structural isomers), or isotopic forms. Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules can be utilized according to this disclosure in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers; in some embodiments, such small molecules can be utilized in the form of racemic mixtures other than those disclosed. Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules can be utilized according to this disclosure in the form of individual tautomers or in a form that interconverts between tautomeric forms. Those skilled in the art will understand that some small molecule compounds have structures that allow isotopic substitution (e.g., 2 H or 3 H replaces H; 11 C 13 C or 14 C replaces 12C;13 N or 15 N replaces 14N; 17 O or 18 O replaces 16O; 36 Cl replaces XXC; 18 F replaces XXF; 131I replaces XXXI; etc.). In some embodiments, such small molecules may be utilized according to this disclosure in one or more isotopically modified forms or mixtures thereof. In some embodiments, reference to a particular small molecule compound may refer to a specific form of the compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in salt form (e.g., acid addition salt 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, when the small molecule compound is a compound that is present or found in nature, the compound may be provided and / or utilized according to this disclosure in a form different from that which is present or found in nature. Those skilled in the art will appreciate that in some embodiments, a formulation of a particular small molecule compound, when containing an absolute or relative amount of the compound or a particular form thereof that differs from the absolute or relative amount (relative to another component of the formulation, including, for example, another form of the compound) present in a reference formulation or source, is distinctly different from the compound present in the reference formulation or source. Therefore, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered a compound in a form different from a racemic mixture of the compound; a specific salt of a small molecule compound may be considered a form different from another salt form of the compound; a preparation containing only one conformational isomer ((Z) or (E)) containing a double bond may be considered a compound in a form different from another conformational isomer ((E) or (Z)) containing a double bond; a preparation in which one or more atoms are isotopes different from the isotopes present in a reference preparation may be considered a different form; etc.

[0080] Subjects:As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including prenatal human forms in some embodiments). In some embodiments, the subject suffers from a relevant disease, condition, or illness. In some embodiments, the subject is susceptible to a disease, condition, or illness. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, condition, or illness. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, condition, or illness. In some embodiments, the subject is a person who has one or more characteristics characteristic of being susceptible to a disease, condition, or illness or at risk of a disease, condition, or illness. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is receiving and / or has received diagnostic and / or therapeutic treatments.

[0081] Suspension: Those skilled in the art will understand that the term "suspension" as used herein can refer to a heterogeneous mixture. In some embodiments, a suspension may comprise particles suspended in a liquid. In some embodiments, a suspension may be used to deliver an active agent. In some embodiments, a suspension may be used for topical delivery of an active agent. In some embodiments, a suspension may refer to an applicable composition.

[0082] Symptom relief: As used in this article, the term "symptom relief" refers to the reduction in the magnitude (e.g., intensity, severity) of one or more symptoms of a particular disease, symptom, or condition. wait () and / or when the frequency decreases. For clarity, a delay in the onset of a particular symptom is considered a form of reduced frequency of that symptom.

[0083] Therapeutic agents As used herein, the term "therapeutic agent" means any agent that, when administered to a subject, has a therapeutic effect and / or induces the desired biological and / or pharmacological action. In some embodiments, the therapeutic agent is an active agent as described herein.

[0084] Effective therapeutic dose: As used herein, "therapeutic amount" means the amount that produces the desired effect of administration. In some embodiments, the term refers to an amount sufficient to treat a disease, condition, and / or illness when administered to a population suffering from or susceptible to such a disease, condition, and / or illness according to a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity and / or delays the onset of one or more symptoms of a disease, condition, and / or illness. Those skilled in the art will understand that the term "therapeutic amount" Therapeutic effective dose"In practice, successful treatment in a particular individual is not required. Rather, a therapeutically effective amount can be the amount that provides a specific, desired pharmacological response in a significant number of subjects when administered to a patient requiring such treatment. In some embodiments, reference to a therapeutically effective amount can refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, symptom, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will understand that in some embodiments, a specific agent or therapy of a therapeutically effective amount 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 (e.g., as part of a dosing regimen)."

[0085] treat As used herein, the term "treatment" (also "treat" or "treating") refers to any application of a therapy that partially or completely reduces, 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, condition, and / or illness. In some embodiments, such treatment may be directed to subjects who do not exhibit signs of the relevant disease, condition, and / or illness and / or to subjects who exhibit only early signs of the disease, condition, and / or illness. Alternatively or additionally, such treatment may be directed to subjects exhibiting one or more identified signs of the relevant disease, condition, and / or illness. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, condition, and / or illness. In some embodiments, treatment may be directed to subjects known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, condition, and / or illness. Attached Figure Description

[0086] Figure 1 The bar graph depicts the amount of skin penetration measured by cumulative amount (µg / mL) of the original composition and the improved composition containing and / or delivering plasminogen activator inhibitor-1 (PAI-1) inhibitor. Detailed Implementation

[0087] This disclosure particularly provides compositions, methods, and kits for formulating active agents for topical application. In some embodiments, the active agent is a PAI-1 inhibitor as described herein.

[0088] In some embodiments, the provided compositions, methods, and kits may be or comprise emulsions. In some embodiments, the provided methods, kits, and compositions may be or comprise crude emulsions. In some embodiments, the provided methods and kits may be or comprise nanoemulsions. In some embodiments, the provided compositions, methods, and kits comprise combination therapies or treatments, wherein, for example, in some embodiments, the provided compositions may be administered in combination with one or more additional treatments. In some embodiments, one or more additional treatments are or comprise other active agents and / or modes of treatment (e.g., one or more PAI inhibitors or other agents), such as known therapeutic agents and / or independently active bioactive agents.

[0089] Surfactant As described herein, this disclosure particularly provides compositions comprising an active agent. As described herein, this disclosure particularly provides compositions for delivering an active agent. In some embodiments, compositions comprising or delivering an active agent as described herein can be used to treat diseases, symptoms, and / or conditions. In some embodiments, the active agent is a PAI-1 inhibitor.

[0090] PAI-1 inhibitors PAI-1 inhibitors can be used to treat or prevent medical conditions or diseases associated with PAI-1 overexpression. In some embodiments, this disclosure covers the understanding that PAI-1 inhibitors may be particularly suitable for the treatment and / or prevention of dermatological conditions such as hair loss, graying hair, scleroderma, keloids, Raynaud's phenomenon, etc. While there are some partially effective preventative or therapeutic treatments for hair loss, there are no highly effective preventative or therapeutic treatments for hair loss, and currently there are no effective preventative or therapeutic techniques for graying hair. In some embodiments, the methods and / or compositions provided provide targeted therapies. For example, in some embodiments, the methods and compositions provided provide surprisingly effective therapies comprising one or more PAI-1 inhibitors. Without wishing to be bound by any particular theory, it is proposed that in some embodiments, administration of a PAI-1 inhibitor as described herein can stimulate hair follicle stem cells (HFSCs) and melanocyte stem cells (MSCs), and such stimulation may contribute to the treatment or prevention of hair loss and graying hair.

[0091] 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 (ACEIs, captopril, or enalapril), angiotensin II receptor antagonists (AIIRA), defibrin polynucleotides (polydeoxyribonucleotides), and any combination thereof. In some embodiments, the PAI-1 inhibitor is a benzopyran compound.

[0092] In some embodiments, the PAI-1 inhibitor is selected from the group consisting of: peptides, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, fragments of therapeutic antibodies, and combinations thereof. In some embodiments, the PAI-1 inhibitor may be a small molecule.

[0093] In some embodiments, the composition comprises or delivers a compound or its active metabolite as described herein.

[0094] In some implementations, the PAI-1 inhibitor is a 2-aminobenzoic acid analog.

[0095] In some implementations, the PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.

[0096] In some implementations, the PAI-1 inhibitor is a compound of formula (1): Equation (1) Wherein, R1 and R2 may be the same or different, and each represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocycloalkyl, heterocycloalkoxy, aryl group optionally having one or two substituents, 5- to 6-membered cycloheteroaryl group optionally having one or two substituents, or benzofused heteroaryl, amino, or carbamoyl group optionally having one or two substituents, each of which is optionally substituted by one or two substituents, or cyano, carboxyl, or alkoxycarbonyl; and R1 and R2 are optionally linked to each other to form a ring; R3 is hydrogen, alkyl, cycloalkyl, or aryl group optionally having one or two substituents; X is -C(R5)=C(R6)-, -C(R7)N-, or -N=C (R8)-, wherein R5, R6, R7 and R8 each represent hydrogen, halogen, alkyl, or alkoxy, optionally having one or two substituents; L is an alkylene group (some carbon atoms in the alkylene group optionally forming a cycloalkyl ring), alkenyl, ynylene, cycloalkylene, alkyloxyalkylene, alkylthioalkylene, alkylene-SO-alkylene, or alkylene-SO2-alkylene, each optionally substituted with one or two substituents, or an alkylene-N(R9)-alkylene group optionally substituted with one or two substituents, wherein R9 represents hydrogen or an alkyl group optionally having one or two substituents; p represents an integer of 0 or 1; A is a group represented by any of the following formulas (2), (3) or (4): Equation (2) Among them, R 10 and R 11 They may be the same or different, and each represents hydrogen or a straight-chain or branched alkyl group; and m represents an integer from 0 to 10. Equation (3) Among them, R 12 and R 13 The same or different, and each represents hydrogen, halogen, or optionally an alkyl group having one or two substituents, a cycloalkyl group having one or two substituents, or an alkoxy group having one or two substituents; Y represents CH or nitrogen; Z represents CH2, oxygen, or N-alkyl; n represents an integer from 0 to 3; U represents alkylene; and t represents an integer of 0 or 1. Equation (4) Among them, R 14 and R 15The same or different, and each represents hydrogen, halogen, or optionally an alkyl group having one or two substituents, a cycloalkyl group having one or two substituents, or an alkoxy group having one or two substituents; V is alkylene, alkyleneoxyalkylene, oxyalkylene, alkyleneoxy, or oxygen; q represents an integer of 0 or 1; U and t are as defined above; and Ar represents an aryl group having one or two substituents (one or two substituents optionally forming a ring with a portion of the carbon atoms in the aryl group), a 5- to 6-membered cycloaryl group having one or two identical or different heteroatoms, optionally having one or two substituents, or a benzofused heteroaryl group having one to three substituents; and B represents COOR. 16 , where R 16 To indicate hydrogen, alkyl, aryl, or aralkyl, it is formed by CH(R) 17 )O----COR 18 Or ----CH(R) 17 )---O---CO---OR 18 The group represented, where R 17 It is hydrogen or alkyl, and R 18 It is an alkyl or cycloalkyl group, represented by the (5-alkyl-2-oxo-1,3-dioxapentane-4-yl)methyl group of the following formula (5): Equation (5) Wherein, R' represents an alkyl or heterocyclic group: 1H-tetrazole-5-yl group, 4,5-dihydro-5-oxo-4H-1,2,4-oxadiazole-3-yl group, 4,5-dihydro-5-thio-4H-1,2,4-oxadiazole-3-yl group or 4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl group represented by the following formulas (6), (7), (8) (from left to right), and (9) (below): Equations (6), (7), (8) (from left to right), and (9) (bottom) In some implementations, the PAI-1 inhibitor is a compound of formula (10). Equation (10) Wherein, R1 and R2 may be the same or different, and each represents hydrogen, halogen, alkyl, or optionally aryl with one or two substituents; R3 is hydrogen or alkyl; R 14 and R 15The same or different, and each represents hydrogen, alkyl or halogen; V is alkylene, oxyalkylene or oxygen; Ar is an aryl group optionally having one or two substituents, an aryl group optionally having one or two substituents having one or two identical or different heteroatoms, or a benzo-fused heteroaryl group optionally having one or three substituents; L is alkylene, alkyloxyalkylene, alkylthioalkylene, alkylene-SO-alkylene, alkylene-SO2-alkylene; and q, U, t, p and B are as defined above.

[0097] In some embodiments, the PAI-1 inhibitor is selected from the group consisting of: 5-chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid, 5-chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, benzopyran compounds, butadiene, spironolactone, imidapril, angiotensin-converting enzyme inhibitors (ACEIs, captopril, or enalapril), angiotensin II receptor antagonists (AIIRA), defibrin polynucleotides (polydeoxyribonucleotides), and any combination thereof. In some embodiments, the PAI-1 inhibitor is 5-chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

[0098] Table 1 below lists exemplary PAI-1 inhibitors.

[0099] Table 1 Examples of PAI-1 Inhibitors

[0100] Compositions and formulations As described herein, this disclosure provides compositions comprising an active agent (e.g., a PAI-1 inhibitor). As described herein, this disclosure provides compositions for delivering an active agent (e.g., a PAI-1 inhibitor). In some embodiments, the compositions comprising and / or delivering an active agent are formulated for topical application. In some embodiments, the compositions comprising and / or delivering an active agent are formulated for topical application to a subject's site. In some embodiments, the compositions comprising and / or delivering an active agent are improved compositions as described herein. In some embodiments, the compositions comprising and / or delivering an active agent are formulated for parenteral administration (e.g., via injection or infusion).

[0101] In some embodiments, the composition comprising and / or delivering an active agent comprises one or more components as described herein. In some embodiments, the components of the composition comprising and / or delivering an active agent have functions as described herein. In particular, the components of the composition comprising and / or delivering an active agent may have more than one function in the composition.

[0102] In some embodiments, the compositions described herein are substantially free of one or more of the components described herein.

[0103] In some embodiments, the compositions described herein are substantially free of ETOH.

[0104] In some embodiments, the compositions described herein are substantially free of sorbitol.

[0105] In some embodiments, the compositions described herein comprise a penetration enhancer. In some embodiments, the penetration enhancer is one or more of glycerol, isopropyl myristate, and / or propylene glycol. In some embodiments, the provided compositions comprise a penetration enhancer in an amount not exceeding 35% by weight of the composition.

[0106] In some embodiments, the compositions described herein comprise isopropyl myristate. In some embodiments, the compositions described herein comprise less than 15% isopropyl myristate by weight of the composition. In some embodiments, the compositions described herein comprise more than 0.1% isopropyl myristate by weight of the composition. In some embodiments, the compositions described herein comprise at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% isopropyl myristate by weight of the composition. In some embodiments, the compositions described herein comprise at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% isopropyl myristate by weight of the composition. In some embodiments, the compositions described herein comprise greater than 1% but not more than 15% by weight of the composition of isopropyl myristate. In some embodiments, the compositions described herein comprise greater than 5% but not more than 15% by weight of the composition of isopropyl myristate. In some embodiments, the compositions described herein comprise greater than 9% but not more than 12% by weight of the composition of isopropyl myristate. In some embodiments, the compositions described herein comprise greater than 9% but not more than 11% by weight of the composition of isopropyl myristate. In some embodiments, the compositions described herein comprise 10% by weight of the composition of isopropyl myristate.

[0107] In some embodiments, the provided composition comprises a solvent. In some embodiments, the solvent is glycerol. In some embodiments, the composition as described herein comprises glycerol. In some embodiments, the composition as described herein comprises less than 15% glycerol by weight of the composition. In some embodiments, the composition as described herein comprises more than 0.1% glycerol by weight of the composition. In some embodiments, the composition as described herein comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% glycerol by weight of the composition. In some embodiments, the composition as described herein comprises at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% glycerol by weight of the composition. In some embodiments, the composition as described herein comprises more than 1% but not more than 15% glycerol by weight of the composition. In some embodiments, the composition described herein contains more than 5% but not more than 15% glycerol by weight of the composition. In some embodiments, the composition described herein contains more than 9% but not more than 11% glycerol by weight of the composition. In some embodiments, the composition described herein contains not more than 10% glycerol by weight of the composition. In some embodiments, the composition described herein contains 10% glycerol by weight of the composition.

[0108] In some embodiments, the compositions described herein comprise propylene glycol. In some embodiments, the compositions described herein comprise less than 20% propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise more than 0.1% propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise more than 5% but not more than 20% propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise more than 14% but not more than 16% of propylene glycol by weight of the composition. In some embodiments, the compositions described herein comprise 15% of propylene glycol by weight of the composition.

[0109] In some embodiments, the compositions described herein comprise an emollient. In some embodiments, the emollient is isopropyl myristate.

[0110] In some embodiments, the provided composition comprises a solvent or carrier. In some embodiments, the solvent or carrier is water. In some embodiments, the composition as described herein comprises less than 70% water by weight of the composition. In some embodiments, the composition as described herein comprises more than 0.1% water by weight of the composition. In some embodiments, the composition as described herein comprises at least 1%, 10%, 20%, 30%, 40%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 58%, or 60% water by weight of the composition. In some embodiments, the composition as described herein comprises at most 1%, 10%, 20%, 30%, 40%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 58%, or 60% propylene glycol by weight of the composition. In some embodiments, the provided composition comprises more than 15% but not more than 70% water by weight of the composition. In some embodiments, the provided composition contains more than 20% water by weight of the composition. In some embodiments, the provided composition contains more than 30% water by weight of the composition. In some embodiments, the provided composition contains more than 40% water by weight of the composition. In some embodiments, the provided composition contains more than 50% water by weight of the composition. In some embodiments, the provided composition contains more than 51% water by weight of the composition. In some embodiments, the provided composition contains more than 52% water by weight of the composition. In some embodiments, the provided composition contains more than 53% water by weight of the composition. In some embodiments, the provided composition contains more than 53.5% water by weight of the composition. In some embodiments, the provided composition contains more than 53.6% water by weight of the composition. In some embodiments, the provided composition contains more than 53.7% water by weight of the composition. In some embodiments, the provided composition contains more than 53.8% water by weight of the composition. In some embodiments, the provided composition contains more than 53.84% water by weight of the composition. In some embodiments, the provided composition contains no more than 54% water by weight of the composition.

[0111] In some embodiments, the composition described herein comprises a suspending agent. In some embodiments, the suspending agent is xanthan gum. In some embodiments, the composition described herein comprises xanthan gum. In some embodiments, the composition described herein comprises less than 0.5% xanthan gum by weight of the composition. In some embodiments, the composition described herein comprises more than 0.1% xanthan gum by weight of the composition. In some embodiments, the composition described herein comprises at least 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% xanthan gum by weight of the composition. In some embodiments, the composition described herein comprises at most 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% xanthan gum by weight of the composition. In some embodiments, the composition described herein comprises more than 0.1% but not more than 0.3% xanthan gum by weight of the composition. In some embodiments, the composition described herein comprises 0.2% xanthan gum by weight of the composition.

[0112] In some embodiments, the compositions described herein comprise an emulsifier or a solubilizer. In some embodiments, the emulsifier or solubilizer is stearyl alcohol polyether 20. In some embodiments, the emulsifier or solubilizer is Tween 80. In some embodiments, the emulsifier or solubilizer is both stearyl alcohol polyether 20 and Tween 80.

[0113] In some embodiments, the composition described herein comprises less than 3% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises more than 0.1% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises at least 1%, 1.5%, 2%, 2.5%, or 3% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises at most 1%, 1.5%, 2%, 2.5%, or 3% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises more than 1% but not more than 3% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises more than 1.5% but not more than 3.0% stearyl alcohol polyether 20 by weight of the composition. In some embodiments, the composition described herein comprises 2.0% stearyl alcohol polyether 20 by weight of the composition.

[0114] In some embodiments, the composition described herein contains less than 6% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains more than 0.1% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains at least 1%, 2%, 3%, 3.5%, 3.6%, 4%, 5%, or 6% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains at most 1%, 2%, 3%, 3.5%, 3.6%, 4%, 5%, or 6% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains more than 1% but not more than 6% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains more than 3.0% but not more than 6% Tween 80 by weight of the composition. In some embodiments, the composition described herein contains 3.5% Tween 80 by weight of the composition.

[0115] In some embodiments, the composition described herein comprises less than 0.5% of methylparaben by weight of the composition. In some embodiments, the composition described herein comprises more than 0.1% of methylparaben by weight of the composition. In some embodiments, the composition described herein comprises at least 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% of methylparaben by weight of the composition. In some embodiments, the composition described herein comprises at most 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% of methylparaben by weight of the composition. In some embodiments, the composition described herein comprises a preservative. In some embodiments, the preservative is methylparaben. In some embodiments, the composition described herein comprises more than 0.1% but not more than 0.3% of methylparaben by weight of the composition. In some embodiments, the composition as described herein comprises methylparaben in an amount of 0.2% by weight of the composition.

[0116] In some embodiments, the preservative is disodium edetate. In some embodiments, the composition described herein contains less than 1% disodium edetate by weight of the composition. In some embodiments, the composition described herein contains more than 0.01% disodium edetate by weight of the composition. In some embodiments, the composition described herein contains at least 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% disodium edetate by weight of the composition. In some embodiments, the composition described herein contains at most 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% disodium edetate by weight of the composition. In some embodiments, the composition as described herein comprises more than 0.02% but not more than 0.06% of disodium edetate by weight of the composition. In some embodiments, the composition as described herein comprises more than 0.04% but not more than 1% of disodium edetate by weight of the composition. In some embodiments, the composition as described herein comprises 0.05% of disodium edetate by weight of the composition.

[0117] In some embodiments, the composition described herein comprises less than 0.15% propylparaben by weight of the composition. In some embodiments, the composition described herein comprises more than 0.05% propylparaben by weight of the composition. In some embodiments, the composition described herein comprises at least 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or 0.15% propylparaben by weight of the composition. In some embodiments, the composition described herein comprises at most 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or 0.15% propylparaben by weight of the composition. In some embodiments, the preservative is propylparaben. In some embodiments, the composition described herein comprises more than 0.05% but not more than 0.15% propylparaben by weight of the composition. In some embodiments, the composition as described herein comprises propylparaben in an amount of 0.10% by weight of the composition.

[0118] In some embodiments, the compositions described herein comprise an oil-soluble antioxidant. In some embodiments, the oil-soluble antioxidant is butylated hydroxytoluene. In some embodiments, the compositions described herein comprise less than 0.15% butylated hydroxytoluene by weight of the composition. In some embodiments, the compositions described herein comprise more than 0.05% butylated hydroxytoluene by weight of the composition. In some embodiments, the compositions described herein comprise at least 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or 0.15% butylated hydroxytoluene by weight of the composition. In some embodiments, the compositions described herein comprise up to 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or 0.15% butylated hydroxytoluene by weight of the composition. In some embodiments, the compositions described herein comprise more than 0.05% but not more than 0.15% butylated hydroxytoluene by weight of the composition. In some embodiments, the composition as described herein comprises 0.10% by weight of butylated hydroxytoluene.

[0119] In some embodiments, the composition as described herein comprises an active agent. In some embodiments, the active agent is the active agent as described herein. In some embodiments, the composition as described herein comprises less than 10% of the active agent by weight of the composition. In some embodiments, the composition as described herein comprises more than 0.1% of the active agent by weight of the composition. In some embodiments, the composition as described herein comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the active agent by weight of the composition. In some embodiments, the composition as described herein comprises at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the active agent by weight of the composition. In some embodiments, the composition as described herein comprises 5% of the active agent by weight of the composition.

[0120] In some embodiments, the provided composition can be formulated for topical and / or transdermal delivery (e.g., as a serum, suspension, lotion, cream, liniment, ointment, powder, gel, drops, etc.). In some embodiments, the provided composition may be or comprises a nanoemulsion. In some embodiments, the provided composition may be or comprises a crude emulsion. In some embodiments, application is combined with microneedling skin conditioning (MSC). In some embodiments, application is performed via injection. In some embodiments, application is combined with laser treatment of the skin. In some embodiments, application is combined with phototherapy of the skin. In some embodiments, phototherapy includes treatment with light of one or more wavelengths or colors. In some embodiments, phototherapy includes treatment with light of a specific range of wavelengths or colors. In some embodiments, phototherapy includes treatment with light wavelengths between 650 nm and 850 nm. In some embodiments, phototherapy includes treatment with light wavelengths between 785 nm and 850 nm.

[0121] lotion In some embodiments, this document provides surprisingly efficient techniques for the application and delivery of active agents. In some embodiments, this disclosure teaches topical formulations and compositions of such active agents for various diseases, conditions, and / or ailments as described herein. In some embodiments, this disclosure teaches methods for treating and / or preventing one or more diseases, conditions, and / or ailments by administering active agent formulations and / or compositions to a subject in need. In some embodiments, the formulations and / or compositions comprise emulsions.

[0122] 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 toxin and / or antibody agents. See, for example, U.S. Patent Publications 2012 / 0328701, 2012 / 0328702, 8,318,181, and 8,658,391, the disclosures of which are incorporated herein by reference in their entirety.

[0123] crude emulsion In some embodiments, this disclosure utilizes crude emulsion compositions comprising an active agent that is particularly effective and / or useful in treatment (e.g., treatment of diseases, conditions, and / or illnesses as described herein). In some embodiments, a particular crude emulsion composition is particularly effective and / or useful for topical application of an active agent as described herein to a subject in need. In some embodiments, the crude emulsion composition may comprise one or more active agents.

[0124] In some embodiments, the crude emulsion can be formulated into a composition suitable for topical application to the skin. In some embodiments, the composition suitable for topical application can be a lotion, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

[0125] In some embodiments, the crude emulsion formulation comprises water, medium-chain triglycerides, Span 65, polysorbate 80, methylparaben, and propylparaben.

[0126] In some embodiments, the provided composition comprises a mixture of the provided crude emulsion composition and one or more pharmaceutically acceptable excipients. In some embodiments, cream and / or lotion formulations comprise a mixture of the provided crude emulsion composition and / or a saline solution.

[0127] In some embodiments, the provided composition comprises a crude emulsion composition containing one or more surfactants. In some embodiments, the provided composition is a cream and / or lotion formulation. In some embodiments, the provided composition comprises a crude emulsion composition. In some embodiments, the composition comprises the provided crude emulsion composition but is not a cream and / or lotion formulation. In some embodiments, a suitable composition is formulated as a cream and / or lotion but does not contain a crude emulsion composition.

[0128] In some embodiments, the provided composition comprises a mixture of the provided crude emulsion composition and one or more pharmaceutically acceptable excipients, for example for topical and / or transdermal application (e.g., via serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.).

[0129] In some embodiments, the crude emulsion can be formulated into a composition suitable for topical application. In some embodiments, the composition suitable for topical application can be a lotion, cream, serum, suspension, powder, ointment, liniment, gel, drops, emollient, balm, or paste. In some embodiments, the crude emulsion can be formulated into an injectable composition. In some embodiments, the injectable composition can be sterile.

[0130] Crude emulsion formulations can act as stabilizers for active agents and / or therapeutic agents. While crude emulsion formulations are not necessarily intended to achieve transdermal delivery of active agents on their own, this disclosure covers the synergistic enhancement of transdermal delivery achieved through the improved stability provided by incorporation into crude emulsion compositions when combined with microneedle technologies as described herein.

[0131] Nanoemulsion In some embodiments, this disclosure utilizes nanoemulsion compositions comprising an active agent that is particularly effective and / or useful in treatment (e.g., treating diseases, conditions, and / or illnesses as described herein). In some embodiments, a particular nanoemulsion composition is particularly effective and / or useful for topical application of an active agent as described herein to a subject in need. In some embodiments, the nanoemulsion composition may comprise one or more active agents.

[0132] In some embodiments, the provided nanoemulsion composition comprises an oil and a surfactant in a ratio ranging from about 0.1:1 to about 2:1. In some embodiments, the provided nanoemulsion composition comprises an oil and a surfactant in a ratio of about 0.1:1 to about 1:1. In some embodiments, the provided nanoemulsion composition comprises an oil and a surfactant in a ratio of about 0.5:1 to about 1:1. In some embodiments, the provided nanoemulsion composition comprises an oil and a surfactant in a ratio of about 0.5:1 to about 1:1.5. In some embodiments, the provided nanoemulsion composition comprises 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 0.55:1, 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, the provided nanoemulsion composition comprises oil and surfactant in a ratio of about 0.67:1.

[0133] In some embodiments, the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) and the surfactant are used at a ratio ranging from 0.01 to 20. In some embodiments, the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) and the surfactant are used at a ratio ranging from 0.1 to 20. In some embodiments, the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) and the surfactant are used at a ratio ranging from 0.5 to 10. In some embodiments, the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) and the surfactant are used at a ratio ranging from 0.5 to 1. In some embodiments, the ratio of the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) to the 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 solution, salt solution, etc.) and surfactant are used at a ratio ranging from 0.5 to 2. In some embodiments, the ratio of aqueous dispersion medium (e.g., water, buffer solution, 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 solution, salt solution, etc.) is about 0.5:1, about 1:1, or about 2:1. In some embodiments, the ratio of the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) to the surfactant is about 1:1. In some embodiments, the composition of the aqueous dispersion medium (e.g., water, buffer solution, salt solution, etc.) and the surfactant using such a ratio comprises a water-in-oil emulsion.

[0134] In some embodiments, the droplets within the nanoemulsion composition have diameters (e.g., average and / or median diameters) in 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 within the nanoemulsion composition have diameters (e.g., average and / or median diameters) in the range of 1 nm to 300 nm, 1 nm to 200 nm, 1 nm to 150 nm, 1 nm to 120 nm, 1 nm to 100 nm, 1 nm to 75 nm, 1 nm to 50 nm, or 1 nm to 25 nm. In some embodiments, the droplets within the nanoemulsion composition have diameters 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 (e.g., average and / or median diameter).

[0135] In some embodiments, the total droplet distribution is encompassed within a specified droplet diameter range. In some embodiments, less than 50%, 25%, 10%, 5%, or 1% of the total droplet distribution is outside the specified droplet diameter range. In some embodiments, less than 1% of the total droplet distribution is outside the specified droplet diameter range. In some embodiments, the nanoemulsion composition is substantially free of droplets with diameters 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 total 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.

[0136] In some embodiments, the droplets within 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 in 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 to about 110 nm. In some embodiments, the average droplet size is about 90 nm to about 100 nm.

[0137] 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 n-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, about -5 mV, or about -1 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 of about 0 mV. In some embodiments, the aqueous dispersion medium and the surfactant are used at a ratio ranging from about 8:1 to about 9:1. In some embodiments, the aqueous dispersion medium and the surfactant are used at ratios 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 the surfactant are used at a ratio of about 8.7:1. In some embodiments, the aqueous dispersion medium and the surfactant are used at a ratio of about 8.8:1.

[0138] In some embodiments, the aqueous dispersion medium and oil are used in a ratio ranging from about 12:1 to about 14:1. In some embodiments, the aqueous dispersion medium and surfactant are used in ratios 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 used in a ratio of about 13.1:1.

[0139] In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 40%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 30%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 20%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 10%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 0% to 5%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 35% to 40%, or 45% to 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 10% to 20%, 10% to 30%, 10% to 40%, or 10% to 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 20% to 30%, 20% to 40%, or 20% to 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 30% to 40% or 30% to 50%. In some embodiments, the percentage of oil in the nanoemulsion ranges from 40% to 50%.

[0140] 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 percentage of oil is about 10%. In some embodiments, the percentage of oil is about 9%. In some embodiments, the percentage of oil is about 8%. In some embodiments, the percentage of oil is about 7%. In some embodiments, the percentage of oil is about 6%. In some embodiments, the percentage of oil is about 5%. In some embodiments, the percentage of oil is about 4%. In some embodiments, the percentage of oil is about 3%. In some embodiments, the percentage of oil is about 2%. In some embodiments, the percentage of oil is about 1%.

[0141] In some embodiments, the nanoemulsion formulation comprises water, medium-chain triglycerides, polysorbate 80, methylparaben, and propylparaben.

[0142] In some embodiments, the nanoemulsion can be formulated into a composition suitable for topical application. In some embodiments, the composition suitable for topical application can be a lotion, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste. In some embodiments, the nanoemulsion can be formulated into an injectable composition. In some embodiments, the injectable composition can be sterile.

[0143] These compositions are particularly useful because they can be used to deliver pharmaceutical agents to subjects in need via topical and / or transdermal application (e.g., via lotions, creams, powders, ointments, liniments, gels, drops, etc.). In some embodiments, the provided compositions can be administered to subjects in need via topical and / or transdermal application (e.g., via serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.). In some embodiments, the provided nanoemulsion compositions can be formulated into cream and / or lotion formulations. In some embodiments, the provided compositions comprising nanoemulsion compositions can be used and / or effectively administered topically to subjects. In some embodiments, the provided nanoemulsion compositions can be mixed with one or more cream components in cream formulations and / or saline solutions to prepare pharmaceutical compositions.

[0144] This disclosure covers the understanding that emulsion compositions (e.g., crude emulsion compositions and nanoemulsion compositions) can be formulated into cream and / or lotion formulations for application to a subject. This disclosure covers the understanding that the provided compositions are particularly suitable for formulating emulsions for application to a subject, such as those described herein.

[0145] Topical preparations The compositions described herein are particularly useful because they can be used to deliver the active agents described herein to a subject in need via topical and / or transdermal application (e.g., via serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.). In some embodiments, the provided compositions comprising the active agents described herein are administered to a subject in need via topical application (e.g., via serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.). In some embodiments, compositions formulated for topical application comprise crude emulsions as described herein. In some embodiments, compositions formulated for topical application comprise nanoemulsions as described herein.

[0146] In some embodiments, the cream and / or lotion formulation comprises purified water, methylparaben, mineral oil, isopropyl myristate, white petrolatum, emulsifying wax, and propylparaben.

[0147] In some embodiments, this disclosure describes that the provided compositions can be formulated into cream and / or lotion formulations as described herein. In some embodiments, the provided compositions are formulated with water. In some embodiments, the provided compositions are formulated with methylparaben. In some embodiments, the provided compositions are formulated with mineral oil. In some embodiments, the provided compositions are formulated with isopropyl myristate. In some embodiments, the provided compositions are formulated with white petrolatum. In some embodiments, the provided compositions are formulated with emulsified wax. In some embodiments, the provided compositions are formulated with propylparaben. In some embodiments, the provided compositions are formulated without any parabens. In some embodiments, the provided compositions are formulated without methylparaben. In some embodiments, the provided compositions are formulated without propylparaben.

[0148] In some embodiments, cream and / or lotion formulations may be used for topical and / or transdermal application. This disclosure covers the understanding that, in some embodiments, the provided compositions are particularly suitable for delivering an active agent to, for example, hair follicles located at the application site. In some embodiments, the treatment site includes areas that previously had hair or hair follicles but no longer do. In some embodiments, the provided compositions are formulated for topical delivery to a subject in need. In some embodiments, the provided compositions are administered to a subject in need via topical delivery.

[0149] In some embodiments, the provided composition is formulated with cosmetically acceptable components. For example, in some embodiments, the provided composition is formulated with water and any cosmetically acceptable solvent, particularly monools, such as alkanols having 1 to 8 carbon atoms (e.g., ethanol, isopropanol, benzyl alcohol, and phenethyl alcohol), polyols, such as alkylene glycols (e.g., glycerol, ethylene glycol, and propylene glycol), and glycol ethers, such as monoethylene glycol monoalkyl ethers, diethylene glycol monoalkyl ethers, and triethylene glycol monoalkyl ethers, such as ethylene glycol monomethyl ethers and diethylene glycol monomethyl ethers, used alone or in mixtures. These components may be present, for example, in proportions of up to 60%, 70%, 80%, or 90% by weight relative to the total composition.

[0150] In some embodiments, the provided composition for topical application contains one or more cosmetically acceptable components that impart desired or appropriate appearance properties to the subject to whom the composition is applied (e.g., a matte appearance, which may be particularly desired or appropriate for a subject with oily skin).

[0151] In some embodiments, the provided composition is formulated with at least one cosmetically acceptable filler material, for example, to obtain a matte product, which may be particularly desirable for individuals with oily skin.

[0152] In some embodiments, one or more active agents are formulated into a composition suitable for topical application. Exemplary active agents include those described herein. In some embodiments, the provided composition may be formulated and delivered in combination with microneedle skin conditioning (MSC) to achieve systemic delivery; in some embodiments, the provided composition may be formulated and / or delivered to achieve local rather than systemic delivery.

[0153] In some embodiments, the composition suitable for topical formulation includes a penetration enhancer. In some embodiments, the penetration enhancer degrades, disrupts, and / or damages skin structure and / or skin. In some embodiments, the penetration enhancer does not degrade, disrupt, 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.

[0154] In some embodiments, the provided composition may be incorporated into a device, such as, for example, a patch. Various transdermal patch structures are known in the art; those skilled in the art will understand that the provided composition can 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 applied to the skin. In some embodiments, the transdermal patch may include multiple needles extending from one side of the patch applied to the skin, wherein the needles extend from the patch to protrude through the stratum corneum of the skin. In some embodiments, the needles do not rupture blood vessels. In some embodiments, the depth of needle penetration is insufficient to reach nerves in the dermis of the skin.

[0155] In some embodiments, the transdermal patch includes an adhesive. Examples of adhesive patches are well known (e.g., see 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 (which will be applied to a patient's skin), a reservoir or receptacle for containing the provided composition, and an outer surface to prevent leakage of the provided composition from the reservoir. The outer surface of the patch may be non-adhesive.

[0156] According to this disclosure, the provided composition is incorporated into a patch such that it remains stable over an extended 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 the adhesive layer of the patch such that the provided composition can diffuse through the skin once the patch is applied. In some embodiments, the adhesive layer may be thermally activated, wherein a temperature of about 37°C causes the adhesive to liquefy slowly, allowing the agent to diffuse through the skin. When stored below 37°C, the adhesive retains its tackiness, and upon application to the skin, the adhesive loses its tackiness upon liquefaction.

[0157] In some embodiments, the provided composition may be provided in the form of a reservoir in a patch, such that pressure applied to the patch causes the provided composition to flow out of the patch through the microneedles and across the stratum corneum. Exemplary embodiments of microneedles have been described above. Suitable devices for intradermal application of the provided composition include those described in U.S. Patent Nos. 4,886,499, 5,190,521, 5,328,483, 5,527,288, 4,270,537, 5,015,235, 5,141,496, and 5,417,662. Intradermal compositions may be applied using devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication WO 99 / 34850 and their functional equivalents.

[0158] In some embodiments, such as to prolong the effect of the provided composition, it may be necessary to slow down the absorption of the provided composition into the skin. In some embodiments, this can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the provided composition depends on its dissolution rate, which in turn can depend on the crystal size and crystal 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).

[0159] Injectable formulations In some embodiments, the composition can be formulated into an injectable formulation. In some embodiments, the provided composition can be formulated into an injectable formulation. In some embodiments, the injectable formulation can be sterile. In some embodiments, the injectable formulation may contain one or more excipients. In some embodiments, the injectable formulation may contain a nanoemulsion. In some embodiments, the injectable formulation may contain a crude emulsion. In some embodiments, the injectable formulation contains water. In some embodiments, the injectable composition contains water, which may be the largest component of the composition (e.g., by weight percentage).

[0160] application This disclosure provides techniques (e.g., compositions, methods, kits, etc.) for treating diseases, conditions, and / or illnesses. In some embodiments, this disclosure provides techniques for treating dermatological conditions or illnesses using any of the compositions provided as described herein (e.g., provided emulsion compositions; cream and / or lotion formulations; combinations of provided emulsion compositions and cream and / or lotion formulations; etc.).

[0161] As described herein, this disclosure provides methods for administering the provided composition to a subject for various applications, including, for example, cosmetic and / or medical applications. In some embodiments, this disclosure provides methods for treating and / or preventing diseases, conditions, and / or ailments related to the activity of epidermal and / or dermal structures (e.g., sweat glands, sebaceous glands, hair follicles, etc.) by administering the provided composition to a subject in need.

[0162] In some embodiments, the provided method involves the topical application of a composition comprising an active agent as described herein. In some embodiments, the provided method involves the topical application of an emulsion composition comprising an active agent. In some embodiments, the emulsion composition is a crude emulsion. In some embodiments, the emulsion composition is a nanoemulsion. In some embodiments, application is performed topically via or in combination with MSCs.

[0163] Transdermal application In some embodiments, this disclosure describes a composition that achieves transdermal delivery without the use of abrasives or other disruptive agents (whether chemical, mechanical, electrical, magnetic, light-based, etc.). In some embodiments, this disclosure achieves transdermal delivery of the provided composition without requiring definitive steps of penetrating or disrupting the stratum corneum.

[0164] In some embodiments, this disclosure contemplates transdermal delivery of the provided compositions to achieve systemic delivery and / or effects. In some embodiments, this disclosure contemplates transdermal delivery of the provided compositions to achieve local delivery and / or effects, for example, without achieving systemic delivery and / or effects.

[0165] In some embodiments, the provided composition is applied directly to the skin. In some embodiments, the applied composition is absorbed through the epidermis. In some embodiments, the provided composition can penetrate the top layer of the skin, including the stratum corneum, dermal pores, and / or dermal glands, without the use of chemical or mechanical skin penetration enhancers or other agents that cause abrasion.

[0166] In some embodiments, this disclosure provides methods and compositions for specifically delivering the provided composition to epidermal and / or dermal structures. In some embodiments, the provided composition is specifically delivered to epidermal and / or dermal structures without significant delivery to subcutaneous structures. In some embodiments, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or about 100% of the provided composition applied to the skin of a subject is specifically delivered to the epidermis and / or dermis. In some embodiments, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the provided composition applied to the skin of a subject is delivered to subcutaneous structures.

[0167] In some embodiments, specific delivery to the epidermis and / or dermis is achieved by applying a dose of the provided composition lower than the dose per unit area used to achieve delivery to the subcutaneous structure. For example, in some embodiments, a volume of the provided composition is applied over a large surface area; in some embodiments, the provided composition contains a reduced amount of the provided composition per unit volume compared to the dose used to achieve delivery to the subcutaneous structure; in some embodiments, the penetration of the provided composition into the skin is reduced (e.g., by combining with a penetration inhibitor and / or adjusting the characteristics of the provided composition, such as component ratios, component identities, etc., and combinations thereof). In some embodiments, such a lower dose is at most about 1 / 2, about 1 / 3, about 1 / 4, about 1 / 5, about 1 / 10, about 1 / 20, about 1 / 30, about 1 / 40, about 1 / 50, about 1 / 100, or greater than about 1 / 100 of the dose per unit area used to achieve delivery to the subcutaneous structure.

[0168] Part According to this disclosure, the active agent can be applied to the site of interest to treat and / or prevent diseases, symptoms and / or conditions at that site.

[0169] The technology disclosed herein is suitable for human and veterinary use. In some embodiments, the disclosed technology can be used to treat subjects suffering from any of the diseases, conditions and / or ailments described herein, who will benefit from topical application of the active agent.

[0170] In some embodiments, the application site may be the skin. In some embodiments, the application site may be or include a site containing hair follicles. In some embodiments, the application site is the skin covering a muscle or muscle group of the subject. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiments, the site is on the back. In some embodiments, the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the 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 on the leaf axil. 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 does. In some implementations, any site suitable for the MSC is a suitable application site.

[0171] In some embodiments, the region of interest contains or does contain multiple hair follicles. In some embodiments, each hair follicle optionally contains a hair disposed therein. In some embodiments, the hair follicles have a normal structure and / or density. In some embodiments, the hair follicles do not contain hair. In some embodiments, the hair follicles contain hair. In some embodiments, the percentage of hair follicles containing 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 [missing information]. 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%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0172] In some embodiments, the hair in the hair follicle is not grayish-white. In some embodiments, the hair in the hair follicle is grayish-white. In some embodiments, the percentage of grayish-white hair is approximately 31%, approximately 32%, approximately 33%, approximately 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%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0173] In some implementation schemes, the site is affected by dermatological conditions.

[0174] In some embodiments, this disclosure provides methods for applying the provided composition via topical and / or transdermal application (e.g., via serum, suspension, lotion, cream, lotion, ointment, powder, gel, drops, etc.).

[0175] In some embodiments, the provided method involves applying the provided composition topically, transdermally, or intradermally to the skin of a subject. In some embodiments, such a route achieves local delivery.

[0176] In some embodiments, the active agent (e.g., a PAI-1 inhibitor) is administered via internal penetration into the skin at approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 5 minutes to approximately 60 minutes. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 5 minutes to approximately 12 minutes. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 5 minutes to approximately 15 minutes. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 15 minutes to approximately 30 minutes. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 1 hour. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 2 hours. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 3 hours. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 4 hours. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 5 hours. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 6 hours. In some embodiments, the active agent is administered via internal penetration into the skin at approximately 7 hours. In some embodiments, the active agent penetrates the skin within approximately 8 hours of application. In some embodiments, the active agent penetrates the skin within approximately 12 hours of application. In some embodiments, the active agent penetrates the skin within approximately 24 hours of application.

[0177] In some embodiments, the active agent (e.g., a PAI-1 inhibitor) is applied internally through the skin layer at approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes. In some embodiments, the active agent is applied internally through the skin layer at approximately 5 minutes to approximately 60 minutes. In some embodiments, the active agent is applied internally through the skin layer at approximately 5 minutes to approximately 12 minutes. In some embodiments, the active agent is applied internally through the skin layer at approximately 5 minutes to approximately 15 minutes. In some embodiments, the active agent is applied internally through the skin layer at approximately 15 minutes to approximately 30 minutes. In some embodiments, the active agent is applied internally through the skin layer at approximately 1 hour. In some embodiments, the active agent is applied internally through the skin layer at approximately 2 hours. In some embodiments, the active agent is applied internally through the skin layer at approximately 3 hours. In some embodiments, the active agent is applied internally through the skin layer at approximately 4 hours. In some embodiments, the active agent is applied internally through the skin layer at approximately 5 hours. In some embodiments, the active agent is applied internally through the skin layer at approximately 6 hours. In some embodiments, the active agent is applied internally through the skin layer at approximately 7 hours. In some embodiments, the active agent penetrates the skin layer within approximately 8 hours of application. In some embodiments, the active agent penetrates the skin layer within approximately 12 hours of application. In some embodiments, the active agent penetrates the skin layer within approximately 24 hours of application.

[0178] In some embodiments, the active agent penetrates the dermal layer after application at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In some embodiments, the active agent penetrates the dermal layer after application at approximately 5 to approximately 60 minutes. In some embodiments, the active agent penetrates the dermal layer after application at approximately 5 to approximately 12 minutes. In some embodiments, the active agent penetrates the dermal layer after application at approximately 5 to approximately 15 minutes. In some embodiments, the active agent penetrates the dermal layer after application at approximately 15 to approximately 30 minutes. In some embodiments, the active agent penetrates the dermal layer after application at approximately 1 hour. In some embodiments, the active agent penetrates the dermal layer after application at approximately 2 hours. In some embodiments, the active agent penetrates the dermal layer after application at approximately 3 hours. In some embodiments, the active agent penetrates the dermal layer after application at approximately 4 hours. In some embodiments, the active agent penetrates the dermal layer after application at approximately 5 hours. In some embodiments, the active agent penetrates the dermal layer after application at approximately 6 hours. In some embodiments, the active agent penetrates the dermal layer after application at approximately 7 hours. In some embodiments, the active agent penetrates the stratum corneum within approximately 8 hours of application. In some embodiments, the active agent penetrates the stratum corneum within approximately 12 hours of application. In some embodiments, the active agent penetrates the stratum corneum within approximately 24 hours of application.

[0179] In some embodiments, the active agent is applied over about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes, penetrating the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands. In some embodiments, the active agent is applied over about 5 minutes to about 60 minutes, penetrating the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands. In some embodiments, the active agent is applied over about 5 minutes to about 12 minutes, penetrating the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands. In some embodiments, the active agent is applied over about 5 minutes to about 15 minutes, penetrating the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands. In some embodiments, the active agent is applied over about 15 minutes to about 30 minutes, penetrating the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 1 hour of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 2 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 3 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 4 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 5 ...6 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within about 7 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within approximately 8 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within approximately 12 hours of application. In some embodiments, the active agent penetrates the top layer of skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands, within approximately 24 hours of application.

[0180] Subjects Typically, the subject is a living organism, usually a mammal (e.g., a human, including prenatal human forms in some embodiments). In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is a human. In one specific embodiment, the human subject is at least 10 years old. In some embodiments, the subject has no hair. In some embodiments, the subject has hair. In some embodiments, the subject has low follicle density. In some embodiments, the subject has high follicle density. In some embodiments, the subject has colored hair. In some embodiments, the subject suffers from a relevant disease, condition, or illness. In some embodiments, the subject is susceptible to a disease, condition, or illness. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, condition, or illness. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, condition, or illness. In some embodiments, the subject is a person who has one or more characteristics characteristic of being susceptible to a disease, condition, or illness or at risk of a disease, condition, or illness. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is receiving and / or has received diagnostic and / or therapeutic treatments.

[0181] The technology disclosed herein is suitable for human and veterinary use. In some embodiments, the disclosed technology can be used to treat subjects suffering from any of the diseases, conditions and / or ailments described herein, who will benefit from topical application of the active agent (e.g., a PAI-1 inhibitor).

[0182] plan Typically, a regimen is selected to deliver a therapeutically effective dose to the relevant site of action. In some embodiments, the compositions and formulations described herein can be administered as a single dose to a subject in need at the relevant site of action. In some embodiments, the compositions and formulations described herein can be administered as multiple doses to a subject in need at the relevant site of action. For example, the compositions and formulations described herein can be administered via any of the various routes of administration described herein (e.g., local, via injection) sufficient to deliver an effective dose of the active agent (e.g., a PAI-1 inhibitor).

[0183] In some implementations, the dosing regimen of a particular active agent (e.g., a PAI-1 inhibitor) may involve intermittent or continuous (e.g., via perfusion or other sustained-release systems) administration, for example, to achieve a particular desired pharmacokinetic profile or other exposure pattern in one or more tissues or fluids of interest in a subject receiving the therapy.

[0184] In some embodiments, administration may also include administering multiple doses of the composition described herein according to a dosing regimen, wherein at least two consecutive doses are spaced at least 12 hours apart from each other.

[0185] In some embodiments, the different agents administered in combination may be administered via different routes of delivery and / or according to different schedules. Alternatively or additionally, in some embodiments, one or more doses of the first active agent are administered substantially simultaneously with one or more other active agents, and in some embodiments, via a common route and / or as part of a single composition.

[0186] Factors to consider when optimizing the route and / or dosing schedule for a given treatment regimen may include, for example, the specific indication being treated, the subject's clinical condition (e.g., age, general health, prior therapy received and / or response to it), the site of drug delivery, the nature of the drug (e.g., antibody or other peptide-based compound), the mode and / or route of drug administration, the presence or absence of combination therapy, and other factors known to the medical practitioner. For example, in the treatment of cancer, relevant characteristics of the indication being treated may include, for example, one or more of the following: cancer type, stage, and location.

[0187] In some embodiments, one or more features of a particular pharmaceutical composition and / or the dosing regimen used may be changed over time (e.g., increasing or decreasing the amount of active agent in any individual dose, increasing or decreasing the time interval between doses) for example, to optimize the desired therapeutic effect or response (e.g., inhibiting the PAI-1 gene or gene product).

[0188] Generally, the type, amount, and frequency of administration of the active agent according to this disclosure depend on the applicable safety and efficacy requirements when one or more related agents are administered to mammals (preferably humans). Typically, such administration characteristics are chosen to provide a specific and generally detectable therapeutic response compared to that observed in the absence of treatment.

[0189] In the context of this disclosure, an exemplary desired therapeutic response may involve, but is not limited to, inhibiting genes and / or gene products encoding the active agent, suppressing and / or reducing the severity and / or prevalence of associated diseases, symptoms, and / or conditions. Such criteria can be readily assessed using any of the various immunological, cytological, and other methods disclosed in the literature.

[0190] In some embodiments, the effective dose (and / or unit dose) of the active agent may be at least about 0.01 ng / kg body weight, at least about 0.01 µg / kg body weight, at least about 0.05 µg / kg body weight, at least about 0.1 µg / kg body weight, at least about 1 µg / kg body weight, at least about 2.5 µg / kg body weight, at least about 5 µg / kg body weight, at least about 10 µg / kg body weight, at least about 100 µg / kg body weight, at least about 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 not exceeding about 500 mg / kg body weight. Those skilled in the art will understand that, in some embodiments, such guidelines may be adjusted for the molecular weight of the active agent. Dosage may also vary depending on the route of administration, treatment duration, or therefore dose escalation regimen, which can be used to determine the maximum tolerated dose and dose-limiting toxicities (if any) associated with increasing the dose of another therapeutic agent (e.g., a PAI-1 antagonist). Consequently, the relative amounts of each agent in the pharmaceutical composition may also vary; for example, each composition may contain 0.001% to 100% (w / w) of the corresponding agent. Therefore, in some embodiments, the effective dose (and / or unit dose) of the active agent may be at least about 0.001% w / w, at least about 0.005% w / w, at least about 0.01% w / w, at least about 0.05% w / w, at least about 0.1% w / w, at least about 0.5% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 2% w / w, at least about 2.5% w / w, at least about 5% w / w, at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, at least about 65% w / w, or at least about 70%. w / w, at least about 75% w / w, at least about 80% w / w, at least about 85% w / w, at least about 90% w / w, at least about 95% w / w, and not exceeding about 100% w / w.

[0191] In some implementations, the toxicity and / or therapeutic efficacy of the active agent can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, such as those used to determine the maximum tolerated dose (MTD) and ED. 50 (Effective dose for 50% maximal response). Typically, the dose-to-treatment ratio between toxicity and therapeutic effect is the therapeutic index; in some implementations, this ratio may be expressed as MTD / ED.50 The ratio between these values. Data obtained from such cell culture assays and animal studies can be used to formulate dosage ranges for human use.

[0192] In some embodiments, dosing can be guided by monitoring the effect of the active agent on one or more pharmacokinetic inhibitory markers in diseased or replacement tissues. For example, cell culture or animal experiments can be used to determine the relationship between the dose required to achieve a change in a pharmacokinetic marker that can be determined in cell culture, animal experiments, or early clinical trials and the dose required for therapeutic effect. In some embodiments, the dosage of the active agent is preferably within the range of ED (extracorporeal membrane oxygenation) containing little or no toxicity. 50 Within the circulating concentration range. In some implementations, the dose may vary within such a range, for example, depending on the dosage form used and / or the route of administration employed. The exact formulation, route of administration, and dose may be selected by an individual physician based on the patient's condition. In the treatment of crises or severe conditions, doses close to the MTD may be required to obtain a rapid response.

[0193] In some embodiments, the dose and / or interval can be adjusted individually, for example, to provide a plasma level sufficient to maintain, for example, the desired effect or minimum effective concentration (MEC) of the active component for a certain period of time required to achieve therapeutic efficacy. In some embodiments, the MEC can be estimated, for example, based on in vitro data and / or animal studies. The dose necessary to achieve the MEC will depend on individual characteristics and route of administration. In some embodiments, high-performance liquid chromatography (HPLC) or bioassays can be used to determine the plasma concentration.

[0194] In some embodiments, MEC values ​​can be used to determine dosing intervals. In some embodiments, the active agent should be administered using a regimen that maintains plasma levels above 10%-90% of the MEC for a sustained period, preferably between 30%-90%, and most preferably between 50%-90%, until the desired symptom improvement is achieved. In other embodiments, different MEC plasma levels will be maintained for different durations. In cases of topical application or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

[0195] Those skilled in the art can choose from a variety of administration regimens and will understand that the effective amount of the active agent may depend on the subject being treated, the subject's weight, the severity of the ailment, the method of administration, and / or the judgment of the prescribing physician.

[0196] In some embodiments, this disclosure relates to administering at least one of the provided compositions according to a dosing regimen sufficient to achieve a reduction of at least about 20% in the degree and / or prevalence of the relevant dermatological condition; in some embodiments, according to a dosing regimen sufficient to achieve a reduction of at least about 25%; in some embodiments, according to a dosing regimen sufficient to achieve a reduction of at least about 30%; and in some embodiments, according to 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 [missing information]. Administered at 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%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more of the dosage regimen.

[0197] In some embodiments, this disclosure relates to the administration of at least one provided composition in combination with MSCs, administered according to a dosing regimen sufficient to achieve a reduction of at least about 20% in the degree and / or prevalence of the relevant dermatological condition; in some embodiments, administered according to a dosing regimen sufficient to achieve a reduction of at least about 25%; in some embodiments, administered according to a dosing regimen sufficient to achieve a reduction of at least about 30%; in some embodiments, administered according to 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 4... Administered at 6%, 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%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more of the dosage regimen.

[0198] In some embodiments, this disclosure relates to administering at least one provided composition, optionally in combination with MSCs, according to a dosing regimen sufficient to achieve a reduction of at least about 20% in the severity and / or prevalence of an associated dermatological condition in a specific percentage of a patient population in which the composition is administered; in some embodiments, according to a dosing regimen sufficient to achieve a reduction of at least about 25% in a specified percentage of a patient population in which the composition is administered; in some embodiments, according to a dosing regimen sufficient to achieve a reduction of at least about 30% in a specified percentage of a patient population in which the composition is administered; and in some embodiments, according to a reduction of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, or about 38% in a specified percentage of a patient population in which the composition is administered. Approximately 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% or more of the dosage regimen. In some embodiments, the specified percentage of the patient population to which the composition is applied 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 name only a few illustrative examples, in some embodiments, this disclosure relates to applying at least one of the provided compositions according to a dosing regimen sufficient to achieve a reduction of at least about 20% in the severity and / or prevalence of an associated dermatological condition in at least about 50% of the patient population to which the composition is applied. In some embodiments, this disclosure relates to applying at least one of the provided compositions according to a dosing regimen sufficient to achieve a reduction of at least about 30% in the severity and / or prevalence of an associated dermatological condition in at least about 50% of the patient population to which the composition is applied.

[0199] This disclosure provides techniques for treating a condition or symptom by applying to a patient a composition as described herein (e.g., the provided emulsion composition; serum and / or suspension formulation; cream and / or lotion formulation; a combination of the provided emulsion composition and cream and / or lotion formulation; etc.), optionally in combination with MSCs. In some embodiments, this disclosure provides techniques for treating a condition or symptom by topically applying to a patient a composition containing the provided emulsion composition, optionally in combination with MSCs as described herein.

[0200] Penetration Enhancement Therapy In some embodiments, the provided composition may be applied in combination with one or more penetration-enhancing treatments (e.g., chemical agents, laser therapy, microneedling, physical massage, etc.) (such as known penetration enhancers and / or penetration-enhancing treatment modalities) to, for example, promote the penetration of the active agent across biological barriers (e.g., skin). In some embodiments, the provided composition includes one or more such other penetration enhancers; in some embodiments, such other penetration enhancers are provided as part of a different composition. In some embodiments, penetration-enhancing treatment involves the simultaneous application of two or more different penetration enhancers and / or penetration-enhancing treatment modalities; in some embodiments, penetration-enhancing treatment involves simultaneous exposure to two or more different penetration-enhancing treatment agents and / or penetration-enhancing treatment modalities, for example, by simultaneous laser therapy and composition application.

[0201] In some embodiments, the penetration enhancer is or comprises a chemical agent. For example, chemical agents that may damage, disrupt, and / or degrade one or more components of the stratum corneum may include, for example, alcohols, such as short-chain alcohols, long-chain alcohols, or polyols; amines and amides, such as ureas, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, pyrrolidone, or derivatives of pyrrolidone; terpenes and terpene derivatives; fatty acids and their esters; macrocyclic compounds; surfactants; or sulfoxides (e.g., dimethyl sulfoxide (DMSO), decylmethyl sulfoxide, etc.); surfactants, such as anionic, cationic, and nonionic surfactants; polyols; essential oils; and / or hyaluronidase. In some embodiments, the penetration enhancer may be an irritant because inflammatory and / or allergic reactions occur when the agent is applied to the skin. In some embodiments, the penetration enhancer is not an irritant. In some embodiments, the penetration enhancer may be or comprises a chemical agent that does not damage, disrupt, or degrade skin structure, but whose presence or level is still associated with increased penetration of the agent of interest across the skin compared to its absence. In some embodiments, the conopeptide, carrier molecule, and carrier peptide can be a penetration enhancer that does not damage, disrupt, and / or degrade skin structures. In some embodiments, the conopeptide, carrier molecule, and carrier peptide can be a non-irritating penetration enhancer. The term "penetration enhancer" does not cover mechanical devices (e.g., needles, scalpels, etc.) or their equivalents (e.g., other destructive treatments). Furthermore, those skilled in the art will understand that structures such as nanoparticles or emulsions are not chemical agents and therefore are not chemical penetration enhancers, even if their presence is associated with skin penetration enhancement of agents of interest that may be related to that structure. In some embodiments, the penetration enhancer is or comprises an alcohol.

[0202] In some embodiments, the enhanced penetration treatment is or includes microneedling. In some embodiments, the enhanced penetration treatment is or includes laser therapy. In some embodiments, the enhanced penetration treatment is or includes physical massage. For example, in some embodiments, the composition may be applied before or after laser treatment of the site. In some embodiments, the enhanced penetration treatment is or includes the application of an electric or magnetic field.

[0203] microneedles In some embodiments, the microneedle (MN) array used according to this disclosure is a minimally invasive system or shares features with minimally invasive systems, developed to overcome some of the drawbacks commonly associated with the use of hypodermal needles and subcutaneous needles, and to improve patient comfort and compliance. Such drawbacks include, for example, the possibility of needle tip misalignment in hypodermal needles, since healthcare professionals cannot see the exact destination of the needle; such misalignment can lead to adverse reactions when injected incorrectly. MNs are less prone to such problems. Other advantages of MNs are that they are unlikely to cause bleeding, minimize the introduction of pathogens through the pores created by the MN, and eliminate the variability of transdermal drug delivery. Other advantages include the possibility of self-application, reduced risk of accidental needlestick injury, reduced risk of spreading infection, and ease of disposal. In some embodiments, the MN is a plurality of microscopic protrusions assembled on one side of a support, such as a patch or device (e.g., impression, roller, array, applicator, pen).

[0204] In some embodiments, the MNs used according to this disclosure may be designed and / or constructed in arrays to improve skin contact and facilitate penetration into the skin. In some embodiments, the MNs utilized have suitable length, width, and shape to minimize contact with nerves when inserted into the skin, while still creating an efficient pathway for drug delivery. Alkilani, AZ et al., “Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratumcorneum” Pharmaceutics. 7:438-470 (2015).

[0205] In some embodiments, a suitable microneedle (MN) can be solid, coated, porous, soluble, hollow, or hydrogel MN. Solid MN creates micropores in the skin, thereby increasing the transport of pharmaceutical formulations (e.g., the "punch and patch" method). Coated MN allows the coated drug to dissolve rapidly into the skin (e.g., the "coating and punch" method). Soluble MN allows for rapid and / or controlled release of drugs incorporated into the microneedle. Hollow MN can be used to puncture the skin and release the composition after active infusion or diffusion of the formulation through the microneedle pores (e.g., the "punch and flow" method). In the case of soluble MN, the MN can act as a drug reservoir, containing the pharmaceutical composition until release by dissolution in the case of soluble MN or by swelling in the case of hydrogel MN (e.g., the "punch and release" method). However, as described herein, in many embodiments, the active agent is not delivered by injection via one or more microneedles. That is, in many embodiments, any microneedles utilized according to such embodiments are not coated, loaded, or manufactured with a bioactive agent in any manner that would achieve the delivery of the bioactive agent. Alternatively, in some embodiments, as described herein, if the bioactive agent is formulated in a crude emulsion or nanoemulsion composition as described herein, the MN utilized according to this disclosure (whether in MSCs or otherwise) may contain and / or deliver the bioactive agent. Therefore, as will be understood by those skilled in the art upon reading the specification described herein, treating the skin with microneedles that deliver the bioactive agent (e.g., by microneedle injection, by releasing a microneedle coating, or by releasing from dissolved microneedles) is not microneedle skin conditioning.

[0206] In some embodiments, the microneedles have a uniform diameter throughout their length. In some embodiments, the diameter of the microneedles is largest at the base of the microneedles. In some embodiments, the microneedles taper to a point distal to the base of the microneedles. In some embodiments, the tumor may be a solid tumor. In some embodiments, the microneedles may be hollow. In some embodiments, the microneedles may be tubular. In some embodiments, the microneedles may be sealed at one end. In some embodiments, the microneedles are part of a microneedle array. In some embodiments, the microneedles may have a length between about 1 μm and about 4,000 μm. In some embodiments, the microneedles may have a length between about 1 μm and about 2,000 μm. In some embodiments, the microneedles may have a length between about 50 μm and about 400 μm. In some embodiments, the microneedles may have a length between about 800 μm and about 1,500 μm.

[0207] In some embodiments, the microneedles used according to this disclosure may be made from different materials using techniques including, but not limited to, microforming processes or lasers. In some embodiments, the microneedles may be manufactured using various types of biocompatible materials, including polymers, metals, ceramics, semiconductors, organics, composites, or silicon. Unless they are designed to break into the skin and dissolve, in some embodiments, the microneedles have mechanical strength to remain intact and deliver drugs or collect biological fluids when inserted into and / or removed from the skin after insertion. In some embodiments, the microneedles are capable of remaining in place for up to several days before complete removal. In some embodiments, the microneedles may be sterilized using standard techniques. In some embodiments, the microneedles are biodegradable. In some embodiments, the microneedles comprise polymeric materials. In some embodiments, the polymeric materials include poly-L-lactic acid, polyglycolic acid, polycarbonate, polylactic-co-glycolic acid (PLGA), polydimethylsiloxane, polyvinylpyrrolidone (PVP), copolymers of methyl vinyl ether and maleic anhydride, sodium hyaluronate, carboxymethyl cellulose, maltose, dextrin, galactose, starch, gelatin, or combinations thereof.

[0208] Suitable MN arrays and MSC devices for transdermal delivery of bioactive agents in combination with compositions containing bioactive agents include those described, for example, in U.S. Patents 6,334,856, 6,503,231, 6,908,453, 8,257,324, and 9,144,671.

[0209] Combination therapy or treatment According to this disclosure, the provided compositions can 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 modes of treatment (e.g., one or more PAI inhibitors or other agents), such as known therapeutic agents and / or independently active bioactive agents. In some embodiments, for example, the provided compositions include one or more of these other active agents; in some embodiments, these other active agents are provided as part of a different composition. In some embodiments, the combination therapy involves the simultaneous administration of one or more doses or units of two or more other active agents and / or modes of treatment; in some embodiments, the combination therapy involves simultaneous exposure to two or more other active agents and / or modes of treatment, for example, through an overlapping dosing regimen.

[0210] In some embodiments, the provided composition includes one or more other active agents or is applied in combination with one or more other active agents that can be used to treat related dermatological diseases or other diseases, conditions and / or illnesses, such as those discussed herein in the context of related diseases, conditions and / or illnesses.

[0211] Reagent test kit In some embodiments, this disclosure provides pharmaceutical packages or kits comprising one or more emulsion compositions containing one or more active agents and / or one or more microneedle devices according to this disclosure. In some embodiments, the pharmaceutical package or kit comprises a formulation or pharmaceutical composition containing the provided composition in one or more containers optionally filled with one or more additional components of the pharmaceutical composition. In some embodiments, the pharmaceutical package or kit includes additional approved therapeutic agents for use in combination therapies. In some embodiments, the notification optionally associated with such containers may be in the form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical product, reflecting that agency's approval for manufacture, use, or sale for human administration.

[0212] Kits are provided that include therapeutic agents and / or active agents (e.g., PAI-1 inhibitors). By way of non-limiting example only, the provided compositions may be provided as a topical formulation and administered as a therapy. The dosage of the drug or its instructions may be provided in the kit for administration to individuals who have a condition or symptom (e.g., those related to the dermal level of the skin) or are at risk of it.

[0213] In some embodiments, the kit may include the provided composition and instructions for applying the composition to the site of application.

[0214] In some embodiments, the kit may comprise (i) the provided composition; and (ii) at least one pharmaceutically acceptable excipient; and optionally (iii) at least one syringe, scraper, glove, or swab for application to the skin; and (iv) instructions for use.

[0215] In some embodiments, the kit may comprise (i) the provided composition; and (ii) at least one pharmaceutically acceptable excipient; and optionally (iii) a device for injection (e.g., syringe and needle, microneedle array, brush, etc.); and (iv) instructions for use. In some embodiments, the device is a patch, roller, impression, or pen.

[0216] Those skilled in the art will understand that the compositions of the present invention for topical application can have cosmetic formulations, such as skin softeners, nourishing lotion-type emulsions, cleansing lotions, cleansing creams, skin lotions, moisturizing lotions, massage creams, moisturizing creams, cosmetic bases, masks or facial gels, cleansing formulations (such as shampoos, rinses, body cleansers, hair growth products, or soaps), or dermatological compositions (such as lotions, ointments, gels, creams, patches, or sprays). In some embodiments, the compositions for topical application are not formulated for application to mucous membranes (e.g., not suitable for application to mucous membranes and / or not formulated to deliver a suitable amount of large amounts of the agent to or across the mucous membrane).

[0217] Diseases, symptoms and conditions In some embodiments, the compositions and methods described herein can be used to treat and / or prevent various diseases, conditions, and / or ailments. In some embodiments, the compositions and methods described herein are particularly useful for treating and / or preventing various dermatological conditions. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent diseases, conditions, or ailments related to the epidermal and / or dermal levels of the skin. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent various non-dermatological conditions. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent pulmonary fibrosis, lung cancer, chronic myeloid leukemia, metabolic syndrome, diabetes, thrombosis, obesity, renal fibrosis, liver fibrosis, cardiac fibrosis, or atherosclerosis.

[0218] In some implementations, the dermatological condition is graying of the hair. In some implementations, the dermatological condition is keloid scarring. In some implementations, the dermatological condition is scleroderma. In some implementations, the dermatological condition is systemic scleroderma. In some implementations, the dermatological condition is cutaneous scleroderma. In some implementations, the dermatological condition is Raynaud's disease (or Raynaud's phenomenon). In some implementations, the dermatological condition is melanoma or cutaneous angiosarcoma.

[0219] In some embodiments, the compositions and methods described herein can be used to treat and / or prevent one or more specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosis, and age-related alopecia, and / or combinations thereof. In some embodiments, the hair loss is radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia due to chronic discoid lupus erythematosus.

[0220] Hair loss In some embodiments, the compositions and methods described herein can be used to treat and / or prevent hair loss. In some embodiments, the provided compositions are characterized in that, when applied to an animal containing one or more hairs, they achieve at least one of the following: (i) reducing hair loss; (ii) preventing hair loss; (iii) delaying the onset of hair loss of one or more hairs; and (iv) increasing the amount of hair on the site.

[0221] Hair loss refers to the absence of hair in areas where hair normally grows, especially on the scalp. The most common form of hair loss is a progressive thinning of hair called androgenetic alopecia or "male pattern baldness," which occurs in adult men and other species. The amount and pattern of hair loss can vary greatly; it ranges from "patterned hair loss" (androgenetic alopecia, also known as androgenetic alopecia or androgenic alopecia) in both men and women; "alopecia areata," which involves the loss of some hair from the scalp; "alopecia totalis," which involves the loss of all hair; and the most extreme form is "alopecia universalis," which involves the loss of all hair on the head and body. The main characteristics of fibrous alopecia frontalis (FFA) are slow, progressive hair loss and scarring on the scalp near the forehead. In some cases, hair loss in this type of hair loss may involve the eyebrows, eyelashes, and / or other body parts. Age-related hair loss (also known as menopausal hair loss) is hair loss caused by aging. Other types of hair loss include, but are not limited to, radiation-induced hair loss, chemotherapy-induced hair loss, hair loss due to chronic discoid lupus erythematosus, postpartum hair loss, and telogen effluvium.

[0222] Current treatments for hair loss include, but are not limited to, botulinum toxin, azasteroids such as finasteride (PROPECIA®; PROSCAR®; etc.) or dutasteride (AVODART®); topical minoxidil, a vasodilator (ROGAINE®); antiandrogens (e.g., ketoconazole, fluconazole, spironolactone, etc.); platelet-rich plasma, saw palmetto; caffeine; copper peptides; nitroxide spin-labeled TEMPO and TEMPOL; unsaturated fatty acids (e.g., gamma-linolenic acid); hedgehog agonists; combinations of azelaic acid and zinc; Chinese knotweed; pumpkin seed; spironolactone; retinoic acid; zinc; nettle; and / or combinations thereof. The pharmaceutical compositions according to this disclosure may be administered alone and / or in combination with these therapies for the treatment of symptoms and / or causes of hair loss for the treatment of hair loss.

[0223] In some embodiments, the provided composition for treating and / or preventing hair loss is formulated as a suspension.

[0224] In some embodiments, the provided composition for treating and / or preventing hair loss is formulated as a suspension, foam, cream, lotion, gel, shampoo, conditioner, ointment, emollient, balm, paste, etc.

[0225] In some embodiments, the provided composition for treating and / or preventing hair loss is applied topically to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0226] Hair turns gray In some embodiments, the compositions and methods described herein can be used to treat and / or prevent dermatological conditions. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent graying of hair.

[0227] In some embodiments, the provided composition is characterized in that, when applied to animals suffering from or susceptible to such hair graying, it achieves at least one of the following: (i) reducing the number of gray hairs (e.g., present at and / or near the application site); (ii) restoring the color of one or more gray hairs; (iii) preventing one or more non-gray hairs (e.g., present at and / or near the application site) from turning gray; and (iv) delaying the onset of graying of one or more non-gray hairs (e.g., present at and / or near the application site).

[0228] Current treatments for premature graying of hair include, but are not limited to, photoprotective agents (such as cinnamamidopropyltrimethylammonium chloride carriers and solid lipid nanoparticles as UV blockers), oral supplementation with L-cysteine ​​and L-methionine, and topical melatonin. The most common treatment or solution for premature graying of hair is the use of temporary hair coloring agents. The pharmaceutical compositions according to this disclosure can be administered alone and / or in combination with these therapies for treating the symptoms and / or causes of premature graying of hair.

[0229] In some embodiments, the provided composition for treating and / or preventing hair from turning gray is formulated as a suspension.

[0230] In some embodiments, the compositions disclosed herein for treating and / or preventing graying of hair are formulated as suspensions, serums, foams, creams, lotions, washes, gels, shampoos, conditioners, ointments, emollients, balms, pastes, etc.

[0231] In some embodiments, the compositions disclosed herein for treating and / or preventing graying of hair are applied topically to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0232] In some implementations, the application is achieved through whole-body delivery. In other implementations, the application is achieved through local delivery.

[0233] In some embodiments, this disclosure relates to the administration of a suspension containing at least one therapeutic agent (e.g., a PAI-1 inhibitor) in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 30%; and in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, or 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%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0234] In some embodiments, this disclosure relates to the application of a nanoparticle composition, or nanoemulsion composition, or emulsion composition, or foaming agent formulation, or cream formulation, or oil, or lotion formulation, or gel, or shampoo, or conditioner containing at least one therapeutic agent (e.g., a PAI-1 inhibitor), in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 30%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of graying hair by at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, or about 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%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0235] Keloids In some embodiments, the compositions and methods described herein can be used to treat and / or prevent keloids.

[0236] Keloids are hypertrophic scar tissues that form at the site of skin injury. In a specific instance, the site of skin injury is a surgical incision or trauma. Unlike hypertrophic scars, keloids are raised scars that grow beyond the boundaries of the original wound. Keloids are caused by the excessive growth of granulation tissue or type 3 collagen at the site of skin injury. Keloids may be hard, rubbery lesions. In some implementations, keloids may be shiny fibrous nodules. While these are benign growths and not contagious, keloids can sometimes be accompanied by pain, itching, and may affect skin movement. It is estimated that 15% of African Americans and Hispanic Americans have keloids.

[0237] While there is no effective treatment, current therapies for keloids include pressure therapy, silicone membranes, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high-dose oxygen therapy using hyperbaric oxygen therapy (HBOT), cryotherapy, and surgical excision, as well as various extracts and topical agents. Surgical excision is currently the most common form of treatment. However, the best treatment is prophylaxis in patients with a known predisposition. The pharmaceutical compositions according to this disclosure can be administered alone and / or in combination with these therapies for treating the symptoms and / or causes of keloids for the treatment of keloids.

[0238] In some embodiments, the provided composition for treating and / or preventing keloids is formulated as a suspension.

[0239] In some embodiments, the provided composition for treating and / or preventing keloids is formulated as a suspension, foam, cream, lotion, gel, shampoo, conditioner, ointment, emollient, balm, paste, etc.

[0240] In some embodiments, the provided composition for treating and / or preventing keloids is applied topically to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0241] In some implementations, the application is achieved through whole-body delivery. In other implementations, the application is achieved through local delivery.

[0242] In some embodiments, this disclosure relates to the application of a suspension containing at least one therapeutic agent (e.g., a PAI-1 inhibitor) in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids of at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids of at least about 30%; and in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids 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%, or 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%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0243] In some embodiments, this disclosure relates to the application of a nanoparticle composition, or nanoemulsion composition, or emulsion composition, or foam formulation, or cream formulation, or oil, or lotion formulation, or gel, or shampoo, or conditioner containing at least one therapeutic agent (e.g., a PAI-1 inhibitor), in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids of at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids of at least about 30%; in some embodiments, the amount is sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of keloids of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, or about 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%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0244] scleroderma In some embodiments, the compositions and methods described herein can be used to treat and / or prevent scleroderma. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent systemic scleroderma. In some embodiments, the compositions and methods described herein can be used to treat and / or prevent cutaneous scleroderma.

[0245] Scleroderma, or systemic sclerosis, is generally considered a chronic systemic autoimmune disease characterized, in particular, by fibrosis or hardening, vascular changes, and autoantibodies.

[0246] In some implementations, scleroderma is also considered a connective tissue disease, typically characterized by excessive accumulation of extracellular matrix proteins in the skin and internal organs, vascular damage, and immune abnormalities.

[0247] Many clinical manifestations of this disease are thought to involve misregulation of vascular remodeling. One of the earliest symptoms of scleroderma is microvascular damage. This microvascular damage is thought to cause increased endothelial cell activation. Activated endothelial cells are believed to express adhesion molecules, leading to altered capillary permeability, which allows inflammatory cells to migrate through the endothelium and become trapped in the vessel wall. Immune activation is thought to contribute to persistent endothelial activation, which leads to the breakdown of endothelial cells. This process is thought to contribute to the loss of elasticity and narrowing of blood vessels commonly observed in scleroderma patients. Furthermore, microvascular damage is thought to lead to perivascular infiltration of mononuclear cells in the dermis, which is thought to contribute to fibroblast activation and many of the associated hallmark symptoms of scleroderma. As fibrosis increases, permeability decreases. As a result, antibodies become more difficult to penetrate diseased tissue. Therefore, the affinity of anti-CCL2 antibodies becomes particularly important for maintaining antibody localization.

[0248] Many clinical manifestations of this disease are generally considered to involve fibroblast misregulation. The primary function of fibroblasts is to maintain the structural integrity of connective tissue by continuously secreting precursors of the extracellular matrix. Fibroblasts provide the structural framework (matrix) for many tissues, play a crucial role in wound healing, and are the most common cells in connective tissue in animals. Fibroblasts are morphologically heterogeneous, exhibiting different appearances depending on their location and activity.

[0249] Scleroderma has two main forms: localized systemic sclerosis / scleroderma and diffuse systemic sclerosis / scleroderma. In localized cutaneous scleroderma, fibrosis of the skin is usually confined to that area. Patients with localized cutaneous scleroderma often experience vascular damage. Skin and organ fibrosis usually progresses slowly in patients with localized scleroderma. Patients with diffuse scleroderma typically experience skin and organ fibrosis that progresses more rapidly than in localized scleroderma and / or more extensive inflammation and / or more severe visceral organ involvement than seen in localized scleroderma.

[0250] Interstitial lung disease leading to pulmonary fibrosis is generally considered the leading cause of scleroderma-related death (Ludwicka-Bradley, A. et al., Coagulation and autoimmunity in scleroderma interstitial lung disease. Semin Arthritis Rheum, 41(2), 212-22, 2011). Other complications leading to scleroderma-related death include, but are not limited to, cancer, heart failure, pulmonary hypertension, renal failure, and malabsorption, or any combination thereof.

[0251] Scleroderma is most commonly diagnosed through examination of the skin. Diagnostic tests include, but are not limited to, visual and / or manual examination of the skin, blood pressure testing, chest X-ray, lung CT scan, echocardiography, urinalysis, skin biopsy, and blood tests, including antinuclear antibody tests, anti-topoisomerase antibody tests, anticentromere antibody tests, anti-U3 antibody tests, anti-RNA antibody tests, other types of antibody tests, erythrocyte sedimentation rate, and rheumatoid factor. Currently, there is no known cure for scleroderma. Treatments administered aim to address the symptoms of the disease. Treatments include angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, COX-2 inhibitors, analgesics, low-dose corticosteroids, anesthetics, antacids, H2 blockers, proton pump inhibitors, prokinetic agents, somatostatin agonists, antibiotics, prostaglandin derivatives, treprostol, iloprost, endothelin receptor antagonists, IP receptor agonists, phosphodiesterase type 5 (PDE5) inhibitors, antifibrotic agents, tyrosine kinase inhibitors, immunosuppressants, alkylating agents, pilucarpine, and combinations thereof.

[0252] In some embodiments, the provided composition for treating and / or preventing scleroderma is formulated as a suspension.

[0253] In some embodiments, the provided compositions for treating and / or preventing scleroderma are formulated as suspensions, foams, creams, lotions, gels, shampoos, conditioners, ointments, emollients, balms, pastes, etc.

[0254] In some embodiments, the provided composition for treating and / or preventing scleroderma is applied topically to the affected area (e.g., scalp, hair follicles, face, neck, back, arms, chest, etc.).

[0255] In some implementations, the application is achieved through whole-body delivery. In other implementations, the application is achieved through local delivery.

[0256] In some embodiments, this disclosure relates to the application of a suspension containing at least one therapeutic agent (e.g., a PAI-1 inhibitor) in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 30%; and in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma by at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 4 ...5%, about 36%, about 37%, about 38%, 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%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0257] In some embodiments, this disclosure relates to the application of a nanoparticle composition, or nanoemulsion composition, or emulsion composition, or foaming agent formulation, or cream formulation, or oil, or lotion formulation, or gel, or shampoo, or conditioner containing at least one therapeutic agent (e.g., a PAI-1 inhibitor), in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma of at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma of at least about 30%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of scleroderma of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, or about [missing information]. 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%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0258] Reynolds phenomenon In some embodiments, the compositions and methods described herein can be used to treat and / or prevent Raynaud's phenomenon.

[0259] Raynaud's phenomenon, or Raynaud's disease, is a condition characterized by vasospasm in the fingers and toes. It typically responds to cold or emotional stress, manifesting as discoloration of the skin in the fingers (white, blue, and / or red, usually in this order) and pain. Severe Raynaud's disease can lead to skin necrosis and eventually necrosis of the fingers and / or toes, resulting in "auto-amputation." Nails may also become brittle in patients with Raynaud's disease. This condition is often associated with connective tissue diseases such as scleroderma and / or rheumatoid arthritis.

[0260] The pharmaceutical compositions according to this disclosure can be administered alone and / or in combination with other agents for treating the symptoms and / or causes of Raynaud's phenomenon for the treatment of Raynaud's phenomenon. In some embodiments, such agents include calcium channel blockers (e.g., nifedipine). wait Alpha-blockers (e.g., hydralazine) wait), nitroglycerin, and angiotensin II receptor antagonists (e.g., losartan). wait Selective serotonin reuptake inhibitors (e.g., fluoxetine) wait ), trinitroglycerin, tadalafil, ginkgo Extracts, SLx-2101, St. John's wort, fasudil, cilostazol, iloprost, relaxin, treprostacyclin diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostacyclin diethanolamine and / or combinations thereof.

[0261] In some embodiments, the provided composition for treating and / or preventing Raynaud's disease is formulated as a suspension.

[0262] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of Raynaud's disease are formulated as suspensions, foams, creams, lotions, washes, gels, shampoos, conditioners, ointments, emollients, balms, pastes, etc.

[0263] In some embodiments, the compositions disclosed herein for the treatment and / or prevention of Raynaud's disease are applied topically to the affected area (e.g., nose, lips, ears, nipples, fingers, toes, scalp, face, neck, back, arms, chest, etc.).

[0264] In some implementations, the application is achieved through whole-body delivery. In other implementations, the application is achieved through local delivery.

[0265] In some embodiments, this disclosure relates to administering a suspension containing at least one therapeutic agent (e.g., a PAI-1 inhibitor) in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon of at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon of at least about 30%; and in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon 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%, or 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%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0266] In some embodiments, this disclosure relates to the application of a nanoparticle composition, or nanoemulsion composition, or emulsion composition, or foaming formulation, or cream formulation, or oil, or lotion formulation, or gel, or shampoo, or conditioner containing at least one therapeutic agent (e.g., a PAI-1 inhibitor), in an amount sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon of at least about 25%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon of at least about 30%; in some embodiments, the amount is sufficient to achieve a reduction in the severity and / or prevalence of one or more symptoms of Raynaud's phenomenon of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, or about 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%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90% or more.

[0267] Example Example 1: Formulation of an improved composition containing a PAI-1 inhibitor This embodiment describes the formulation of a composition comprising and / or delivering a PAI-1 inhibitor for local application according to one embodiment of the present disclosure. In some embodiments, the composition comprising and / or delivering the PAI-1 inhibitor as described herein is an improved composition relative to the original composition comprising and / or delivering the PAI-1 inhibitor.

[0268] The original composition containing and / or delivering a PAI-1 inhibitor is formulated as an ethanol-based composition. For example, an original composition containing a PAI-1 inhibitor is formulated according to the formulations in Table 2.

[0269] Table 2

[0270] In particular, the insights of this disclosure indicate that the active agent in ethanol-based compositions containing and / or delivering PAI-1 inhibitors can settle to the bottom of the container over time. That is, this disclosure identifies the source of the problem with such ethanol-based compositions. This disclosure specifically provides, for example, PAI-1 inhibitor compositions having reduced ethanol content relative to a suitable reference composition (e.g., the original composition described herein). When compared to a suitable reference composition (e.g., the original composition described herein) (e.g., an ethanol-based composition containing a PAI-1 inhibitor), such PAI-1 inhibitor compositions with reduced ethanol are found to prevent the PAI-1 inhibitor from settling over time.

[0271] The composition containing and / or delivering a PAI-1 inhibitor is reformulated to prevent the active agent from settling to the bottom of the container. An improved composition containing and / or delivering a PAI-1 inhibitor is formulated, containing less ethanol than a suitable reference composition containing and / or delivering the same PAI-1 inhibitor (e.g., the original composition as described herein). In some embodiments, the provided composition is substantially ethanol-free.

[0272] Alternatively or additionally, in some embodiments, the provided composition contains more water than such reference (e.g., original) compositions containing and / or delivering the relevant PAI-1 inhibitor. In some embodiments, the provided composition contains about 50% or more (e.g., about 50% to about 60% or about 50% to about 55%) of water.

[0273] Alternatively or additionally, in some embodiments, the provided composition comprising and / or delivering a PAI-1 inhibitor as described herein (e.g., as presented in Table 3, for example) is substantially free of sorbitol.

[0274] In some embodiments, the provided composition contains about 50% or more (e.g., about 50% to about 60% or about 50% to about 55%) water and is substantially free of ethanol.

[0275] In some embodiments, the provided composition contains about 50% or more (e.g., about 50% to about 60% or about 50% to about 55%) water and is substantially free of ethanol and sorbitol.

[0276] Table 3 illustrates specific improvements in compositions that contain and / or deliver a PAI-1 inhibitor according to this disclosure.

[0277] Table 3

[0278] Therefore, this embodiment describes the formulation of a substantially ethanol-free (ETOH) composition for topical application containing and / or delivering a PAI-1 inhibitor.

[0279] Example 2: Topical formulations containing PAI-1 inhibitors showed improved skin penetration. This embodiment demonstrates surprising results, namely that an improved composition containing and / or delivering a substantially ethanol-free PAI-1 inhibitor formulated for topical application exhibits improved skin penetration compared to an ethanol-based composition containing and / or delivering an ethanol-based composition containing and / or delivering an ethanol-based composition formulated for topical application of a PAI-1 inhibitor.

[0280] According to standard procedures, the local penetration properties of the original and novel compositions described herein were tested using a Franz pool diffusion chamber with human skin. To effectively compare the original and novel compositions (as described, for example, in Example 1), each composition was newly prepared with the same concentration of PAI-1 inhibitor prior to testing. Each composition was completely suspended at the time of testing. Surprisingly, 24 hours after application to the skin surface, the novel composition exhibited approximately 2.5 times (p=0.0003) greater skin penetration than the original composition. Figure 1 As shown. This result was achieved through a newly manufactured, fully suspended composition, although the formulation was changed from the original composition to a new composition, including the removal of ethanol (a known skin penetration enhancer) and the replacement of ethanol with water (not a skin penetration enhancer).

[0281] In some embodiments, a smaller amount of active ingredient can be used in the new composition to achieve a comparable therapeutic effect compared to the original composition.

[0282] Therefore, this embodiment demonstrates that, compared to ethanol-based compositions that contain and / or deliver a PAI-1 inhibitor, a composition that contains and / or delivers a PAI-1 inhibitor and is formulated for topical application to a subject's site (the composition is substantially ethanol-free) achieves greater skin penetration.

[0283] Equivalent solution Those skilled in the art will recognize, or can ascertain by conventional experimentation, many equivalent embodiments of the invention described herein. The scope of this disclosure is not intended to be limited to the foregoing description, but rather as set forth in the appended claims.

Claims

1. A composition comprising or delivering a PAI-1 inhibitor and formulated for topical application to a subject site, said composition being substantially free of ETOH.

2. The composition of claim 1, wherein the site is skin.

3. The composition of claim 2, wherein the region contains or actually contains a plurality of hair follicles.

4. The composition of claim 3, wherein each hair follicle optionally includes a hair disposed therein.

5. The composition of claim 1, wherein the composition is substantially free of all alcohols.

6. The composition of claim 1, wherein the composition is substantially free of sorbitol.

7. The composition of claim 1, wherein no more than 35% by weight of the composition comprises a penetration enhancer.

8. The composition of claim 7, wherein the penetration enhancer is one or more of glycerol, isopropyl myristate, and / or propylene glycol.

9. The composition of claim 8, wherein the composition comprises more than 1% but not more than 15% of glycerol by weight of the composition.

10. The composition of claim 9, wherein the composition comprises 10% by weight of glycerol.

11. The composition of claim 8, wherein the composition comprises propylene glycol in an amount greater than 1% but not more than 15% by weight of the composition.

12. The composition of claim 11, wherein the composition comprises 10% by weight of propylene glycol.

13. The composition of claim 8, wherein the composition comprises less than 15% by weight of isopropyl myristate.

14. The composition of claim 13, wherein the composition comprises greater than 1% but not more than 15% by weight of the composition, of isopropyl myristate.

15. The composition of claim 14, wherein the composition comprises 10% by weight of isopropyl myristate.

16. The composition of claim 1, wherein the composition comprises more than 1% but not more than 3% by weight of the composition of stearyl alcohol polyether 20.

17. The composition of claim 16, wherein the composition comprises 2% stearyl alcohol polyether 20 by weight of the composition.

18. The composition of claim 1, wherein the composition comprises more than 1% but not more than 6% of Tween 80 by weight of the composition.

19. The composition of claim 18, wherein the composition comprises 3.5% by weight of Tween 80.

20. The composition of claim 1, wherein the composition comprises propylparaben in an amount greater than 0.05% but not more than 0.15% by weight of the composition.

21. The composition of claim 20, wherein the composition comprises 0.10% by weight of propylparaben.

22. The composition of claim 1, wherein the composition comprises more than 0.05% but not more than 0.15% by weight of the composition of butylated hydroxytoluene.

23. The composition of claim 22, wherein the composition comprises 0.10% by weight of butylated hydroxytoluene.

24. The composition of claim 1, wherein the composition comprises water in an amount greater than 15% but not more than 70% by weight of the composition.

25. The composition of claim 24, wherein the composition comprises water in an amount not exceeding 54% by weight of the composition.

26. The composition of claim 1, wherein the composition comprises xanthan gum.

27. The composition of claim 26, wherein the composition comprises xanthan gum in an amount greater than 0.1% but not more than 0.3% by weight of the composition.

28. The composition of claim 27, wherein the composition comprises 0.2% xanthan gum by weight of the composition.

29. The composition of claim 1, wherein the composition comprises methylparaben in an amount greater than 0.1% but not more than 0.3% by weight of the composition.

30. The composition of claim 29, wherein the composition comprises methylparaben in an amount of 0.2% by weight of the composition.

31. The composition of claim 1, wherein the composition comprises disodium edetate.

32. The composition of claim 31, wherein the composition comprises more than 0.01% but not more than 0.1% of disodium edetate by weight of the composition.

33. The composition of claim 32, wherein the composition comprises 0.05% by weight of disodium edetate.

34. The composition of claim 1, wherein the PAI-1 inhibitor is selected from the group consisting of: peptides, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, fragments of therapeutic antibodies, and combinations thereof.

35. The composition of claim 1, wherein the PAI-1 inhibitor is a 2-aminobenzoic acid analog.

36. The composition of claim 1, wherein the PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.

37. The composition of claim 1, wherein the PAI-1 inhibitor is a compound of formula (1). Equation (1) in, R1 and R2 may be the same or different, and each represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocycloalkyl, heterocycloalkoxy, aryl group optionally having one or two substituents, 5- to 6-membered cycloheteroaryl group optionally having one or two substituents, or benzofused heteroaryl, amino, or carbamoyl group optionally having one or two substituents, each of which is optionally substituted by one or two substituents, or cyano, carboxyl, or alkoxycarbonyl; and R1 and R2 are optionally linked to each other to form a ring; R3 is hydrogen, alkyl, cycloalkyl, or optionally aryl with one or two substituents; X is -C(R5)=C(R6)-, -C(R7)N- or -N=C(R8)-, where R5, R6, R7 and R8 each represent hydrogen, halogen, alkyl group having one or two substituents, or alkoxy group; L is an alkylene group (some carbon atoms in the alkylene group optionally form a cycloalkyl ring), alkenyl, ynylene, cycloalkylene, alkyloxyalkylene, alkylthioalkylene, alkylene-SO-alkylene, or alkylene-SO2-alkylene, each of which is optionally substituted with one or two substituents, or alkylene-N(R9)-alkylene group optionally substituted with one or two substituents, wherein R9 represents hydrogen or an alkyl group optionally having one or two substituents; p represents an integer that is either 0 or 1; A is a group represented by any one of the following formulas (2), (3) or (4): Equation (2) in, R 10 and R 11 They may be the same or different, and each represents hydrogen or a straight-chain or branched alkyl group; and m represents an integer from 0 to 10. Equation (3) in, R 12 and R 13 The same or different, and each represents hydrogen, halogen, or optionally an alkyl group having one or two substituents, a cycloalkyl group having one or two substituents, or an alkoxy group having one or two substituents; Y represents CH or nitrogen; Z represents CH2, oxygen, or N-alkyl; n represents an integer from 0 to 3; U represents an alkylene group; and t represents an integer that is either 0 or 1. Equation (4) in, R 14 and R 15 The same or different, and each represents hydrogen, halogen, or optionally an alkyl group having one or two substituents, a cycloalkyl group having one or two substituents, or an alkoxy group having one or two substituents; V is alkylene, alkyleneoxyalkylene, oxyalkylene, alkyleneoxy, or oxygen; q represents an integer that is either 0 or 1; U and t are as defined above; and Ar represents an aryl group having one or two substituents (the one or two substituents optionally forming a ring with a portion of the carbon atoms in the aryl group), a 5- to 6-membered cyclic aryl group having one or two identical or different heteroatoms and optionally having one or two substituents, or a benzofused heteroaryl group optionally having one to three substituents; and B indicates COOR 16 , where R 16 To indicate hydrogen, alkyl, aryl, or aralkyl, it is formed by CH(R) 17 )O----COR 18 Or ----CH(R) 17 )---O---CO---OR 18 The group represented, where R 17 It is hydrogen or alkyl, and R 18 It is an alkyl or cycloalkyl group; a (5-alkyl-2-oxo-1,3-dioxapentane-4-yl)methyl group represented by the following formula (5): Equation (5) Wherein, R' represents an alkyl or heterocyclic group: 1H-tetrazole-5-yl group, 4,5-dihydro-5-oxo-4H-1,2,4-oxadiazole-3-yl group, 4,5-dihydro-5-thio-4H-1,2,4-oxadiazole-3-yl group, or 4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl group represented by the following formulas (6), (7), (8) (from left to right), and (9) (bottom): Equations (6), (7), (8) (from left to right), (9) (bottom).

38. The composition of claim 1, wherein the PAI-1 inhibitor is a compound of formula (10). Equation (10) in, R1 and R2 may be the same or different, and each represents hydrogen, halogen, alkyl or optionally aryl with one or two substituents; R3 is hydrogen or alkyl; R 14 and R 15 They may be the same or different, and each represents hydrogen, alkyl, or halogen; V is an alkylene, oxyalkylene, or oxygen; Ar is an aryl group that optionally has one or two substituents, an aryl group that optionally has one or two substituents and has one or two identical or different heteroatoms, or a benzofused heteroaryl group that optionally has one or three substituents. L represents alkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene, and alkylene-SO2-alkylene; and q, U, t, p, and B are as defined in claim 37.

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

40. The composition of claim 39, wherein the PAI-1 inhibitor is 5-chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]aminobenzoic acid.

41. The composition of claim 1, wherein the PAI-1 inhibitor is delivered in an amount sufficient to reduce the graying of one or more hairs.

42. The composition of claim 1, wherein the PAI-1 inhibitor is delivered in an amount sufficient to treat a dermatological condition.

43. The composition of claim 1, wherein the PAI-1 inhibitor is delivered in an amount sufficient to treat non-dermatological conditions.

44. The composition of claim 43, wherein the non-dermatological condition is pulmonary fibrosis, lung cancer, chronic myeloid leukemia, metabolic syndrome, diabetes, thrombosis, obesity, renal fibrosis, liver fibrosis, cardiac fibrosis, or atherosclerosis.

45. The composition of claim 1, wherein the composition is characterized in that, when applied to an animal containing one or more gray-white hairs, it achieves at least one of the following: (i) Reduce the number of gray hairs; (ii) Restore the color of the one or more gray hairs; (iii) To prevent one or more non-gray hairs from turning gray; and (iv) Delay the onset of the graying of one or more non-gray hairs.

46. ​​The composition of claim 1, wherein the composition is characterized in that, when applied to an animal containing one or more hairs, it achieves at least one of the following: (i) Reduce hair loss; (ii) Prevent hair loss; (iii) Delaying the onset of hair loss of one or more of the aforementioned hairs; and (iv) Increase the amount of hair on the area.

47. A method for treating or preventing hair from turning gray, the method comprising: Provide the composition as claimed in claim 1; The composition is applied to a site on a subject, wherein the site contains or actually contains a plurality of hair follicles, each hair follicle having a hair disposed therein, such that the PAI-1 inhibitor is delivered to the subject.

48. A method for treating or preventing hair loss, the method comprising: Provide the composition as claimed in claim 1; The composition is applied to a subject, wherein the subject's site contains or actually contains a plurality of hair follicles, each hair follicle having a hair disposed therein, such that the PAI-1 inhibitor is delivered to the subject.

49. A method for treating or preventing dermatological conditions, the method comprising: Provide the composition as claimed in claim 1; The composition is applied to a subject, wherein the subject's site contains or actually contains a plurality of hair follicles, each hair follicle having a hair disposed therein, such that the PAI-1 inhibitor is delivered to the subject.

50. The method of claims 47 to 49, wherein the hair is grayish-white.

51. The method of claims 47 to 49, wherein the hair is not grayish-white.

52. The method of claims 47 to 51, wherein the composition is applied in combination with microneedle skin conditioning (MSC) at the site.

53. The method of claim 52, wherein the MSC at the site is performed prior to the application of the composition.

54. The method of claim 52, wherein the MSC at the site is performed after the application of the composition.

55. The method of claim 52, wherein the application of the MSC and the composition at the site occurs substantially simultaneously.

56. The method of claim 52, further comprising administering multiple doses of the composition according to a dosing regimen, wherein at least two consecutive doses are spaced at least 12 hours apart from each other.

57. The method of claim 49, wherein the dermatological condition is keloid or scleroderma.

58. The method of claim 57, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group comprising: pressure therapy, silicone membranes, intralesional triamcinolone acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high-dose oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy, surgical resection, topical agents, and combinations thereof.

59. The method of claim 49, wherein the dermatological condition is scleroderma.

60. The method of claim 49, wherein the dermatological condition is systemic scleroderma.

61. The method of claim 49, wherein the dermatological condition is scleroderma.

62. The method of claim 59, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group comprising: 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, treprostacyclin, iloprost, endothelin receptor antagonists, IP receptor agonists, phosphodiesterase type 5 (PDE5) inhibitors, antifibrotic agents, tyrosine kinase inhibitors, immunosuppressants, alkylating agents, pilucarpine, and combinations thereof.

63. The method of claim 49, wherein the dermatological condition is Raynaud's phenomenon.

64. The method of claim 63, further comprising administering one or more other active agents, wherein the one or more other active agents are selected from the group consisting of: calcium channel blockers, alpha-blockers, nitroglycerin, angiotensin II receptor antagonists, selective serotonin reuptake inhibitors, trinitroglycerin, tadalafil, etc. ginkgo Extracts, SLx-2101, St. John's wort, fasudil, cilostazol, iloprost, relaxin, treprostacyclin diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostacyclin diethanolamine, and combinations thereof.

65. The method of claim 49, wherein the dermatological condition is or includes graying of hair.

66. The method of claim 65, further comprising applying one or more other active agents, wherein the one or more other active agents are selected from the group consisting of: cinnamamidopropyltrimethylammonium chloride, solid lipid nanoparticles, L-cysteine, L-methionine, melatonin, and combinations thereof.

67. The method of any of the preceding claims, wherein the application comprises maintaining the composition on the skin surface for a certain period of time.

68. The method of claim 67, further comprising removing the remaining composition from the site after the said time period.

69. The method as claimed in any of the preceding claims, wherein the step of applying the composition comprises massaging the composition into the site.

70. The method of claim 67, wherein the time period is at least 1 minute.

71. The method of claim 67, wherein the time period is at least 1 hour.

72. The method of claim 67, wherein the time period is in the range of 1 minute to 10 minutes.

73. The method of any of the preceding claims, wherein the composition is or comprises a suspension.

74. The method of any of the preceding claims, wherein the composition is or comprises a foaming agent.

75. The method of any of the preceding claims, wherein the composition comprises an emulsion.

76. The method of any of the preceding claims, wherein the emulsion is a nanoemulsion.

77. The method as described in any of the preceding claims, further comprising the step of administering an osmotic treatment.

78. The method of claim 77, wherein the permeation therapy is or includes a non-irritating chemical agent.

79. The method of claim 77, wherein the osmotic treatment is or includes the application of an electric field or a magnetic field.

80. The method of claim 77, wherein the penetration therapy is or includes microneedles.

81. The method of claim 77, wherein the penetration therapy is or includes laser therapy.

82. The method of any of the preceding claims, wherein the PAI-1 inhibitor penetrates the site within about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes of application.

83. The method of any of the preceding claims, wherein the PAI-1 inhibitor penetrates the site within about 5 minutes to about 60 minutes, about 5 minutes to about 12 minutes, about 5 minutes to about 15 minutes, or about 15 minutes to about 30 minutes of application.

84. The method of any of the preceding claims, wherein the PAI-1 inhibitor penetrates the site within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or 24 hours of application.

85. The method of any of the preceding claims, wherein the PAI-1 inhibitor penetrates the site within about 1 hour to about 12 hours, about 8 hours to about 12 hours, or 12 hours to about 24 hours after application.

86. The method as claimed in any of the preceding claims, comprising applying the composition more than once over time.

87. The method of claim 86, wherein the interval between each administration of the PAI-1 inhibitor is specified over a time period.

88. The composition of claim 1, for use in the treatment of dermatological conditions.

89. The composition of claim 1, for use in the treatment or prevention of graying of hair.

90. The composition of claim 1, for use in the treatment or prevention of hair loss.

91. The composition of claim 90, wherein the hair loss is androgenetic alopecia, alopecia areata, frontal fibrosis, and age-related hair loss.

92. Use of the composition of claim 1 in the manufacture of a medicament for treating graying of hair.

93. Use of the composition of claim 1 in the manufacture of a medicament for treating hair loss.

94. Use of the composition of claim 1 in the manufacture of a medicament for treating dermatological conditions.

95. The use as claimed in claim 94, wherein the dermatological condition is selected from scleroderma, keloids, Raynaud's phenomenon, or graying of hair.

96. A kit comprising the composition of claim 1 and instructions for applying the composition to the site.

97. The kit of claim 96, wherein the kit further comprises gloves.

98. A kit comprising the composition of claim 1 and a patch for covering the composition after application to the site.

99. A kit comprising the composition of claim 1, means for promoting penetration of the composition into a site on a subject, and instructions for applying the composition to the site.

100. The kit of claim 98, wherein the device comprises a plurality of needles.

101. The kit of claim 99, wherein the device is a patch, roller, impression, or pen.

102. The compositions of claims 1 to 46 and 87 to 91, wherein the compositions are formulated as lotions, serums, suspensions, creams, powders, ointments, liniments, gels, drops, emollients, balms, or pastes.

103. The method of claims 47 to 87, wherein the composition is formulated as a lotion, serum, suspension, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

104. The use as described in claims 92 to 95, wherein the composition is formulated as a lotion, serum, suspension, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

105. The kit according to claims 96 to 101, wherein the composition is formulated as a lotion, serum, suspension, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

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