Topical compositions and regimens

Abstract

The present disclosures provides new technologies for treatment and / or prevention of certain dermatological conditions, specifically including hair loss and hair graying. Among other things, the present disclosure provides an insight that topical compositions comprising plasminogen activator inhibitor -1 (PAI-1) inhibitors may be safe, effective, and efficient in the treatment and / or prevention of certain dermatological conditions, and in particular in treatment and / or prevention of hair loss and hair graying.

Description

Attorney Docket No. : 2012317-0366TOPICAL COMPOSITIONS AND REGIMENSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 740,276, filed December 30, 2024, the entire contents of which are hereby incorporated by reference in their entirety.BACKGROUND

[0002] Hair loss and hair graying often promote significant anxiety; many people go to great lengths to re-grow or darken their hair, particularly if hair loss or graying occurs prematurely. Previously available therapies have largely proven unsatisfactory, hence new treatment options are needed.SUMMARY

[0003] The present disclosure provides, inter alia, technologies (e.g., methods, kits, compositions, etc.) for treatment and / or prevention of certain types of dermatological conditions (e.g. hair loss, hair graying). Among other things, the present disclosure provides an insight that topical compositions and formulations comprising or delivering plasminogen activator inhibitor-1 (PAI-1) inhibitors (e.g. 5% w / w ET-02) may be particularly safe and useful in the treatment and / or prevention of alopecia (hair loss) and / or hair graying.Specifically, the present disclosure provides technologies (e.g., methods, kits, compositions, etc.) which in some embodiments, may be particularly safe and useful in the treatment and / or prevention of specific types of hair loss (or alopecia), including androgenetic alopecia (also called androgenic alopecia), alopecia areata, frontal fibrosing alopecia, and senescent alopecia than other treatment technologies. In some embodiments, the present disclosure provides technologies that achieve improvement(s) in hair loss independent of any impact on hair color (e.g., hair graying); in some such embodiments, hair may darken; in some such embodiments, hair may lighten; in some such embodiments, no significant impact on hair color may be observed.

[0004] Furthermore, the present disclosure provides an insight that technologies described herein may offer particular advantages including, for example, that they may beAttorney Docket No. : 2012317-0366more effective and / or result in fewer adverse effects than other technologies for treatment and / or prevention of alopecia and / or hair graying.

[0005] Hair loss and hair graying are common disorders, and significant investments have been made in developing treatments, yet conventional treatment strategies require frequent dosing, unpleasant side effects, and / or are plagued by limited efficacy.

[0006] For example, minoxidil is one of the most common hair loss treatments, used to treat types of baldness in both adult men and women. A typical dosing regimen for topical minoxidil is twice daily application, for several months. The Mayo clinic notes limitations of minoxidil efficacy, stating, “If hair growth is going to occur with the use of minoxidil, it usually occurs after the medicine has been used for several months and lasts only as long as the medicine continues to be used.” (mayoclinic.org / drugs-supplements / minoxidil-topical-route / description / drg-20068750). Per its product label, topical minoxidil must be applied to the scalp twice daily. Thus even the most reputable treatment centers lament that existing hair loss treatments require dosing regimens with frequent application, over several months, for effective results. The present disclosure demonstrates, among other things, a surprising result that topical PAI-1 inhibitor compositions and formulations (e.g. 5% w / w ET-02) can achieve comparable results to minoxidil in a much shorter time period (e.g. 5 weeks), with a less frequent dosing regimen (e.g. fewer than two applications a day). This result has advantages for the patient because the treatment is more convenient, not requiring twice a day treatment applications, and is more cost-effective to manufacture and / or purchase than treatments requiring twice a day applications.

[0007] Those skilled in the art will further appreciate the desire to minimize unpleasant side effects of therapeutic agents. Existing hair loss treatments can have numerous unpleasant side effects, including but not limited to itching or skin rash, acne at site of application, burning of scalp, facial hair growth, increased hair loss, inflammation or soreness at root of hair, reddened skin, and swelling of the face (see mayoclinic.org / drugs-supplements / minoxidil-topical-route / description / drg-20068750). Furthermore, overabsorption of minoxidil in the body can result in chest pain, dizziness, fast or irregular heartbeat, headache, and weight gain, among many other effects (see mayoclinic.org / drugs-supplements / minoxidil-topical-route / description / drg-20068750). A recent study by Shadi found that 13.8% of patients treated with topical minoxidil experienced itching, 12.3% experienced facial hair growth, 5% experienced headache, and 0.5% experienced dizzinessAttorney Docket No. : 2012317-0366(Compliance to Topical Minoxidil and Reasons for Discontinuation among Patients with Androgenetic Alopecia. Dermatol Ther (Heidelb) 13, 2023, 1157-1169). Thus, prior to the present disclosure, hair loss treatments were demonstrated to have widespread negative side effects. The present disclosure, among other things, surprisingly demonstrates that topical PAI-1 inhibitor compositions and formulations (e.g. 5% w / w ET-02) can achieve hair-regrowth when applied only once per day. Furthermore, the present disclosure surprisingly demonstrates that topical PAI-1 inhibitor compositions and formulations (e.g. 5% w / w ET-02) can achieve hair-regrowth while giving rise to a reduced (relative to minoxidil) level of -e.g., few or no - adverse events related to the PAI-1 inhibitor in a population. In addition, the present disclosure surprisingly demonstrates that topical PAI-1 inhibitor compositions and formulations (e.g. 5% w / w ET-02) can achieve hair-regrowth while giving rise to a reduced (relative to minoxidil) level of - e.g., few or no - instances of skin irritation in a population.

[0008] In addition, one skilled in the art appreciates that in addition to increased hair growth and hair count, increased hair thickness is a desirable outcome in the treatment of hair loss, as increased hair thickness increases hair strength and results in a more desirable physical appearance. Existing hair loss treatments are associated with increased hair thickness. For example, as Tosti and Piraccini note when discussing finasteride: “The prolongation of anagen induced by the drug results in progressive thickening and elongation of miniaturized and intermediate hair. This effect explains why patients continue to experience improvement of the appearance of the hair even if the hair count remains stable.” (Finasteride and the hair cycle, Journal of the American Academy of Dermatology, 42(5) 2000, 848-849). Such a teaching suggests that although existing hair loss treatments are associated with increased hair thickness, prior to the present disclosure, it was unknown if this desirable outcome could occur as a result of other hair loss treatments, with different mechanisms of action. The present disclosure, among other things, surprisingly demonstrates that, despite a different mechanism of action than existing hair loss treatments, topical compositions or formulations comprising and / or delivering a PAI-1 inhibitor (e.g. 5% w / w ET-02) increase hair thickness, a desirable outcome in the treatment and / or prevention of hair loss.

[0009] Furthermore, those skilled in the art appreciate that subjects suffering from hair loss likely desire re-growth of hair that is not gray. However, existing hair loss treatments have been linked to hair graying. For example, a study by Alhayaza et al.Attorney Docket No. : 2012317-0366(Dermatol Reports. Topical minoxidil reported hair discoloration: a cross-sectional study, 2023 Aug 10; 16(1):9745) reports that “51.13% of enrolled patients experienced hair changes while they were on topical minoxidil course” and further finds that “42.1% of the physicians noticed graying of hair on their patients after using minoxidil.” Thus, prior to the present disclosure, an existing hair loss treatment was linked to hair graying, an undesirable result of hair loss treatments. The present disclosure surprisingly demonstrates that topical PAI-1 inhibitor compositions and formulations (e.g., 5% w / w ET-02) can treat and / or prevent hair loss without triggering hair graying; even more surprisingly, such treatment and / or prevention of hair loss can even occur concomitant with increased hair darkness score (i.e., the desired opposite of graying).

[0010] Those skilled in the art are aware that, like hair loss, hair graying is an undesirable condition. However, existing treatments for hair graying, such as permanent hair dyes, “can cause irritation of the scalp, allergic reactions, and damage to the hair shaft” (Yale et al., Medication-Induced Repigmentation of Gray Hair: A Systematic Review, Skin Appendage Disord. 2019 Dec 17;6(1): 1— 10.) Less aggressive treatments for hair graying, for example, semi -permanent hair dyes, require consistent maintenance. Beyond the aforementioned permanent and semi-permanent hair dyes, prior to the present disclosure there was no effective treatment available for hair re-pigmentation. The present disclosure surprisingly demonstrates that topical compositions and formulations comprising a PALI inhibitor (e.g. 5% w / w ET-02) can treat and / or prevent hair graying, with a reduction (relative to one or more other treatments), and even elimination, of one or more unpleasant or undesired side effects and / or a reduction (relative to one or more other treatments), and even elimination of one or more onerous maintenance features.

[0011] The provided compositions and formulations described in the present disclosure demonstrate such surprising effects that it may be reasonable to conclude that the benefits described herein (e.g. increased hair count, increased hair thickness, increased hair darkness score, less frequent dosing regimen, no adverse effects due to the provided composition or formulation...) could also be achieved with non-topical regimens of compositions or formulations comprising or delivering a PAI-1 inhibitor, for example, oral administration of a composition or formulation that comprises or delivers a PALI inhibitor, and / or injection of a composition or formulation that comprises or delivers a PALI inhibitor.Attorney Docket No. : 2012317-0366

[0012] Those skilled in the art are aware that over-expression of PAI- 1 is associated with the prevention of the conversion of plasminogen to plasmin which is essential to fibrinolysis, which is the physiological breakdown of blood clots. The present disclosure provides a surprising insight that topical application of compositions comprising PAI-1 inhibitors (e.g. 5% w / w ET-02) may be particularly effective in treating and / or preventing hair loss and / or hair graying. The present disclosure is particularly surprising, given that PAI-1 inhibitors have a different mechanism of action than other treatments of hair loss and / or hair graying. The present disclosure provides a surprising insight that provided new technologies (e.g., methods, kits, compositions, etc.) are effective for treatment and / or prevention of certain types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, and / or hair graying. Furthermore, in some embodiments, the present disclosure provides a surprising insight that provided new technologies utilizing a PAI-1 inhibitor (e.g. 5% w / w ET-02) may be effective for hair regrowth and / or increase hair thickness in subjects who have androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.

[0013] In some embodiments, the present disclosure provides methods of treating a subject comprising providing a composition that comprises or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor (e.g. ET-02); administering the composition to a site of the subject, wherein the site contains or did contain a plurality of hair follicles, each hair follicle optionally comprising a hair disposed therein, so that the PAI-1 inhibitor is delivered to the subject, wherein the subject is suffering from one or more treatable conditions, and wherein the one or more treatable conditions is / are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.

[0014] In some embodiments, the present disclosure provides methods of treating a subject comprising providing a composition that comprises or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor (e.g. ET-02); topically administering the composition to a subject, wherein a site of the subject contains or did contain a plurality of hair follicles, each hair follicle optionally comprising a hair disposed therein, so that the PAI-1 inhibitor is delivered to the subject, wherein the subject is suffering from one or more treatable conditions, and wherein the one or more treatable conditions is / are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.Attorney Docket No. : 2012317-0366

[0015] In some embodiments, the present disclosure provides methods of preventing the occurrence or progression of one or more conditions in a subject comprising (a) providing a composition that comprises or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor (e.g. 5% w / w ET-02); (b) administering the composition topically to a site of the subject, wherein the site is a skin surface that contains or contained a plurality of hair follicles, each optionally comprising a hair disposed therein, wherein the one or more conditions is / are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia senescent alopecia, and combinations thereof; and (c) leaving the composition on the site for a period of time, so that the PAI-1 inhibitor is delivered to the subject.

[0016] In some embodiments, the present disclosure provides methods of hair regrowth in a subject comprising providing a composition that comprises or delivers a plasminogen activator inhibitor-1 (PAI-1) inhibitor (e.g. 5% w / w ET-02); administering the composition to a site of the subject, wherein the site contains or did contain a plurality of hair follicles, each hair follicle optionally may or may not be active, so that the PAI-1 inhibitor is delivered to the subject, wherein the subject is suffering from one or more treatable conditions, and wherein the one or more treatable conditions is / are selected from the group consisting of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia.

[0017] In some embodiments, the present disclosure provides new technologies for treating and / or preventing the occurrence or progression of certain types of alopecia and / or hair graying. In some embodiments, alopecia is or comprises androgenetic alopecia. In some embodiments, alopecia is or comprises alopecia areata. In some embodiments, alopecia is or comprises frontal fibrosing alopecia. In some embodiments, alopecia is or comprises senescent alopecia. In some embodiments, alopecia is not radiation-induced alopecia. In some embodiments, alopecia is not chemotherapy-induced alopecia. In some embodiments, alopecia is not alopecia due to chronic discoid lupus erythematosus.

[0018] In some embodiments, the present disclosure provides new technologies for hair re-growth in subjects with certain types of alopecia. In some embodiments, alopecia is or comprises androgenetic alopecia. In some embodiments, alopecia is or comprises alopecia areata. In some embodiments, alopecia is or comprises frontal fibrosing alopecia. In some embodiments, alopecia is or comprises senescent alopecia.Attorney Docket No. : 2012317-0366

[0019] In some embodiments, the present disclosure provides compositions and formulations that comprise and / or deliver a therapeutically effective amount of a PAI-1 inhibitor (e.g. ET-02). In certain embodiments, the present disclosure provides compositions that comprise and / or deliver a therapeutically effective amount of a PAI-1 inhibitor and a pharmaceutically acceptable carrier. In some embodiments, a therapeutically effective weight percentage of the PAI-1 inhibitor in the composition is about 2%, about 3%, about 4%, or about 5%.

[0020] In some embodiments, the present disclosure provides one or more dosing regimens for the treatment and / or prevention of hair loss and / or hair graying by topical application of a composition or formulation comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02). In some embodiments, such a composition or formulation is administered less frequently than twice a day, once a day, twice a week, or weekly. In some embodiments, such a composition or formulation is administered with treatment duration (i.e., a period of time during which treatment is administered) that is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or over 3 years.

[0021] In some embodiments, a provided composition or formulation e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve an increase in hair count. In some embodiments, a provided composition or formulation is administered to a population according to a regimen demonstrated to achieve an increase in hair count of at least 12% on average in the population. In some embodiments, a provided composition or formulation (e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve an increase in hair thickness. In some embodiments, a provided composition or formulation (e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve an increase in hair thickness of at least 9% on average in the population. In some embodiments, a provided composition or formulation (e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve an increase in hair darkness score. In some embodiments, a provided composition or formulation (e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve an increase in hair darkness score of at least 8% on average in the population.Attorney Docket No. : 2012317-0366

[0022] In some embodiments, a provided composition or formulation (e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve no adverse events in the population related to the composition or formulation. In some embodiments, a provided composition or formulation e.g. 5% w / w ET-02) is administered to a population according to a regimen demonstrated to achieve no instances of skin irritation in the population.

[0023] In some embodiments, a provided composition is characterized in that, when administered to an animal suffering from or susceptible to at least one of the disclosed types of alopecia, it achieves at least one of: (i) treatment of at least one type of alopecia in an animal; (ii) delay, retardation, or prevention of progression of at least one type of alopecia in an animal. In certain particular embodiments, for example when a type of alopecia is or comprises androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senescent alopecia and any combination thereof, a provided new composition may be characterized in that, when administered to an animal suffering from or susceptible to at least one type of alopecia as described herein, achieves at least one of: (i) an increase in the number of hairs (e.g., present at and / or near a site of administration); (ii) prevention of hair loss (alopecia) (e.g., present at and / or near a site of administration); (iii) a delayed onset of hair loss of one or more hairs (e.g., present at and / or near a site of administration); and (iv) an increase in the number of hair follicles.

[0024] In some embodiments, the present disclosure provides topical compositions and formulations comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) characterized in that, when administered to a subject suffering from or susceptible to hair graying, achieves at least one of: (i) a reduction in the number of gray hairs (e.g., present at and / or near a site of administration); (ii) prevention of graying of one or more non-gray hairs (e.g., present at and / or near a site of administration) and (iii) a delayed onset of graying of one or more nongray hairs (e.g., present at and / or near a site of administration).

[0025] In general, administration of a composition in accordance with the present disclosure may be by any of a variety of routes. In some preferred embodiments, administration is topical.

[0026] In some embodiments, administration achieves systemic delivery. In some embodiments, administration achieves local delivery.Attorney Docket No. : 2012317-0366

[0027] In some embodiments administration is or comprises maintaining a composition at or on a site for a period of time. In some embodiments administration is or comprises massaging a composition into a site.

[0028] In some embodiments, a composition is maintained at or on a site for a period of time that is at least 1 minute. In some embodiments, a period of time is at least 1 hour. In some embodiments, a period of time is within a range of 1 to 10 minutes. In some embodiments, a period of time is within a range of about 1 to about 10 minutes, about 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes, about 1 to about 12 hours, about 8 to about 12 hours or 12 hours to about 24 hours.

[0029] In some embodiments, provided methods of treating a certain type of alopecia may include, removing administered composition (e.g., removing composition that may remain after a period of time) from its site of administration. In some embodiments, such removing is or comprises rinsing or wiping (e.g., using a wipe that, in some embodiments may be wet or, in some embodiments, may be dry).

[0030] In some embodiments, a site to which a composition is administered in accordance with the present disclosure may be on a skin surface. In some embodiments, a site is or comprises hair follicles. In some embodiments a site comprises hair. In some embodiments a site is or comprises skin overlying a muscle or muscle group. In some embodiments a site is hairless. In some embodiments a site is on the torso. In some embodiment a site is on the back. In some embodiments a site is on the chest. In some embodiments a site is on the buttocks. In some embodiments a site is on the crotch. In some embodiments a site is on the groin. In some embodiments a site is on the head. In some embodiments a site is on the scalp. In some embodiments a site is on the face. In some embodiments the site is on the neck. In some embodiments a site is on the decollete. In some embodiments a site is in the armpit. In some embodiments a site is on the axillae. In some embodiments a site is on the hands. In some embodiments a site is on the feet. In some embodiments a site is on the arms. In some embodiments a site is on the legs. In some embodiments a site formerly had hair or hair follicles but no longer has hair or hair follicles. In some embodiments, a site has hair follicles. In some embodiments, hair follicles present at a site have normal structure and / or density. In some embodiments, a site has hair; in some embodiments, such hair is gray but in some embodiments such hair is not gray.Attorney Docket No. : 2012317-0366

[0031] In some embodiments, a PAI-1 inhibitor is selected from a group consisting of: polypeptides, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, fragments of therapeutic antibodies, and / or combinations thereof. In some embodiments, a PAI-1 inhibitor is a 2-aminobenzoic acid analog. In some embodiments, a PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.

[0032] In some embodiments, a PAI-1 inhibitor for use in accordance with the present disclosure is or comprises 5-Chloro-2-{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid (ET-02).

[0033] In some embodiments, the present disclosure provides and / or utilizes a composition that comprises and / or delivers a PAI-1 inhibitor (e.g. 5% w / w ET-02). In some embodiments, such a composition is or comprises a suspension. In some embodiments, such a composition is or comprises a foam. In some embodiments, such a composition is or comprises an emulsion, e.g., a nanoemulsion. In some embodiments, such a composition is formulated as a suspension, a foam, a lotion, a cream, a gel, an oil, a powder, a liniment, or drops.

[0034] In some embodiments, provided methods of treating certain types of alopecia comprises a step of administering a penetrating treatment. In some embodiments, a penetrating treatment is or comprises a non-irritating chemical agent. In some embodiments, a penetrating treatment is or comprises administration of an electric or magnetic field. In some embodiments, a penetrating treatment is or comprises microneedling. In some embodiments, a penetrating treatment is or comprises laser treatment.

[0035] In some embodiments, provided technologies aide in PAI-1 inhibitor penetration of site of administration. In some embodiments, a provided PAI-1 inhibitor (e.g., in or from a composition as described herein) penetrates its site of administration within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a provided PAI-1 inhibitor penetrates site of administration within about 1 to about 10 minutes, 5 to about 60 minutes, about 5 to about 12 minutes, about 5 to about 15 minutes, or about 15 to about 30 minutes of administration. In some embodiments, a provided PAI-1 inhibitor penetrates site of administration within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 24 hours of administration. In some embodiments, a provided PAI-1 inhibitor penetrates site of administration within about 1 to about 12 hours, about 8 to about 12 hours or 12 hours to about 24 hours of administration.Attorney Docket No. : 2012317-0366

[0036] In some embodiments, according to the present disclosure, methods of treatment and / or prevention of certain types of alopecia comprises two or more administrations of a PAI-1 inhibitor composition overtime. In some embodiments, administration of two or more administrations of a composition is separated by a specified period of time. In some embodiments, according to the present disclosure, a specified period of time for administering a composition may be longer than a specified period of time for administering a reference treatment regimen.

[0037] Disclosed herein, in certain embodiments, are kits comprising compositions that comprise or deliver a PAI-1 inhibitor (e.g., ET-02).

[0038] In some embodiments, provided kits comprise a patch. In some embodiments, a patch is arranged, constructed, and / or utilized for administration to cover an administered composition. Alternatively or additionally, in some embodiments, a patch may contain or comprise a composition that comprises and / or delivers a PAI-1 inhibitor. In some embodiments, a patch comprises microneedles.

[0039] In some embodiments, provided kits comprise a device for application of a composition to a site on a subject. In some embodiments, the device may be a bottle with a dropper attachment.

[0040] In some embodiments, provided kits comprise a device for facilitating penetration of a composition into a site on a subject. In some such embodiments, a provided device may be or comprises a brush, a comb, patch, a roller, a pen, etc.

[0041] In some embodiments, provided kits comprise instructions for administering a composition as described herein. In some embodiments, the present disclosure provides insight into administering combination therapy and / or treatment to treat or prevent the occurrence of a certain type of alopecia (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senescent alopecia, etc.). In some embodiments, the combination therapy or treatment, comprises administering a PAI-1 inhibitor as described herein in combination with one or more other active agents. In some embodiments, for example certain types of alopecia (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senescent alopecia, etc.) one or more other active agents, wherein the one or more other active agents is selected from the group comprising of minoxidil, finasteride, dutasteride, platelet-rich plasma, cinnamidopropyltrimonium chloride, solid lipid nanoparticles, 1-cystine, 1-methionine, melatonin, pressure therapy, silicone gel sheeting, intra-lesional triamcinoloneAttorney Docket No. : 2012317-0366acetonide (TAC), cryosurgery, radiation, laser therapy, IFN, 5-FU, high doses of oxygen using hyperbaric oxygen therapy (HBOT), cryotherapy, surgical excision, topical agents, Angiotensin II Receptor Antagonists, Angiotensin Converting Enzyme (ACE) Inhibitors, NS AIDs, COX-2 Inhibitors, Analgesics, Low-Dose Corticosteroids, Narcotics, Antacids, H2 Blockers, Proton Pump Inhibitors, Prokinetic Agents, Somatostatin Agonist, Antibiotics, Prostaglandin Derivatives, Treprostinil, Iloprost, Endothelin Receptor Antagonists, IP Receptor Agonist, Phosphosdiesterase type 5 (PDE5) inhibitors, Anti-Fibrotic Agent, Tyrosine Kinase Inhibitor, Immunosuppressants, Alkylating agents, Pilocarpine, and combinations thereof. In some embodiments, for example for Raynaud’s disease or Raynaud’s phenomenon, one or more other active agents is selected from the group comprising of calcium channel blockers, alpha blockers, nitroglycerin, angiotensin II receptor antagonists, selective serotonin reuptake inhibitors, glyceryl trinitrate, tadalafil, Ginkgo biloba extract, SLx-2101, St. John’s Wort, fasudil, cilostazol, iloprost, relaxin, treprostinil diethanolamine, sildenafil, atorvastatin, imatinib mesylate, treprostinil diethanolamine, and combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1 presents a bar graph comparing hair count change from baseline at 5 weeks in subjects treated topically with vehicle or 1.25% ET-02 and 5% ET-02, and illustrates, for example, that 5% w / w topical ET-02 results in more hair re-growth than vehicle or 1.25% ET-02.

[0043] FIG. 2 presents a bar graph comparing subjects that experienced hair loss when treated topically with vehicle or 1.25% ET-02 and 5% ET-02, and illustrates, for example, that 5% w / w topical ET-02 results in no subjects that lost hair.

[0044] FIG. 3 presents a bar graph comparing hair count change from baseline in subjects after various hair re-regrowth treatments, and illustrates, for example, comparable to superior rates of hair growth over a shorter time period of 5% w / w topical ET-02 formulation when compared to other hair re-growth treatments.

[0045] FIG. 4 presents a bar graph comparing hair width change from baseline at 5 weeks in subjects treated topically with vehicle or 1.25% ET-02 and 5% ET-02, and illustrates, for example, that 5% w / w ET-02 results in greater hair width increase than vehicle or 1.25% ET-02.Attorney Docket No. : 2012317-0366

[0046] FIG. 5 presents a bar graph comparing hair darkness score at 5 weeks in subjects treated topically with vehicle or 1.25% ET-02 and 5% ET-02, and illustrates, for example, that 5% w / w ET-02 results in greater hair darkness score than vehicle or 1.25% ET-02.DEFINITIONS

[0047] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included.

[0048] In this application, the terms “graying” and “greying” may be understood to be interchangeable terms.

[0049] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0050] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system to achieve delivery of an agent that is, or is included in, the composition. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., byAttorney Docket No. : 2012317-0366intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0051] Agent : In general, the term “agent”, as used herein, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof. In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some cases, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises 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 is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety.

[0052] Agonist: Those skilled in the art will appreciate that the term “agonist” may be used to refer to an agent condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e., the agonized agent). In general, an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant activating activity. In some embodiments, an agonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments,Attorney Docket No. : 2012317-0366an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, so that level or activity of the target is altered).

[0053] Antagonist: Those skilled in the art will appreciate that the term “antagonist”, as used herein, may be used to refer to an agent condition, or event whose presence, level, degree, type, or form correlates with decreased level or activity of another agent (i.e., the inhibited agent, or target). In general, an antagonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant inhibitory activity. In some embodiments, an antagonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, an antagonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, so that level or activity of the target is altered).

[0054] Animal: As used herein refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, genetically engineered animal, and / or a clone.

[0055] Biologically active agent'. As used herein, the phrase “biologically active agent” refers to any substance that has activity in a biological system and / or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism is considered to be biologically active. In some embodiments, where a substance (e.g., a polypeptide, nucleic acid, antibody, etc. is biologically active, a portion of that substance that shares at least one biological activity of the whole substance is typically referred to as a “biologically active” portion.

[0056] Carrier: as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineralAttorney Docket No. : 2012317-0366oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0057] Cosmetic formulation: The term “cosmetic formulation” is used herein to refer to a topically applied composition that contains one or more agents having cosmetic properties. To give but a few examples, a cosmetic formulation may be a skin softener, nutrition lotion type emulsion, cleansing lotion, cleansing cream, skin milk, emollient lotion, massage cream, emollient cream, make-up base, lipstick, facial pack or facial gel, cleaner formulation such as shampoos, rinses, body cleanser, hair-tonics, or soaps, and / or a dermatological composition such as a lotion, ointment, gel, cream, patch, deodorant, antiperspirant, and / or spray.

[0058] Composition: Those skilled in the art will appreciate that the term “composition”, as used herein, may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0059] Comprising: A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method "consisting essentially of (or which "consists essentially of) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of (or "consists of) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0060] Cream: The term “cream” refers to a spreadable composition, typically formulated for application to the skin. Creams typically contain an oil and / or fatty acidAttorney Docket No. : 2012317-0366based-matrix. Creams formulated according to the present invention may contain nanoparticles and may be capable of substantially complete penetration (e.g., of such nanoparticles) through the skin upon topical administration. Such a cream could also act as a carrier for incorporated materials (e.g., for example, for one or more known therapeutic agents and / or independently active biologically active agents).

[0061] Dispersion medium: The term “dispersion medium” as used herein, refers to a liquid medium in which particles (e.g., empty nanoparticles and / or nanoparticles containing one or more known therapeutic agents and / or independently active biologically active agents) are dispersed. In general, a dispersion is formed when at least two immiscible materials are combined. An “oil-in-water” dispersion is one in which oily particles are dispersed within an aqueous dispersion medium. A “water-in-oil” dispersion is one in which aqueous particles are dispersed within an oily dispersion medium. Those of ordinary skill in the art will appreciate that a dispersion can be formed from any two immiscible media and is not limited strictly to combinations of aqueous and oily media. The term “dispersion medium” therefore applies broadly to any dispersion medium notwithstanding that it is common to refer to “aqueous” and “oily” categories.

[0062] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate 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 administration of multiple dosage forms.

[0063] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individualAttorney Docket No. : 2012317-0366doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0064] Excipient: as used herein, 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, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0065] In vitro'. The term “in vitro” as used herein refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0066] In vivo: as used herein refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0067] Macroemulsion: The term “macroemulsion,” as used herein, refers to an emulsion in which at least some droplets have diameters in the several hundred nanometers to micrometers size range. As will be understood by those of ordinary skill in the art, a macroemulsion is characterized by droplets greater than 300 nm in diameter. In some embodiments, a macroemulsion composition utilized in accordance with the present disclosure includes one or more large agents or one or more biologically active agents. In some embodiments, a large agent included in a macroemulsion composition may be a biologically active agent. It will be appreciated by those of ordinary skill in the art that aAttorney Docket No. : 2012317-0366macroemulsion composition for use in accordance with the present disclosure may be prepared according to any available means including, for example, chemical or mechanical means. In some embodiments, droplets in a macroemulsion have a size within a range of about 301 nm and about 1000 pm. In some embodiments, a macroemulsion has droplets in a size distribution of between about 301 nm and about 1000 pm. In some embodiments, droplets in a macroemulsion have a size within a range of about 500 nm and about 5000 pm. In some embodiments, a macroemulsion has droplets in a size distribution of between about 500 nm and about 5000 pm.

[0068] Nanoemulsion: The term “nanoemulsion,” as used herein, refers to an emulsion in which at least some droplets have diameters in the nanometer size range. As will be understood by those of ordinary skill in the art, a nanoemulsion is characterized by droplets 300 nm or smaller in diameter. In some embodiments, a nanoemulsion composition utilized in accordance with the present disclosure includes one or more large agents or one or more biologically active agents. In some embodiments, a large agent included in a nanoemulsion composition may be a biologically active agent. It will be appreciated by those of ordinary skill in the art that a nanoemulsion composition for use in accordance with the present disclosure may be prepared according to any available means including, for example, chemical or mechanical means. In some embodiments, droplets in a nanoemulsion have a size within a range of about 1 nm and about 300 nm. In some embodiments, a nanoemulsion has droplets in a size distribution of between about 1 nm and about 300 nm.

[0069] Nanoparticle: As used herein, the term “nanoparticle” refers to a solid particle having a diameter of less than 300 nm, as defined by the National Science Foundation. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health.

[0070] Nanoparticle composition: As used herein, the term “nanoparticle composition” refers to any substance that contains at least one nanoparticle. In some embodiments, a nanoparticle composition is a uniform collection of nanoparticles. In some embodiments, nanoparticle compositions are dispersions or emulsions. In general, a dispersion or emulsion is formed when at least two immiscible materials are combined. An “oil-in-water” dispersion is one in which oily particles (or hydrophobic or non-polar) are dispersed within an aqueous dispersion medium. A “water-in-oil” dispersion is one in which aqueous (or hydrophilic or polar) particles are dispersed within an oily dispersionAttorney Docket No. : 2012317-0366medium. Those of ordinary skill in the art will appreciate that a dispersion can be formed from any two immiscible media and is not limited strictly to combinations of aqueous and oily media. The term “dispersion medium” therefore applies broadly to any dispersion medium notwithstanding that it is common to refer to “aqueous” and “oily” categories. In some embodiments, nanoparticle compositions are nanoemulsions. In some embodiments, nanoparticle compositions comprise micelles. In some embodiments, nanoparticle compositions are stable. In some embodiments, nanoparticle compositions include one or more biologically active agents to be delivered in conjunction with the nanoparticles. In some embodiments, nanoparticle compositions are empty nanoparticle compositions (e.g., they do not contain any known therapeutic agents and / or independently active biologically active agents).

[0071] 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 in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0072] Penetration enhancing agent or Penetrating Treatment: As used herein, the term “penetration enhancing agent” or “penetrating treatment” refers to an agent whose presence or level correlates with increased penetration of an agent of interest across skin, as compared with that observed in its absence. In some embodiments, a penetration enhancing agent is characterized in that it degrades and / or disrupts skin structure. In some embodiments, a penetration enhancing agent is or comprises a chemical agent (e.g., aAttorney Docket No. : 2012317-0366chemical or enzyme, for example) For example, chemical agents that that may damage, disrupt, and / or degrade one or more stratum corneum components) may include, for example, alcohols, such as short chain alcohols, long chain alcohols, or polyalcohols; amines and amides, such as urea, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, pyrrolidones, or derivatives of pyrrolidones; terpenes and derivatives of terpenes; fatty acids and their esters; macrocyclic compounds; tensides; or sulfoxides (e.g., dimethylsulfoxide (DMSO), decylmethylsulfoxide, etc.); surfactants, such as anionic, cationic, and nonionic surfactants; polyols; essential oils; and / or hyaluronidase. In some embodiments, a penetration enhancing agent may be an irritant in that an inflammatory and / or allergic reaction occurs when the agent is applied to skin. In some embodiments, a penetration enhancing agent is not an irritant. In some embodiments, a penetration enhancing agent may be or comprise a chemical agent that does not damage, disrupt, or degrade skin structure but whose presence or level nonetheless correlates with increased penetration of an agent of interest across skin, as compared with that observed in its absence. In some embodiments, co-peptides, carrier molecules, and carrier peptides may be penetration enhancing agents which do not damage, disrupt, and / or degrade skin structure(s). In some embodiments, co-peptides, carrier molecules, and carrier peptides may be penetration enhancing agents which do not irritate the skin. The term “penetration enhancing agent” does not encompass mechanical devices (e.g., needles, scalpels, etc.), or equivalents thereof (e.g., other damaging treatments). Also, those skilled in the art will appreciate that a structure such as a nanoparticle or an emulsion is not a chemical agent and therefore not a chemical penetration enhancing agent even if its presence correlates with enhanced skin penetration of an agent of interest that may be associated with the structure.

[0073] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;Attorney Docket No. : 2012317-0366gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0074] Prevent or prevention . As used herein when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0075] Self -administration: The term “self-administration,” as used herein, refers to the situation where a subject has the ability to administer a composition to him or herself without requiring medical supervision. In some embodiments of the invention, selfadministration may be performed outside of a clinical setting. To give but one example, in some embodiments of the invention, a facial cosmetic cream may be administered by a subject in one’s own home.

[0076] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, 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 include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not anAttorney Docket No. : 2012317-0366oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, efc.). In some embodiments, a small molecule is not a lipid. In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent. Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms, salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc. Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form. Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms. Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;,nC,13C or14C for 12C; ,13N or15N for 14N;17O or18O for 160;36C1 for XXC;18F for XXF; 13 II for XXXI; etc). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof. In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form. In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that,Attorney Docket No. : 2012317-0366in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0077] Subject: As used herein, the term “subject” refers an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0078] Symptoms are reduced: As used herein, the term “symptoms are reduced” refers to when one or more symptoms of a particular disease, disorder or condition is reduced in magnitude (e.g., intensity, severity, etcj and / or frequency. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom.Attorney Docket No. : 2012317-0366

[0079] Therapeutic agent'. As used herein, the term “therapeutic agent” refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect, when administered to a subject.

[0080] Therapeutically effective amount: As used herein, is meant an amount that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and / or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, and / or delays onset of, one or more symptoms of the disease, disorder, and / or condition. Those of ordinary skill in the art will appreciate that the term "therapeutically effective amount" does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and / or administered in a plurality of doses, for example, as part of a dosing regimen.

[0081] Treatment. As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibilityAttorney Docket No. : 2012317-0366factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and / or condition.DETAILED DESCRIPTIONPlasminogen Activator Inhibitor 1 (PAI-1)

[0082] Plasminogen Activator Inhibitor (PAI-1) is a serine protease inhibitor (serpin) protein encoded by the SERPINE 1 gene. PAI-1 is originally known for its involvement in maintaining homeostatic equilibrium in the body, as it is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA). Elevated PAI-1 has also been reported to be associated with organ fibrosis and disease in multiple organ systems (e.g., heart, lung, liver, kidney, and skin).

[0083] The present disclosure, in some embodiments, provides a surprising insight that certain topical formulations of PAI-1 inhibitors (e.g. 5% w / w ET-02) can be particularly safe and effective in treating and / or preventing hair loss and / or hair graying in human subjects. The present disclosure, in some embodiments, provides a surprising insight that certain topical formulations of PAI-1 inhibitors may be safe and particularly useful in the treatment and / or prevention of specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. The present disclosure, in some embodiments, provides a surprising insight that topical formulations of PAI-1 inhibitors may be more effective, and / or give rise to results more quickly in the treatment and / or prevention of specific types of hair loss (or alopecia) than other hair loss treatments. The present disclosure, in some embodiments, provides a surprising insight that certain topical formulations of PAI- 1 inhibitors (e.g 5% w / w ET-02) may be particularly safe and effective in the treatment and / or prevention of hair graying.

[0084] While the growth cycle and physiology of the hair is well known and understood, there are currently no highly effective prevention or treatment techniques for hair loss, specifically, for example specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. In some embodiments, provided methods and / or compositions provide targeted therapy. For example, in some embodiments, provided methods and compositions provide surprisingly safe and effective therapies comprising one or more PAI-1 inhibitors (e.g. 5% w / w ET-02) . Without wishing to be bound by any particular theory, it is proposed that, in someAttorney Docket No. : 2012317-0366embodiments, administration of a PAI-1 inhibitor as described herein may impact the function of stem cells associated with hair growth and color, and such impact may contribute to treatment or prevention of hair loss and / or treatment and / or prevention in hair graying.

[0085] In some embodiments provided methods, kits and compositions may be or comprise emulsions. In some embodiments provided methods, kits and compositions may be or comprise macroemulsions. In some embodiments provided methods, kits and compositions may be or comprise nanoemulsions. In some embodiments provided methods, kits and compositions comprise a combination therapy or treatment, wherein for example, in some embodiments, provided compositions may be administered in combination with one or more additional treatments. In some embodiments the one or more additional treatments is or comprises other active agents and / or therapeutic modalities (e.g. one or more PAI-inhibitors, or other agents), such as known therapeutic agents and / or independently active biologically active agents.Diseases, Disorders, and Conditions

[0086] The present invention provides technologies for treating and / or preventing certain types of alopecia and / or hair graying. In some embodiments, the present invention provides technologies (e.g. topical 5% w / w ET-02) for treating and / or preventing diseases, disorders or conditions associated with the epidermal and / or dermal level of the skin. In some embodiments, the present invention provides technologies (e.g. topical 5% w / w ET-02) for treating and / or preventing any one or a combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. In some embodiments, the prevent invention provides compositions and formulations (e.g. topical 5% w / w ET-02) for treating and / or preventing hair graying.

[0087] In some embodiments, the present invention provides technologies for treating and / or preventing one or more of specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, and / or combinations thereof. In some embodiments, the present invention provides technologies for treating and / or preventing specific types of hair loss (or alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, but not treating or preventing other types of alopecia such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia due to chronic discoid lupus erythematosus.Attorney Docket No. : 2012317-0366

[0088] In some embodiments, the present invention provides technologies for treating and / or preventing a dermatological condition. In some embodiments, the present invention provides technologies for treating and / or preventing hair graying. In some embodiments, the present invention provides technologies for treating and / or preventing hair graying that is caused by smoking, stress, genetics, vitamin deficiencies, aging, and / or thyroid disease. In some embodiments, the present invention provides technologies for treating and / or preventing hair graying that occurs with other diseases, disorders, or conditions.Hair Loss

[0089] In some embodiments, provided technologies are useful for treating and / or preventing hair loss. Baldness involves the state of lacking hair where it often grows, especially on the head. The most common form of baldness is a progressive hair thinning condition called androgenic alopecia or “male pattern baldness” that occurs in adult male humans and other species. The amount and patterns of baldness can vary greatly; it ranges from male and female “pattern alopecia” (androgenic alopecia, also called androgenetic alopecia or alopecia androgenetica); “alopecia areata,” which involves the loss of some of the hair from the head; “alopecia totalis,” which involves the loss of all head hair; to the most extreme form, “alopecia universalis,” which involves the loss of all hair from the head and the body. Frontal fibrosing alopecia (FFA) is characterized primarily by slowly progressive hair loss and scarring on the scalp near the forehead. In some cases, the hair loss in this type of alopecia may involve the eyebrows, eye lashes, and / or other body parts.Senescent alopecia, also known as involutional alopecia, is hair loss caused by old age. Other types of alopecia include, but are not limited to, radiation-induced alopecia, chemotherapy-induced alopecia, alopecia due to chronic discoid lupus erythematosus, postpartum alopecia, and telogen effluvium.

[0090] Current therapies used in the treatment of hair loss include, but are not limited to, botulinum toxin, aza-steroids, such as finasteride (PROPECIA®; PROSCAR®; etc.) or dutasteride (AVODART®); topically administered minoxidil, a vasodilator (ROGAINE®); antiandrogens (e.g., ketoconazole, fluconazole, spironolactone, etc.); platelet-rich plasma, saw palmetto; caffeine; copper peptides; nitroxide spin labels TEMPO and TEMPOL; unsaturated fatty acids (e.g., gamma linolenic acid); hedgehog agonists;Attorney Docket No. : 2012317-0366azelaic acid and zinc in combination; Chinese knotweed; pumpkin seed; spironolactone; tretinoin; zinc; stinging nettle; and / or combinations thereof. Pharmaceutical compositions in accordance with the present invention may be administered alone and / or in combination with these therapies that are used to treat the symptoms and / or causes of hair loss, for the treatment of hair loss.

[0091] In some embodiments, provided topical compositions for treatment and / or prevention of hair loss are formulated into a suspension.

[0092] In some embodiments, provided topical compositions for treatment and / or prevention of hair loss are formulated into a suspension, a foam, a cream, a liniment, a lotion, a gel, a shampoo, a conditioner, etc.

[0093] In some embodiments, provided topical compositions for treatment and / or prevention of hair loss are administered locally to an affected site (e.g., scalp, hair follicle, face, neck, back, arms, chest, etc.).

[0094] In some embodiments, the present invention involves topical administration of at least one PAI-1 inhibitor (e.g., ET-02) in a suspension, in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 10%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 11%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 12%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 13%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 14%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 15%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 20%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 25%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 30%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or moreAttorney Docket No. : 2012317-0366symptoms of hair loss of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0095] In some embodiments, the present invention involves topical administration of at least one PAI-1 inhibitor (e.g., ET-02) in a nanoparticle composition or a nanoemulsion composition or an emulsion composition or a foam formulation or a cream formulation or an oil or a lotion formulation or a gel or a shampoo or a conditioner, in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 10%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 11%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 12%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 13%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 14%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 15%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 20%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 25%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 30%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair loss of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%,Attorney Docket No. : 2012317-0366about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0096] In some embodiments, the present invention involves topical administration of at least one PAI-1 inhibitor (e.g., ET-02) in a suspension, in an amount sufficient to achieve an increase in hair width of at least 5%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 7%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 8%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 10%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 15%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 20%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 25%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 30%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0097] In some embodiments, the present invention involves topical administration of at least one PAI-1 inhibitor (e.g., ET-02) in a nanoparticle composition or a nanoemulsion composition or an emulsion composition or a foam formulation or a cream formulation or an oil or a lotion formulation or a gel or a shampoo or a conditioner, in an amount sufficient to achieve an increase in hair width of at least 5%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 7%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 8%; in someAttorney Docket No. : 2012317-0366embodiments in an amount sufficient to achieve an increase in hair width of at least about 10%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 15%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 20%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 25%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 30%; in some embodiments in an amount sufficient to achieve an increase in hair width of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.Hair Graying

[0098] In some embodiments, the present invention provides technologies for treating and / or preventing a dermatological condition. In some embodiments, the present invention provides technologies for treating and / or preventing hair graying.

[0099] Current therapies for hair graying include, but is not limited to photoprotectors, such as cinnamidopropyltrimonium chloride and solid lipid nanoparticles as carriers for UV blockers, oral supplementation with 1-cystine and 1-methionine, and topical melatonin. The most commonly used treatment or solution to premature hair graying is the use of temporary hair colorants. Pharmaceutical compositions in accordance with the present invention may be administered alone and / or in combination with these therapies that are used to treat the symptoms and / or causes of hair graying, for the treatment of hair graying.

[0100] In some embodiments, provided topical compositions for treatment and / or prevention of hair graying are formulated into a suspension.

[0101] In some embodiments, the topical compositions disclosed herein for treatment and / or prevention of hair graying are formulated into a suspension, a foam, a cream, a liniment, a lotion, a gel, a shampoo, a conditioner, etc.Attorney Docket No. : 2012317-0366

[0102] In some embodiments, topical compositions disclosed herein (e.g. 5% w / w ET-02) for treatment and / or prevention of hair graying are administered locally to an affected site (e.g., scalp, hair follicle, face, neck, back, arms, chest, etc.).

[0103] In some embodiments, the present invention involves administration of at least one PAI-1 inhibitor (e.g., ET-02) in a suspension, in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 7%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 8%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 9%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 10%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 15%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 20%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 25%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 30%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.

[0104] In some embodiments, the present invention involves administration of at least one PAI-1 inhibitor (e.g., ET-02) in a nanoparticle composition or a nanoemulsion composition or an emulsion composition or a foam formulation or a cream formulation or an oil or a lotion formulation or a gel or a shampoo or a conditioner, in an amount sufficient toAttorney Docket No. : 2012317-0366achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 7%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 8%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 9%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 10%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 15%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 20%; in some embodiments in in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 25%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 30%; in some embodiments in an amount sufficient to achieve a reduction in the degree and / or prevalence of one or more symptoms of hair graying of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more.PAI-1 Inhibitors

[0105] PAI-1 inhibitors can be used to treat or prevent medical conditions or diseases associated with over-expression of PAI-1. The present disclosure, in some embodiments, encompasses a recognition that PAI-1 inhibitors (e.g. ET-02) may be particularly useful in the treatment and / or prevention of dermatological conditions, such as hair loss, hair graying, scleroderma, keloids, Raynaud’s Phenomenon, etc. While there areAttorney Docket No. : 2012317-0366some partially effective techniques for prevention or treatment for hair loss, there are no highly effective prevention or treatment for hair loss and there are currently no effective prevention or treatment techniques for hair graying. In some embodiments, provided methods and / or compositions provide targeted therapy. For example, in some embodiments, provided methods and compositions 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 may impact the function of Hair Follicle Stem Cells (HFSC) and Melanocyte Stem Cells (MSC), and such impact may contribute to treatment or prevention of hair loss and hair graying.

[0106] PAI-1 inhibitors can be antibodies, peptides, polypeptides, proteins, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, or any combinations thereof. In some embodiments, a PAI-1 inhibitor is an siRNA. In some embodiments, a PAI-1 inhibitor is a benzopyran compound, a butadiene, spironolactone, imidapril, an angiotensin converting enzyme inhibitor (ACEI, captopril, or enalapril), an angiotensin II receptor antagonist (AURA), a defibrotide (a polydeoxyribonucleotide) and any combination thereof. In some embodiments, a PAI-1 inhibitor is a benzopyran compound.

[0107] In some embodiments, a PAI-1 inhibitor is selected from a group consisting of polypeptides, nucleic acids, lipids, carbohydrates, small molecules, metals, polymers, therapeutic antibodies, fragments of therapeutic antibodies, and combinations thereof. In some embodiments, a PAI-1 inhibitor may be a small molecule.

[0108] In some embodiments, a composition comprises or delivers a compound as set forth herein or an active metabolite thereof.

[0109] In some embodiments, a PAI-1 inhibitor is a 2-aminobenzoic acid analog.

[0110] In some embodiments, a PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.[OHl] In some embodiments, a PAI-1 inhibitor is a compound of Formula (1):Attorney Docket No. : 2012317-0366Formula (1)wherein, Ri and R2 are the same or different, and each represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl, hydroxyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocyclic-alkyl, heterocyclicalkyloxy, aryl optionally having one or two substituents, 5- to 6-membered ring heteroaryl optionally having one or two substituents, or benzo-fused heteroaryl optionally having one or two substituents, amino or carbomyl, each of which is optionally substituted with one or two substituents, or cyano, carboxy, or alkoxycarbonyl; and Ri and R2 are optionally adjoined with each other to form a ring; R3 is hydrogen, alkyl, cycloalkyl, or aryl optionally having one or two substituents; X is -C(Rs)=C(R6)-, -C(R?) N-, or -N=C (Rs)-, wherein R5, Re, R7 and Rs each represents hydrogen, halogen, alkyl optionally having one or two substituents, or alkoxy; L is alkylene (some carbon atoms in the alkylene optionally form a cycloalkyl ring), alkenylene, alkynylene, cycloalkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene, or alkylene-SCh-alkylene, each of which is optionally substituted with one or two substituents, or alkylene-N(R9)-alkylene optionally substituted with one or two substituents, wherein R9 represents hydrogen, or alkyl optionally having one or two substituents; p represents an integer of 0 or 1; A is a group represented by any one of the following Formulae (2), (3), or (4):Formula (2)wherein, Rio and Rn are the same or different, and each represents hydrogen or straight- or branched-chain alkyl; and m represents an integer of 0 to 10,Attorney Docket No. : 2012317-0366Formula (3)wherein, R12 and R13 are the same or different, and each represents hydrogen, halogen, or alkyl optionally having one or two substituents, cycloalkyl optionally having one or two substituents, or alkoxy optionally having one or two substituents; Y represents CH or nitrogen; Z represents CH2, oxygen, or N-alkyl; n represents an integer of 0 to 3; U represents alkylene; and t represents an integer of 0 or 1,Formula (4)wherein, R14 and R15 are the same or different, and each represents hydrogen, halogen, or alkyl optionally having one or two substituents, cycloalkyl optionally having one or two substituents, or alkoxy optionally 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 aryl having one or two substituents (the one or two substituents optionally form a ring with a part of carbon atoms in the aryl group), 5-to 6-membered ring aryl group having one or two identical or different heteroatoms optionally having one or two substituents, or benzo-fused heteroaryl optionally having one to three substituents; and B represents COOR16, wherein Ri6 represents hydrogen, alkyl, aryl or aralkyl, a group represented by CH(Rn)O — CORis or — CH(Rn) — O — CO — ORis, wherein R17 is hydrogen or alkyl, and Ris is alkyl or cycloalkyl, a (5-alkyl-2-oxo-l,3-dioxolen-4-yl)methyl group represented by the following Formula (5):Attorney Docket No. : 2012317-0366Formula (5)wherein, R' represents alkyl, or a heterocyclic group: a lH-tetrazol-5-yl group, a 4,5-dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl group, a 4,5-dihydro-5-thioxo-4H-l,2,4-oxadiazol-3-yl group, or a 4,5-dihydro-5-oxo-l,2,4-thiadiazol-3-yl group, represented by the following Formulae (6), (7), (8) (sequentially from the left), (9) (below):Formula (6), (7), (8) (sequentially from the left), (9) (bottom)

[0112] In some embodiments, a PAI-1 inhibitor is a compound of Formula (10)Formula (10)wherein, Ri and R2 are the same or different, and each represents hydrogen, halogen, alkyl, or aryl optionally having one or two substituents; R3 is hydrogen or alkyl; R14 and R15 are the same or different, and each represents hydrogen, alkyl, or halogen; V is alkylene, oxyalkylene, or oxygen; Ar is aryl optionally having one or two substituents, aryl group having one or two identical or different heteroatoms optionally having one or two substituents, or benzofused heteroaryl optionally having one or three substituents; L is alkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene, alkylene-SCh-alkylene; and q, U, t, p, and B are as defined above.

[0113] In some embodiments, a PAI-1 inhibitor is selected from a group consisting of: 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid, 5-Chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, a butadiene, spironolactone, imidapril, an angiotensin converting enzymeAttorney Docket No. : 2012317-0366inhibitor (ACEI, captopril, or enalapril), an angiotensin II receptor antagonist (AURA), a defibrotide (a polydeoxyribonucleotide), and any combination thereof

[0114] In some embodiments, a PAI-1 inhibitor is 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino benzoic acid (ET-02). In some embodiments, a PAI-1 inhibitor is 5-Chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid.

[0115] Table 1 below lists exemplary PAI-1 inhibitors.Table 1: Exemplary PAI-1 inhibitorsCompositions and Formulations

[0116] As described herein, the present disclosure provides compositions that comprise a PAI-1 inhibitor (e.g. ET-02) for topical application. As described herein, the present disclosure provides topical formulations that deliver a PAI-1 inhibitor, for example ET-02. In some embodiments, a composition that comprises and / or delivers an active agent is formulated for topical administration. In some embodiments, a composition that comprises and / or delivers an active agent is formulated for topical application to a site of a subject. In some embodiments, a composition that comprises and / or delivers a PAI-1 inhibitor is an improved composition, as described herein.

[0117] In some embodiments, a composition provided and / or utilized in accordance with the present disclosure comprises a PAI-1 Inhibitor in an amount that is about 2% byAttorney Docket No. : 2012317-0366weight of the composition. In some embodiments, a composition provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 2.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 3% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 3.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 4% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 4.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is about 5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 2% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 2.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 3% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 3.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 4% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 4.5% by weight of the composition. In some embodiments, a composition as provided and / or utilized in accordance with the present disclosure comprises a PAI-1 inhibitor in an amount that is at least 5% by weight of the composition.

[0118] In some embodiments, the weight percentage or amount of a PAI-1 inhibitor in a composition described herein is determined based on degree of hair loss and / or graying in a subject to whom the composition is administered; in some embodiments, for the same subject, a desirable and / or effective amount of PAI-1 inhibitor (e.g., the weight percentageAttorney Docket No. : 2012317-0366or amount) of a PAI-1 inhibitor in a composition provided and / or utilized in accordance with the present disclosure, may change over time, e.g., in light of changes in the occurrence and / or progression of hair loss and / or graying in that subject. In some embodiments, an effective amount of a topical composition or formulation (e.g., an effective dose of a PAI-1 inhibitor) as described herein may decrease as hair thickness increases. In some embodiments, an effective amount of a topical composition or formulation (e.g., an effective amount of a PAI-1 inhibitor) as described herein may decrease as hair count increases. In some embodiments, an effective amount of a topical composition or formulation (e.g., an effective amount of a PAI-1 inhibitor) as described herein may decrease as hair darkness score increases.

[0119] In some embodiments, the weight percentage of a PAI-1 inhibitor in a composition utilized in accordance with a particular embodiment of the present disclosure may depend on the particular disease or condition to be treated and / or prevented.

[0120] In some embodiments, the weight percentage of a PAI-1 inhibitor in a composition utilized in accordance with a particular embodiment of the present disclosure may depend on height, weight, or sex of the subject. In some embodiments, the weight percentage of a PAI-1 inhibitor in a composition utilized in accordance with a particular embodiment of the present disclosure may depend on the site to which the composition is applied.

[0121] In some embodiments, a composition that comprises and / or delivers a PAI-1 inhibitor (e.g. ET-02) comprises one more components as described herein. In some embodiments, components of a composition that comprises and / or delivers an active agent have a function as described herein. Among other things, the present disclosure appreciates that components of a composition that comprises and / or delivers an active agent can have more than one function in a composition.

[0122] In some embodiments, a topical composition as described herein is substantially free of one or more components as described herein.

[0123] In some embodiments, a topical composition as described herein is substantially free of ETOH.

[0124] In some embodiments, a topical composition as described herein is substantially free of sorbitol.Attorney Docket No. : 2012317-0366

[0125] In some embodiments, a topical composition as described herein comprises a penetration enhancer. In some embodiments, a penetration enhancer is one or more of glycerin, isopropyl myristate and / or propylene glycol. In some embodiments, provided compositions comprise a penetration enhancer in an amount that is not more than 35% of a composition by weight.

[0126] In some embodiments, a topical composition as described herein comprises isopropyl myristate. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount that is less than 15% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount that is at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount greater than 1% but no more than 15% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount greater than 5% but no more than 15% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount greater than 9% but no more than 12% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount greater than 9% but no more than 11% by weight of a composition. In some embodiments, a composition as described herein comprises isopropyl myristate in an amount that is 10% by weight of a composition.

[0127] In some embodiments, provided topical compositions comprise a solvent. In some embodiments, a solvent is glycerin. In some embodiments, a topical composition as described herein comprises glycerin. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is less than 15% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,Attorney Docket No. : 2012317-036616%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is greater than 1% but no more than 15% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is greater than 5% but no more than 15% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is greater than 9% but no more than 11% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is no more than 10% by weight of a composition. In some embodiments, a topical composition as described herein comprises glycerin in an amount that is 10% by weight of a composition.

[0128] In some embodiments, a topical composition as described herein comprises propylene glycol. In some embodiments, a topical composition as described herein comprises propylene glycol in an amount that is less than 20% by weight of a composition. In some embodiments, a topical composition as described herein comprises propylene glycol in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is greater than 5% but no more than 20% by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is greater than 14% but no more than 16% by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is 15% by weight of a composition.

[0129] In some embodiments, a topical composition as described herein comprises an emollient. In some embodiments, an emollient is isopropyl myristate.Attorney Docket No. : 2012317-0366

[0130] In some embodiments, provided compositions comprise a solvent or carrier. In some embodiments, a solvent or carrier is water. In some embodiments, a composition as described herein comprises water in an amount that is less than 70% by weight of a composition. In some embodiments, a composition as described herein comprises water in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises water in an amount that is at least 1%, 10%, 20%, 30%, 40%, 50% 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 58%, or 60%, by weight of a composition. In some embodiments, a composition as described herein comprises propylene glycol in an amount that is at most 1%, 10%, 20%, 30%, 40%, 50% 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 58%, or 60% by weight of a composition. In some embodiments provided compositions comprise water in an amount that is greater than 15% but no more than 70% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 20% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 30% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 40% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 50% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 51% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 52% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53.5% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53.6% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53.7% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53.8% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is greater than 53.84% by weight of a composition. In some embodiments, provided compositions comprise water in an amount that is no more than 54% by weight of a composition.Attorney Docket No. : 2012317-0366

[0131] In some embodiments, a composition as described herein comprises a suspending agent. In some embodiments, a suspending agent is xanthan gum. In some embodiments, a composition as described herein comprises xanthan gum. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is less than 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is at least 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is at most 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is greater than 0.1% but no more than 0.3% by weight of a composition. In some embodiments, a composition as described herein comprises xanthan gum in an amount that is 0.2% by weight of a composition.

[0132] In some embodiments, a composition as described herein comprises an emulsifier or solubilizer. In some embodiments, an emulsifier or solubilizer is Steareth 20. In some embodiments, an emulsifier or solubilizer is Tween 80. In some embodiments, an emulsifier or solubilizer is Steareth 20 and Tween 80.

[0133] In some embodiments, a composition as described herein comprises Steareth 20 in an amount that is less than 3% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in an amount that is at least 1%, 1.5%, 2%, 2.5% or 3% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in an amount that is at most 1%, 1.5%, 2%, 2.5%, or 3% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in amount that is greater than 1% but no more than 3% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in amount that is greater than 1.5% but no more than 3.0% by weight of a composition. In some embodiments, a composition as described herein comprises Steareth 20 in amount that is 2.0% by weight of a composition.

[0134] In some embodiments, a composition as described herein comprises Tween 80 in an amount that is less than 6% by weight of a composition. In some embodiments, aAttorney Docket No. : 2012317-0366composition as described herein comprises Tween 80 in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises Tween 80 in an amount that is at least 1%, 2%, 3%, 3.5%, 3.6%, 4%, 5%, or 6% by weight of a composition. In some embodiments, a composition as described herein comprises Tween 80 in an amount that is at most 1%, 2%, 3%, 3.5%, 3.6%, 4%, 5%, or 6% by weight of a composition. In some embodiments, a composition as described herein comprises Tween 80 in amount that is greater than 1% but no more than 6% by weight of a composition. In some embodiments, a composition as described herein comprises Tween 80 in amount that is greater than 3.0% but no more than 6% by weight of a composition. In some embodiments, a composition as described herein comprises Tween 80 in amount that is 3.5% by weight of a composition.

[0135] In some embodiments, a composition as described herein comprises methyl paraben in an amount that is less than 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises methyl paraben in an amount that is greater than 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises methyl paraben in an amount that is at least 0.1%, 0.15% 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises methyl paraben in an amount that is at most 0.1%, 0.15% 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of a composition. In some embodiments, a composition as described herein comprises a preservative. In some embodiments, a preservative is methyl paraben. In some embodiments, a composition as described herein comprises methyl paraben in an amount that is greater than 0.1% but no more than 0.3% by weight of a composition. In some embodiments, a composition as described herein comprises methyl paraben in an amount that is 0.2% by weight of a composition.

[0136] In some embodiments, a preservative is edetate disodium. In some embodiments, a composition as described herein comprises edetate disodium in an amount that is less than 1% by weight of a composition. In some embodiments, a composition as described herein comprises edetate disodium in an amount that is greater than 0.01% by weight of a composition. In some embodiments, a composition as described herein comprises edetate disodium in an amount that is at least 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises edetate disodium in an amountAttorney Docket No. : 2012317-0366that is at most 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0.1% by weight of a composition. In some embodiments, a composition as described herein comprises edetate di sodium in an amount that is greater than 0.02% but no more than 0.06% by weight of a composition. In some embodiments, a composition as described herein comprises edetate di sodium in an amount that is greater than 0.04% but no more than 1% by weight of a composition. In some embodiments, a composition as described herein comprises edetate disodium in an amount that is 0.05% by weight of a composition.

[0137] In some embodiments, a composition as described herein comprises propyl paraben in an amount that is less than 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises propyl paraben in an amount that is greater than 0.05% by weight of a composition. In some embodiments, a composition as described herein comprises propyl paraben in an amount that is at least 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1% or 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises propyl paraben in an amount that is at most 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1% or 0.15% by weight of a composition. In some embodiments, a preservative is propyl paraben. In some embodiments, a composition as described herein comprises propyl paraben in an amount that is greater than 0.05% but no more than 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises propyl paraben in an amount that is 0.10% by weight of a composition.

[0138] In some embodiments, a composition as described herein comprises an oilsoluble antioxidant. In some embodiments, an oil-soluble antioxidant is butylated hydroxyl toluene. In some embodiments, a composition as described herein comprises butylated hydroxyl toluene in an amount that is less than 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises butylated hydroxyl toluene in an amount that is greater than 0.05% by weight of a composition. In some embodiments, a composition as described herein comprises butylated hydroxyl toluene in an amount that is at least 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1% or 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises butylated hydroxyl toluene in an amount that is at most 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1% or 0.15% by weight of a composition. In some embodiments, a composition as described herein comprises butylated hydroxyl toluene in an amount that is greater than 0.05% but no more than 0.15% by weight of a composition. In some embodiments, a composition as describedAttorney Docket No. : 2012317-0366herein comprises butylated hydroxyl toluene in an amount that is 0.10% by weight of a composition.

[0139] In some embodiments, provided compositions may be formulated for topical and / or transdermal delivery (e.g., as serums, suspensions, lotions, creams, liniments, ointments, powders, gels, drops, etc.). In some embodiments, provided compositions may be or include a nanoemulsion. In some embodiments, provided compositions may be or include a macroemulsion. In some embodiments administration is in combination with microneedle skin conditioning (MSC). In some embodiments, administration is via injection. In some embodiments, administration is in combination with laser treatment of the skin. In some embodiments, administration is in combination with light treatment of the skin. In some embodiments, light treatment comprises treatment with one or more wavelengths or colors of light. In some embodiments, light treatment comprises treatment with a specific range of wavelengths or colors of light. In some embodiments, light treatment comprises treatment with wavelengths of light between 650 and 850 nm. In some embodiments, light treatment comprises treatment with wavelengths of light between 785 and 850 nm.Emulsions

[0140] In some embodiments, provided herein are surprisingly effective technologies for administration and delivery of PAI-1 inhibitors (e.g. ET-02). In some embodiments, the present disclosure teaches topical formulations and compositions of such PAI-1 inhibitors for various diseases, disorders, and / or conditions as described herein. In some embodiments, the present disclosure teaches methods of treating and / or preventing one or more diseases, disorders and / or conditions through the administration of PAI-1 inhibitor formulations and / or compositions to a subject in need thereof. In some embodiments, a formulation and / or composition comprises emulsions.

[0141] Moreover, the present disclosure appreciates that certain liquid nanoemulsion technologies have been demonstrated to provide remarkable transdermal delivery attributes, even for very large molecules, such as botulinum and / or antibody agents. See, e.g., U.S. Patent Publication No. 2012 / 0328701, U.S. Patent Publication No. 2012 / 0328702, 8,318,181, and U.S. Patent No. 8,658,391, the disclosures of which are herein incorporated by reference in their entireties.MacroemulsionsAttorney Docket No. : 2012317-0366

[0142] In some embodiments, the present disclosure utilizes macroemulsion compositions comprising a PAI-1 inhibitor that are particularly effective and / or useful in a therapeutic, e.g., treatment of a disease, disorder and / or a condition as described herein. In some embodiments, particular macroemulsion compositions are particularly effective and / or useful for topical administration of a PAI-1 inhibitor as described herein to a subject in need thereof. In some embodiments macroemulsion compositions may comprise of one or more active agents.

[0143] In some embodiments, a macroemulsion may be formulated into a composition suitable for topical administration on skin. In some embodiments, a composition suitable for topical administration may be a lotion, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste.

[0144] In some embodiments, macroemulsion formulations comprise water, medium chain triglyceride, span 65, polysorbate 80, methylparaben, and propylparaben. In some embodiments, macroemulsion formulations comprise water, medium chain triglyceride, span 65, and polysorbate 80.

[0145] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharmaceutically acceptable excipients. In some embodiments, cream and / or lotion formulations comprise a mixture of a provided macroemulsion composition and / or a saline solution.

[0146] In some embodiments, provided compositions comprise macroemulsion compositions comprising one or more active agents. In some embodiments, provided compositions are cream and / or lotion formulations. In some embodiments, provided compositions comprise macroemulsion compositions. In some embodiments, compositions comprise provided macroemulsion compositions but are not cream and / or lotion formulations. In some embodiments, suitable compositions are formulated into creams and / or lotions but do not comprise a macroemulsion composition.

[0147] In some embodiments, provided compositions comprise a mixture of a provided macroemulsion composition and one or more pharmaceutically acceptable excipients, e.g., for topical and / or transdermal (e.g., by serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.) administration.

[0148] In some embodiments, a macroemulsion may be formulated into a composition suitable for topical administration. In some embodiments, a compositionAttorney Docket No. : 2012317-0366suitable for topical administration may be a lotion, cream, serum, suspension, powder, ointment, liniment, gel, drops, emollient, balm, or paste. In some embodiments, a macroemulsion may be formulated into an injectable composition. In some embodiments, an injectable composition may be sterile.

[0149] Macroemulsion formulations may act to stabilize an active agent and / or therapeutic agent. Macroemulsion formulations would not necessarily be expected in and of themselves to achieve transdermal delivery of active agents, nonetheless, the present disclosure encompasses that stabilization improvement that may be provided by incorporation into a macroemulsion composition might, when combined with microneedling technologies as described herein, achieve synergistic enhancement of transdermal delivery.Nanoemulsions

[0150] In some embodiments, the present disclosure utilizes nanoemulsion compositions comprising an active agent that are particularly effective and / or useful in a therapeutic, e.g., treatment of a disease, disorder and / or a condition as described herein. In some embodiments, particular nanoemulsion compositions are particularly effective and / or useful for topical administration of an active agent as described herein to a subject in need thereof. In some embodiments nanoemulsion compositions may comprise of one or more active agents.

[0151] In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio ranging between about 0.1:1 to about 2: 1. In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio of about 0.1:1 to about 1:1. In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio of about 0.5:1 to about 1:1. In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio of about 0.5:1 to about 1:1.5. In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio of about 0.1:1, about 0.15:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.35:1, about 0.4:1, about 0.45:1, about 0.5:1, about 0.5:1, about 0.55:1, about 0.6:1, about 0.65:1, about 0.7:1, about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, or about 1:1 In some embodiments, provided nanoemulsion compositions comprise oil and surfactant at a ratio of about 0.67: 1.

[0152] In some embodiments, an aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized at a ratio ranging between 0.01 and 20. In someAttorney Docket No. : 2012317-0366embodiments, an aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized at a ratio ranging between 0.1 and 20. In some embodiments, an aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized at a ratio ranging between 0.5 and 10. In some embodiments, an aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized at a ratio ranging between 0.5 and 1. In some embodiments, a ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is approximately 0.01:1, approximately 0.02:1, approximately 0.03:1, approximately 0.04:1, approximately 0.05:1, approximately 0.06:1, approximately 0.07:1, approximately 0.08:1, approximately 0.0:1, approximately 0.1:1, approximately 0.2:1, approximately 0.3:1, approximately 0.4:1, approximately 0.5:1, approximately 1:1, approximately 2:1, approximately 3:1, approximately 4:1, approximately 5:1, approximately 6:1, approximately 7:1, approximately 8:1, approximately 9:1 or approximately 10:1. In some embodiments, the ratio of surfactant to water is approximately 0.5:1, approximately 1:1, approximately 2:1, approximately 3:1, approximately 4:1, approximately 5:1, approximately 6:1, approximately 7:1, approximately 8:1, approximately 9:1, approximately 10:1, approximately 11:1, approximately 12:1, approximately 13:1, approximately 14:1, approximately 15:1, approximately 16:1, approximately 17:1, approximately 18:1, approximately 19:1, or approximately 20:1. In some embodiments, aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) and surfactant are utilized at a ratio ranging between 0.5 and 2. In some embodiments, a ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is approximately 0.5:1, approximately 1:1, or approximately 2:1. In some embodiments, a ratio of surfactant to aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) is approximately 0.5:1, approximately 1:1, or approximately 2:1. In some embodiments, a ratio of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant is approximately 1:1. In some embodiments, compositions utilizing such ratios of aqueous dispersion medium (e.g., water, buffer, salt solution, etc.) to surfactant comprise water-in-oil emulsions.

[0153] In some embodiments, droplets within nanoemulsion compositions have diameters (e.g., average and / or median diameters) within a 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, droplets within nanoemulsion compositions have diameters (e.g., averageAttorney Docket No. : 2012317-0366and / or median diameters) within a 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, droplets within nanoemulsion compositions have diameters (e.g., average and / or median 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.

[0154] In some embodiments, a total droplet distribution is encompassed within a specified range of droplet diameter size. In some embodiments, less than 50%, 25%, 10%, 5%, or 1% of a total droplet distribution is outside of a specified range of droplet diameter sizes. In some embodiments, less than 1% of a total droplet distribution is outside of a specified range of droplet diameter sizes. In some embodiments, a nanoemulsion composition is substantially free of droplets having a diameter larger 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 a total droplet distribution have diameters larger than 300 nm, 250 nm, 200 nm, 150 nm, 120 nm, 100 nm, 75 nm, 50 nm, or 25 nm.

[0155] In some embodiments, droplets within nanoemulsion compositions have an average droplet size that is under 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, average droplet size is within a range of about 10 nm and about 300 nm, about 50 nm and about 250, about 60 nm and about 200 nm, about 65 nm and about 150 nm, or about 70 nm and about 130 nm. In some embodiments, average droplet size is about 80 nm and about 110 nm. In some embodiments, average droplet size is about 90 nm and about 100 nm.

[0156] In some embodiments, nanoemulsion droplets have a zeta potential ranging between -80 mV and +80 mV. In some embodiments, nanoemulsion droplets have a zeta potential ranging between -50 mV and +50 mV. In some embodiments, nanoemulsion droplets have a zeta potential ranging between -25 mV and +25 mV. In some embodiments, nanoemulsion droplets have a zeta potential ranging between n -10 mV and +10 mV. In some embodiments, 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 -ImV. In some embodiments, nanoemulsion droplets have a zeta potential of about +50 mV, about +40 mV,Attorney Docket No. : 2012317-0366about +30 mV, about +25 mV, about +20 mV, about +15 mV, about +10 mV, or about +5 mV. In some embodiments, nanoemulsion droplets have a zeta potential that is about 0 mV

[0157] In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio ranging between about 8:1 and about 9:1. In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio of about 8:1, about 8.1:1, about 8.2:1, about 8.3:1, about 8.4:1, about 8.5:1, about 8.6:1, about 8.7:1, about 8.8:1, about 8.9:1, about 9:1, etc. In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio of about 8.7:1. In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio of about 8.8:1.

[0158] In some embodiments, aqueous dispersion media and oil are utilized at a ratio ranging between about 12:1 and about 14:1. In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio of about 12:1, about 12.1:1, about 12.2:1, about 12.3:1, about 12.4:1, about 12.5:1, about 12.6:1, about 12.7:1, about 12.8:1, about 12.9:1, about 13:1, about 13.1:1, about 13.2:1, about 13.3:1, about 13.4:1, about 13.5:1, about 13.6:1, about 13.7:1, about 13.8:1, about 13.9:1, about 14:1, etc. In some embodiments, aqueous dispersion media and surfactant are utilized at a ratio of about 13.1:1.

[0159] In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 50%. In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 40%. In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 30%. In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 20%. In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 10%. In some embodiments, a percent of oil in a nanoemulsion ranges between 0% and 5%. In some embodiments, a percent of oil in a nanoemulsion ranges between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, between 35% and 40%, or between 45% and 50%. In some embodiments, a percent of oil in a nanoemulsion ranges between 10% and 20%, between 10% and 30%, between 10% and 40%, or between 10% and 50%. In some embodiments, a percent of oil in a nanoemulsion ranges between 20% and 30%, between 20% and 40%, between 20% and 50%. In some embodiments, a percent of oil in the nanoemulsion ranges between 30% and 40% or between 30% and 50%. In some embodiments, a percent of oil in a nanoemulsion ranges between 40% and 50%.Attorney Docket No. : 2012317-0366

[0160] In some embodiments a percent of oil is approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, 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%, or approximately 50%. In some embodiments a percent of oil is approximately 10%. In some embodiments a percent of oil is approximately 9%. In some embodiments a percent of oil is approximately 8%. In some embodiments a percent of oil is approximately 7%. In some embodiments the percent of oil is approximately 6%. In some embodiments a percent of oil is approximately 5%. In some embodiments a percent of oil is approximately 4%. In some embodiments a percent of oil is approximately 3%. In some embodiments a percent of oil is approximately 2%. In some embodiments a percent of oil is approximately 1%.

[0161] In some embodiments, nanoemulsion formulations comprise water, medium chain triglyceride, polysorbate 80, methylparaben, and propylparaben. In some embodiments, nanoemulsion formulations comprise water, medium chain triglyceride, and polysorbate 80.

[0162] In some embodiments, a nanoemulsion may be formulated into a composition suitable for topical administration. In some embodiments, a composition suitable for topical administration may be a lotion, cream, powder, ointment, liniment, gel, drops, emollient, balm, or paste. In some embodiments, a nanoemulsion may be formulated into an injectable composition. In some embodiments, an injectable composition may be sterile.

[0163] These compositions are particularly useful in that they can be used for delivery of agents to a subject in need thereof via topical and / or transdermal (e.g., by lotions, creams, powders, ointments, liniments, gels, drops, etc.) administration. In someAttorney Docket No. : 2012317-0366embodiments, provided compositions may be administered to a subject in need thereof via topical and / or transdermal (e.g., by serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.) administration. In some embodiments, provided nanoemulsion compositions may be formulated into cream and / or lotion formulations. In some embodiments, provided compositions comprising nanoemulsion compositions may be useful and / or effective for topical administration to a subject. In some embodiments, provided nanoemulsion compositions may be admixed with one or more cream components in a cream formulation and / or a saline solution for preparation of a pharmaceutical composition.

[0164] The present disclosure encompasses a recognition that emulsion compositions (e.g., macroemulsion compositions and nanoemulsion compositions) may be formulated into cream and / or lotion formulations for administration to a subject. The present disclosure encompasses a recognition that provided compositions can be particularly useful for formulating emulsions, such as those described herein, for administration to a subject.Topical Formulations

[0165] Compositions as described herein are particularly useful in that they can be used for delivery of a PAI-1 inhibitor (e.g. ET-02) as described herein to a subject in need thereof (e.g. a subject suffering from a dermatological condition) via topical and / or transdermal (e.g., by serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.) administration. In some embodiments, provided compositions comprising a PAI-1 inhibitor, as described herein, are administered to a subject in need thereof via topical (e.g., by serums, suspensions, lotions, creams, powders, ointments, liniments, gels, drops, etc.) administration. In some embodiments, compositions formulated for topical administration comprise macroemulsions, as described herein. In some embodiments, compositions formulated for topical administration comprise nanoemulsions, as described herein.

[0166] In some embodiments, cream and / or lotion formulations comprise purified water, methylparaben, mineral oil, isopropyl myristate, white petrolatum, emulsifying wax, and propylparaben. In some embodiments, cream and / or lotion formulations comprise purified water, mineral oil, isopropyl myristate, white petrolatum, and emulsifying wax.Attorney Docket No. : 2012317-0366

[0167] In some embodiments, the present disclosure describes that provided compositions may be formulated into cream and / or lotion formulations as described herein. In some embodiments, provided compositions are formulated with water. In some embodiments, provided compositions are formulated with methylparaben. In some embodiments, provided compositions are formulated with mineral oil. In some embodiments, provided compositions are formulated with isopropyl myristate. In some embodiments, provided compositions are formulated with white petrolatum. In some embodiments, provided compositions are formulated with emulsifying wax. In some embodiments, provided compositions are formulated with propylparaben. In some embodiments, provided compositions are not formulated with any parabens. In some embodiments, provided compositions are not formulated with methylparaben. In some embodiments, provided compositions are not formulated with propylparaben.

[0168] In some embodiments, cream and / or lotion formulations may be useful for topical and / or transdermal administration. The present disclosure encompasses a recognition that, in some embodiments, provided compositions can be particularly useful for delivery of an active agent, for example, to a hair follicle located in a site of administration. In some embodiments, sites treated include those which used to have hair or hair follicles but no longer have hair or hair follicles. In some embodiments, provided compositions are formulated for topical delivery to a subject in need thereof. In some embodiments, provided compositions are administered to a subject in need thereof via topical delivery.

[0169] In some embodiments, provided compositions are formulated with cosmetically acceptable components. For example, in some embodiments, provided compositions are formulated with water and also any cosmetically acceptable solvent, in particular, monoalcohols, such as alkanols having 1 to 8 carbon atoms (like ethanol, isopropanol, benzyl alcohol and phenylethyl alcohol), polyalcohols, such as alkylene glycols (like glycerine, ethylene glycol and propylene glycol), and glycol ethers, such as mono-, di-, and tri-ethylene glycol monoalkyl ethers, for example, ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, used singly or in a mixture. Such components can be present, for example, in proportions of up to as much as 60%, 70%, 80%, or 90% by weight, relative to the weight of the total composition.

[0170] In some embodiments, provided compositions for topical administration include one or more cosmetically acceptable components that impart appearance attributesAttorney Docket No. : 2012317-0366desirable or appropriate for a subject to which a composition is to be administered (e.g., a matte appearance, which may be particularly desirable or appropriate for administration to subjects having greasy skin).

[0171] In some embodiments, provided compositions are formulated with at least one cosmetically acceptable filler material, for example, in order to obtain a matte product, which may be especially desired for individuals with greasy skin.

[0172] In some embodiments, one or more active agents are formulated into compositions suitable for topical administration. Exemplary active agents include those described herein. In some embodiments, provided compositions may be formulated and delivered in combination with microneedle skin conditioning (MSC) so that systemic delivery is achieved; in some embodiments, provided compositions may be formulated and / or delivered so that local, but not systemic, delivery is achieved.

[0173] In some embodiments, compositions suitable for topical formulation comprise a penetration enhancing agent. In some embodiments, a penetration enhancing agent degrades, disrupts and / or damages skin structure(s) and / or skin. In some embodiments, a penetration enhancing agent does not degrade, disrupt and / or damage skin structure(s) and / or skin. In some embodiments, a penetration enhancing agent is an irritant. In some embodiments, a penetration enhancing agent is not an irritant.

[0174] In some embodiments, provided compositions may be incorporated into a device such as, for example, a patch. A variety of transdermal patch structures are known in the art; those of ordinary skill will appreciate that provided compositions may readily be incorporated into any of a variety of such structures. In some embodiments, a transdermal patch may comprise a plurality of needles extending from one side of a patch that is administered to skin. In some embodiments, a transdermal patch may comprise a plurality of needles extending from one side of the patch that is administered to skin, wherein needles extend from a patch to project through a stratum comeum of skin. In some embodiments, needles do not rupture a blood vessel. In some embodiments, needles do not penetrate deeply enough to reach nerves in a dermis of skin.

[0175] In some embodiments, a transdermal patch includes an adhesive. Some examples of adhesive patches are well known (for example, 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 generallyAttorney Docket No. : 2012317-0366characterized as having an adhesive layer, which will be administered to a patient’s skin, a depot or reservoir for holding a provided composition, and an exterior surface that prevents leakage of the provided composition from the depot. The exterior surface of a patch may be non-adhesive.

[0176] In accordance with the present disclosure, a provided composition is incorporated into a patch so that it remains stable for extended periods of time. For example, in some embodiments, a provided composition may be incorporated into a polymeric matrix that stabilizes an active agent, and permits the agent to diffuse from the matrix and the patch. A provided composition may also be incorporated into an adhesive layer of a patch so that once the patch is administered to the skin, the provided composition may diffuse through skin. In some embodiments, an adhesive layer may be heat-activated where temperatures of about 37 °C cause the adhesive to slowly liquefy so that the agent diffuses through skin. An adhesive may remain tacky when stored at less than 37°C, and once administered to skin, an adhesive loses its tackiness as it liquefies.

[0177] In some embodiments, a provided composition can be provided in a depot in a patch so that pressure applied to the patch causes the provided composition to be directed out of the patch through microneedles and through the stratum comeum. Exemplary embodiments of microneedles are described above. Suitable devices for use in administering provided compositions intradermally include devices such as those described in U.S. Patent Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositions may be administered by devices which limit the effective penetration length of a needle into skin, such as those described in PCT publication WO 99 / 34850 and functional equivalents thereof.

[0178] In some embodiments, for example in order to prolong effect of a provided composition, it may be desirable to slow absorption of a provided composition into skin. In some embodiments, this may be accomplished by use of a liquid suspension of crystalline or amorphous material with poor water solubility. A rate of absorption of a provided composition then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. In some embodiments, depending upon a ratio of provided composition to polymer and the nature of the particular polymer employed, a rate of provided composition release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).Attorney Docket No. : 2012317-0366Administration

[0179] The present invention provides technologies for treating and / or preventing specific types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, and hair graying, using any of the provided compositions (e.g, provided emulsion compositions; cream and / or lotion formulations; combination of provided emulsion compositions and cream and / or lotion formulation; etc.} as described herein. In some embodiments, the provided compositions are administered in combination with MSC.

[0180] As described herein, the present invention provides methods of topically administering provided compositions to a subject for various applications including, for example, cosmetic and / or medical applications. In some embodiments, the present invention provides methods of treating and / or preventing diseases, disorders, and / or conditions associated with activity of epidermal and / or dermal structures (e.g, sweat glands, sebaceous glands, hair follicles, etc. by administering provided compositions to a subject in need thereof.Sites

[0181] According to the present disclosure, a composition comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) can be topically administered to a site of interest for treatment and / or prevention of any one or a combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. According to the present disclosure, a composition comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) can be administered to a site of interest for treatment and / or prevention of hair graying.

[0182] Technologies of the invention are suitable for both human and veterinary use. In some embodiments, subjects suffering from any one or a combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senescent alopecia, and hair graying which would benefit from topical administration of a PAI-1 inhibitor may be treated with the disclosed technologies.Attorney Docket No. : 2012317-0366

[0183] Any site suitable site for MSC is a suitable administration site. In some embodiments, an administration site is the skin overlying a muscle or muscle group of a subject. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiment the site is on the back. In some embodiments the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the crotch. In some embodiments, the site is on the groin. In some embodiments, the site is on the head. In some embodiments the site is on the scalp. In some embodiments, the site is on the face. In some embodiments the site is on the neck. In some embodiments the site is on the decollete. In some embodiments, the site is in the armpit. In some embodiments, the site is on the axillae. In some embodiments the site is on the hands. In some embodiments the site is on the feet. In some embodiments the site is on the arms. In some embodiments the site is on the legs. In some embodiments, the site used to have hair or hair follicles but no longer have hair or hair follicles.

[0184] In some embodiments, the site of interest has hair follicles. In some embodiments, the hair follicles have normal structure and / or density. In some embodiments, the hair follicles do not comprise hairs. In some embodiments, the hair follicles comprise hairs. In some embodiments, percentage of hair follicles with hair is 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%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.

[0185] In some embodiments, the hairs in the hair follicles are not gray in color. In some embodiments, the hairs in the hair follicles are gray in color. In some embodiments, percentage gray is 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%,Attorney Docket No. : 2012317-0366about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.

[0186] In some embodiments the site is affected by a dermatologic condition.

[0187] In some embodiments, the length of the microneedles used in MSC is adjusted based on skin thickness of the treatment site.

[0188] In some embodiments, MSC comprises one impression of microneedle (MN) or MN array. In some embodiments, MSC comprises two impressions of MN or MN array. In some embodiments, MSC comprises three impressions of MN or MN array. In some embodiments, MSC comprises four impressions of MN or MN array. In some embodiments, MSC comprises five impressions of MN or MN array. In some embodiments, MSC comprises six impressions of MN or MN array. In some embodiments, MSC comprises seven impressions of MN or MN array. In some embodiments, MSC comprises eight impressions of MN or MN array. In some embodiments, MSC comprises nine impressions of MN or MN array. In some embodiments, MSC comprises ten impressions of MN or MN array. In some embodiments, MSC comprises eleven impressions of MN or MN array. In some embodiments, MSC comprises twelve impressions of MN or MN array. In some embodiments, MSC comprises thirteen impressions of MN or MN array. In some embodiments, MSC comprises fourteen impressions of MN or MN array. In some embodiments, MSC comprises fifteen impressions of MN or MN array. In some embodiments, MSC comprises sixteen impressions of MN or MN array. In some embodiments, MSC comprises seventeen impressions of MN or MN array. In some embodiments, MSC comprises eighteen impressions of MN or MN array. In some embodiments, MSC comprises nineteen impressions of MN or MN array. In some embodiments, MSC comprises twenty impressions of MN or MN array. In some embodiments, the MSC comprises rolling the MN or MN array over the skin one or moreAttorney Docket No. : 2012317-0366times. In some embodiments, an MN array is rotated between impressions. In some embodiments an MN array is not rotated between impressions. In some embodiments impressions are made on the same site. In some embodiments impressions are made on overlapping sites. In some embodiments, impressions are made on different sites. In some embodiments, impressions are made by stamping of a MN array. In some embodiments, impressions are made by rolling a microneedle roller over a site one or more times. In accordance with established MN practices, in some embodiments, the MN array skin impressions last under one second or, alternatively, in some embodiments, they last over one second and may, for example, last for 30 seconds or more, 60 seconds or more, two minutes or more, five minutes or more, ten minutes or more, thirty minutes or more, etc.Subject

[0189] In general the subject is an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, the subject is male. In some embodiments, subject is female. In some embodiments, the subject is human. In a particular 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 a high follicle density. In some embodiments, the subject has colored hair. In some embodiments, the subject has gray hair. In some embodiments, a subject is suffering from a relevant disease, disorder or condition (e.g. specific types of alopecia disclosed herein, hair graying). In some embodiments, a subject is susceptible to a disease, disorder, or condition (e.g. specific types of alopecia disclosed herein, hair graying). In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition (e.g. specific types of alopecia disclosed herein, hair graying). In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition (e.g. specific types of alopecia disclosed herein, hair graying). In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition (e.g. specific types of alopecia disclosed herein, hair graying). In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.Attorney Docket No. : 2012317-0366

[0190] The technologies of the invention are suitable for both human and veterinary use. In some embodiments, subjects suffering from any one or a combination of androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, which would benefit from topical administration of a composition comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) may be treated with the disclosed technologies. In some embodiments, subjects suffering from hair graying which would benefit from topical administration of a composition comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) may be treated with the disclosed technologies.Route

[0191] In general, route is selected to achieve delivery of a therapeutically effective amount to a relevant site of action. Without wishing to be bound by any particular theory, in some embodiments, a site of action may be or comprise a site comprising a hair follicle. In some embodiments, an administration site is the skin overlying a muscle or muscle group of a subject. In some embodiments, the site is hairless. In some embodiments, the site is on the torso. In some embodiment the site is on the back. In some embodiments the site is on the chest. In some embodiments, the site is on the buttocks. In some embodiments, the site is on the crotch. In some embodiments, the site is on the groin. In some embodiments, the site is on the head. In some embodiments the site is on the scalp. In some embodiments, the site is on the face. In some embodiments the site is on the neck. In some embodiments the site is on the decollete. In some embodiments, the site is in the armpit. In some embodiments, the site is on the axillae. In some embodiments the site is on the hands. In some embodiments the site is on the feet. In some embodiments the site is on the arms. In some embodiments the site is on the legs.

[0192] In some embodiments, provided methods involve topical, transdermal, or intradermal administration of provided compositions comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02) to the skin of a subject. In some embodiments, such routes achieve local delivery.

[0193] In some particular embodiments, provided methods involve topical administration of an emulsion composition comprising a PAI-1 inhibitor (e.g. 5% w / w ET-02). In some particular embodiments, the emulsion composition is a macroemulsion. In some particular embodiments, the emulsion composition is a nanoemulsion. In some particular embodiments, topical application is via or in conjunction with MSC.Attorney Docket No. : 2012317-0366

[0194] In some embodiments, a PAI-1 inhibitor (e.g. ET-02) penetrates the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 to about 12 minutes of administration. In some embodiments, a biologically active agent penetrates the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 2 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 4 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 5 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 6 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 7 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 8 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 12 hours of administration. In some embodiments, a biologically active agent penetrates the skin within about 24 hours of administration.

[0195] In some embodiments, a PAI-1 inhibitor (e.g., ET-02) penetrates a layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 hours of administration. In some embodiments, a PAI-1Attorney Docket No. : 2012317-0366inhibitor penetrates a layer of the skin within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 24 hours of administration.

[0196] In some embodiments, a PAI-1 inhibitor (e.g. ET-02) penetrates the top layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 24 hours of administration.

[0197] In some embodiments, a PAI-1 (e.g. ET-02) inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin,Attorney Docket No. : 2012317-0366including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 24 hours of administration.RegimenAttorney Docket No. : 2012317-0366

[0198] In general, regimen is selected to achieve delivery of a therapeutically effective amount of PAI-1 inhibitor (e.g. ET-02) to a relevant site of action. In some embodiments the compositions and formulations described herein may be administered to a subject in need thereof at a relevant site of action in a single dose. In some embodiments the compositions and formulations described herein may be administered to a subject in need thereof a relevant site of action in multiple doses. For example, the compositions and formulations described herein, can be topically administered in a manner sufficient to achieve delivery of effective amount of the PAI-1 inhibitor (e.g., ET-02).

[0199] In some embodiments, a dosing regimen for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) may be less frequent than the dosing regimen typically utilized with a conventional hair loss treatment. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be fewer than twice a day. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be once a day. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be once every-other day. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be twice a week. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be weekly. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be biweekly. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may be monthly.

[0200] In some embodiments, a dosing regimen for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) may change over treatment course (e.g., administered to a particular subject). In some embodiments, a dosing regimen for a topical composition or formulation as described herein may become less frequent over time. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may become less frequent after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months of treatment. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may become less frequent after 1, 2, 3, 4, or 5 years of treatment.

[0201] In some embodiments, a dosing regimen for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) may be altered due to changes in the occurrence and / or progression of hair loss and / or hair graying. In some embodiments, aAttorney Docket No. : 2012317-0366dosing regimen for a topical composition or formulation as described herein may become less frequent over time as hair count increases. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may become less frequent over time as hair thickness increases. In some embodiments, a dosing regimen for a topical composition or formulation as described herein may become less frequent over time as hair darkness score increases. In some embodiments, treatment duration for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) is over a defined period of time. In some embodiments, treatment duration for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) is at least 7, 8, 9, 10, 11, 12, or 13 days. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 1 week. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 2 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 3 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 4 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 5 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 16 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 26 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein is at least 48 weeks. In some embodiments, treatment duration for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In some embodiments, treatment duration for a topical composition or formulation as described herein (e.g. 5% w / w ET-02) is greater than 10 years.

[0202] In some embodiments, a therapeutically effective dosage volume for a topical composition or formulation as described herein (e.g. 5% w / w ET-02 is ImL. In some embodiments, a therapeutically effective dosage volume for a topical composition or formulation as described herein varies based on the site to which a topical composition or formulation is being applied.

[0203] In some particular embodiments, a therapeutically effective dosing regimen is once daily topical application of ImL 5% w / w ET-02 on at least seven consecutive days.Attorney Docket No. : 2012317-0366

[0204] In some embodiments, 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 a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and / or as part of a single composition with, one or more other active agents.

[0205] Factors to be considered when optimizing routes and / or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and / or response thereto) the site of delivery of the agent, the nature of the agent (e.g. an antibody or other polypeptide-based compound), the mode and / or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners. For example, in the treatment of cancer, relevant features of the indication being treated may include, for example, one or more of cancer type, stage, location.

[0206] In some embodiments, one or more features of a particular pharmaceutical composition and / or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing the amount of active agent in any individual dose, increasing or decreasing time intervals between doses), for example in order to optimize a desired therapeutic effect or response (e.g., inhibition of the PAI-1 gene or gene product).

[0207] In general, type, amount, and frequency of dosing of active agents in accordance with the present invention are governed by safety and efficacy requirements that apply when one or more relevant agent(s) is / are administered to a mammal, preferably a human. In general, such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared to what is observed absent therapy.

[0208] In the context of the present invention, an exemplary desirable therapeutic response may involve, but is not limited to, inhibition of PAI- 1 gene and / or gene product, inhibition and / or a reduction in the degree and / or prevalence of a relevant alopecia, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, and / or inhibition and / or a reduction in the degree and / or prevalence of gray hairs. Such criteria can be readily assessed by any of a variety of immunological, cytological, and other methods that are disclosed in the literature.

[0209] In some embodiments, an effective dose (and / or a unit dose) of an active agent, may be at least about 0.01 ng / kg body weight, at least about 0.01 pg / kg body weight,Attorney Docket No. : 2012317-0366at least about 0.05 pg / kg body weight; at least about 0.1 gg / kg body weight, at least about 1 pg / kg body weight, at least about 2.5 gg / kg body weight, at least about 5 gg / kg body weight, at least about 10 gg / kg body weight, at least about 100 gg / kg body weight, at least about 1 mg / kg body weight, at least about 10 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 300 mg / kg body weight, at least about 400 mg / kg body weight, and not more than about 500 mg / kg body weight. It will be understood by one of skill in the art that in some embodiments such guidelines may be adjusted for the molecular weight of the active agent. The dosage may also be varied for route of administration, the cycle of treatment, or consequently to dose escalation protocol that can be used to determine the maximum tolerated dose and dose limiting toxicity (if any) in connection to the administration of the PAI-1 antagonist and / or an additional therapeutic agent at increasing doses. Consequently, the relative amounts of each agent within a pharmaceutical composition may also vary, for example, each composition may comprise between 0.001 % and 100% (w / w) of the corresponding agent.

[0210] In some embodiments, a “therapeutically effective amount” or “therapeutically effective dose” is an amount of a PAI-1 antagonist, or a combination of two or more PAI-1 antagonists, or a combination of a PAI-1 antagonist with one or more additional therapeutic agent(s), which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. In some embodiments, a therapeutically effective amount can be an amount which is prophylactically effective. In some embodiments, an amount which is therapeutically effective may depend upon a patient’s size and / or gender, the condition to be treated, severity of the condition and / or the result sought. In some embodiments, a therapeutically effective amount refers to that amount of a PAI-1 antagonist that results in amelioration of at least one symptom in a patient. In some embodiments, for a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.

[0211] In some embodiments, toxicity and / or therapeutic efficacy of PAI-1 antagonists can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective dose for 50% maximal response). Typically, the dose ratio between toxic and therapeutic effects is the therapeutic index; in some embodiments, this ratio can be expressed as the ratio between MTD and ED50. Data obtained from such cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.Attorney Docket No. : 2012317-0366

[0212] In some embodiments, dosage may be guided by monitoring a PAI-1 antagonist’s effect on one or more pharmacodynamic markers of inhibition in diseased or surrogate tissue. For example, cell culture or animal experiments can be used to determine the relationship between doses required for changes in pharmacodynamic markers and doses required for therapeutic efficacy can be determined in cell culture or animal experiments or early stage clinical trials. In some embodiments, dosage of a PAI-1 antagonist lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. In some embodiments, dosage may vary within such a range, for example depending upon the dosage form employed and / or the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient’s condition. In the treatment of crises or severe conditions, administration of a dosage approaching the MTD may be required to obtain a rapid response.

[0213] In some embodiments, dosage amount and / or interval may be adjusted individually, for example to provide plasma levels of an active moiety which are sufficient to maintain, for example a desired effect, or a minimal effective concentration (MEC) for a period of time required to achieve therapeutic efficacy. In some embodiments, MEC for a particular PAI-1 antagonist can be estimated, for example, from in vitro data and / or animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In some embodiments, high pressure liquid chromatography (HPLC) assays or bioassays can be used to determine plasma concentrations.

[0214] In some embodiments, dosage intervals can be determined using the MEC value. In certain embodiments, compositions and formulations described herein (e.g. 5% w / w ET-02) should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of a symptom is achieved. In other embodiments, different MEC plasma levels will be maintained for differing amounts of time. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0215] One of skill in the art can select from a variety of administration regimens and will understand that an effective amount of a particular composition comprising a PAI-1Attorney Docket No. : 2012317-0366inhibitor may be dependent on the subject being treated, on the subject’s weight, the severity of the affliction, the manner of administration and / or the judgment of the prescribing physician.

[0216] In some embodiments, the present invention involves topical administration of at least one provided composition (e.g. 5% w / w ET-02), administered according to a dosing regimen sufficient to achieve a reduction in the degree and / or prevalence of a relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia) and / or hair graying of at least about 7%; in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 10% ; in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 15%;in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 20%; 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%; 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 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.

[0217] In some embodiments, the present invention involves administration of at least one provided composition (e.g. 5% w / w ET-02) , administered in combination with MSC, according to a dosing regimen sufficient to achieve a reduction in the degree and / or prevalence of a relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia) and / or hair graying of at least about 7%; in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 10%; in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 15%; in some embodiments according to a dosing regimen sufficient to achieve a reduction of at least about 20%; in someAttorney Docket No. : 2012317-0366embodiments 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%; 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 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.

[0218] In some embodiments, the present invention involves topical administration of at least one provided composition (e.g. 5% w / w ET-02), administered according to a dosing regimen sufficient to achieve an increase in hair width of at least about 5%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 7%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 8%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 10%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 15%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 20%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 25%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 30%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.Attorney Docket No. : 2012317-0366

[0219] In some embodiments, the present invention involves administration of at least one provided composition (e.g. 5% w / w ET-02) , administered in combination with MSC, according to a dosing regimen sufficient to achieve an increase in hair width of at least about 5%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 7%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 8%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 10%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 15%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 20%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 25%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 30%; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or more.

[0220] In some embodiments, the present invention involves topical administration of at least one provided composition (e.g. 5% w / w ET-02), administered optionally in combination with MSC, according to a dosing regimen sufficient to achieve a reduction in the degree and / or prevalence of a relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia) and / or hair graying of at least about 7% in a specified percentage of a population of patients to which the composition was administered; in some embodiments of at least about 10% in a specified percentage of a population of patients to which the composition was administered; in some embodiments of at least about 15% in a specified percentage of a population of patients to which the composition was administered; in some embodiments of at least about 20% in a specified percentage of a population of patients to which the composition was administered; in some embodiments according to a dosing regimen sufficient to achieve aAttorney Docket No. : 2012317-0366reduction of at least about 25% in a specified percentage of a population of patients to which the composition was 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 population of patients to which the composition was administered; 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 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more in a specified percentage of a population of patients to which the composition was administered. In some embodiments, the specified percentage of population of patients to which the composition was administered is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. To give but a few illustrative examples, in some embodiments, the present invention involves administration of at least one provided composition according to a dosing regimen sufficient to achieve a reduction in the degree and / or prevalence of a relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia) of at least about 10% in at least about 50% of the population of patients to which the composition was administered. In some embodiments, the present invention involves administration of at least one provided composition according to a dosing regimen sufficient to achieve a reduction in the degree and / or prevalence of a relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia) of at least about 12% in at least about 50% of the population of patients to which the composition was administered.

[0221] In some embodiments, the present invention involves topical administration of at least one provided composition (e.g. 5% w / w ET-02), administered optionally in combination with MSC, according to a dosing regimen sufficient to achieve an increase in hair width of at least about 5% in a specified percentage of a population of patients to whichAttorney Docket No. : 2012317-0366the composition was administered; in some embodiments of at least about 7% in a specified percentage of a population of patients to which the composition was administered; in some embodiments of at least about 8% in a specified percentage of a population of patients to which the composition was administered; in some embodiments of at least about 10% in a specified percentage of a population of patients to which the composition was administered; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 15% in a specified percentage of a population of patients to which the composition was administered; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 20% in a specified percentage of a population of patients to which the composition was administered; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 25% in a specified percentage of a population of patients to which the composition was administered; in some embodiments according to a dosing regimen sufficient to achieve an increase of at least about 30% in a specified percentage of a population of patients to which the composition was administered; 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 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more in a specified percentage of a population of patients to which the composition was administered. In some embodiments, the specified percentage of population of patients to which the composition was administered is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. To give but a few illustrative examples, in some embodiments, the present invention involves administration of at least one provided composition according to a dosing regimen sufficient to achieve an increase in hair width of at least about 5% in at least about 50% of the population of patients to which the composition was administered. In some embodiments, the present invention involvesAttorney Docket No. : 2012317-0366administration of at least one provided composition according to a dosing regimen sufficient to achieve an increase in hair of at least about 7% in at least about 50% of the population of patients to which the composition was administered.

[0222] In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying (e.g. 5% w / w ET-02) are administered to a population according to a regimen demonstrated to achieve an increase in hair count. In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying are administered to a population according to a regimen demonstrated to achieve an increase in hair count of at least 12% on average in the population.

[0223] In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying (e.g. 5% w / w ET-02) are administered to a population according to a regimen demonstrated to achieve an increase in hair thickness. In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying are administered to a population according to a regimen demonstrated to achieve an increase in hair thickness of at least 9% on average in the population.

[0224] In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying (e.g. 5% w / w ET-02) are administered to a population according to a regimen demonstrated to achieve an increase in hair darkness score. In some embodiments, provided compositions and formulations for treating and / or preventing hair loss and / or hair graying are administered to a population according to a regimen demonstrated to achieve an increase in hair darkness score of at least 8% on average in the population.

[0225] In some embodiments, incidence of adverse events related to a provided composition (e.g., 5% w / w ET-02) in a population that has received topical administration of the provided composition (e.g. 5% w / w ET-02), is less than about 13.8%; in some embodiments, such incidence is less than 12.3%, 9.8%, 3.3%, or 2.5%; in some embodiments, such incidence is zero. In some embodiments, incidence of an adverse event selected from the group consisting of skin irritation, itching, skin rash, acne, scalp burning, facial swelling inflammation or soreness at root of hair, excess facial hair growth, and combinations thereof that is associated with a provided composition (e.g., 5% w / w ET-02)Attorney Docket No. : 2012317-0366in a population that has received topical administration of the provided composition (e.g. 5% w / w ET-02), is less than about 13.8%; in some embodiments, such incidence is less than 12.3%, 9.8%, 3.3%, or 2.5%; in some embodiments, such incidence is zero.

[0226] In some embodiments, incidence of systemic adverse events related to a provided composition (e.g. 5% w / w ET-02) in a population that has received topical administration of the provided composition (e.g. 5% w / w / ET-02) is less than about 5%; in some embodiments, such incidence is less than 0.5% or 0.3%; in some embodiments, such incidence is zero. In some embodiments, incidence of an adverse event selected from the group consisting of headache, dizziness, lightheadedness, nausea, heartbeat irregularities, numbness, chest pain, fainting, swelling of extremities, heightened blood pressure, sexual dysfunction, and combinations thereof that is associated with a provided composition (e.g., 5% w / w ET-02) in a population that has received topical administration of the provided composition (e.g. 5% w / w ET-02), is less than about 5%; in some embodiments, such incidence is less than 0.5% or 0.3%; in some embodiments, such incidence is zero.

[0227] In some embodiments, the present disclosure provides PAI-1 inhibitor compositions and dosing regimens as described herein that are characterized by adverse events in in less than 0.1% of a population of patients to which the composition was topically administered according to the regimen; in some embodiments, the present disclosure provides PAI-1 inhibitor compositions and dosing regimens as described herein that are characterized in that less than 0.1% of a population of patients to which the composition was topically administered according to the regimen suffer an adverse event selected from the group consisting of skin irritation, itching, skin rash, acne, scalp burning facial swelling inflammation or soreness at root of hair, excess facial hair growth, and combinations thereof.

[0228] In some embodiments, the present disclosure provides PAI-1 inhibitor compositions and dosing regimens as described herein that are characterized by systemic adverse events in in less than 0.1% of a population of patients to which the composition was topically administered according to the regimen; in some embodiments, the present disclosure provides PAI-1 inhibitor compositions and dosing regimens as described herein that are characterized in that less than 0.1% of a population of patients to which the composition was topically administered according to the regimen suffer a systemic adverse event selected from the group consisting of headache, dizziness, nausea, lightheadedness,Attorney Docket No. : 2012317-0366heartbeat irregularities, numbness, chest pain, fainting, swelling of extremities, heightened blood pressure, sexual dysfunction, and combinations thereof.

[0229] The present invention provides technologies for treating conditions or disorders by administering to a patient a provided composition as described herein (e.g., a provided emulsion composition; cream and / or lotion formulation; combination of provided emulsion composition and cream and / or lotion formulation; etc.), optionally in combination with MSC. In some embodiments, the present invention provides technologies for treating conditions or disorders by topically administering to a patient a composition containing a provided emulsion composition, optionally in combination with MSC as described herein.

[0230] In some embodiments, an active agent or PAI-1 inhibitor (e.g.ET-02) penetrates the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the skin within about 24 hours of administration.

[0231] In some embodiments, a PAI-1 inhibitor (e.g., ET-02) penetrates a layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of theAttorney Docket No. : 2012317-0366skin within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates a layer of the skin within about 24 hours of administration.

[0232] In some embodiments, a PAI-1 inhibitor (e.g. ET-02) penetrates the top layer of the skin within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 7 hours of administration. In someAttorney Docket No. : 2012317-0366embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin within about 24 hours of administration.

[0233] In some embodiments, a PAI-1 inhibitor (e.g. ET-02) penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 60 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 12 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 to about 15 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 15 to about 30 minutes of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 1 hour of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 2 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 3 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 4 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 5 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 6 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 7 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin,Attorney Docket No. : 2012317-0366including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 8 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 12 hours of administration. In some embodiments, a PAI-1 inhibitor penetrates the top layer of the skin, including the stratum corneum, dermal pores, hair follicles, and / or dermal glands within about 24 hours of administration.Penetration Enhancing Treatment

[0234] According to the present invention, in some embodiments, compositions and formulations as described herein (e.g. 5% w / w ET-02) may be administered topically in combination with one or more penetrating enhancing treatments (e.g. chemical agents, laser treatment, microneedling, physical massage etc.), such as known penetration enhancing agents and / or penetration enhancing treatment modalities, to for example, facilitating penetration of PAI- 1 inhibitors across biological barrier (e.g., skin). In some embodiments, compositions and formulations as described herein include one or more such other penetration enhancing agents; in some embodiments, such other penetration enhancing agents are provided as part of distinct compositions. In some embodiments, penetration enhancing treatment involves simultaneous administration of two or more different penetration enhancing agents 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 through simultaneous laser treatment and composition administration.

[0235] In some embodiments, penetration enhancing agents is or comprises chemical agents. For example, chemical agents that that may damage, disrupt, and / or degrade one or more stratum corneum components) may include, for example, alcohols, such as short chain alcohols, long chain alcohols, or polyalcohols; amines and amides, such as urea, amino acids or their esters, amides, AZONE®, derivatives of AZONE®, pyrrolidones, or derivatives of pyrrolidones; terpenes and derivatives of terpenes; fatty acids and their esters; macrocyclic compounds; tensides; or sulfoxides (e.g., dimethylsulfoxide (DMSO), decylmethylsulfoxide, etc.); surfactants, such as anionic, cationic, and nonionic surfactants; polyols; essential oils; and / or hyaluronidase. In some embodiments, a penetration enhancing agent may be anAttorney Docket No. : 2012317-0366irritant in that an inflammatory and / or allergic reaction occurs when the agent is administered to skin. In some embodiments, a penetration enhancing agent is not an irritant. In some embodiments, a penetration enhancing agent may be or comprise a chemical agent that does not damage, disrupt, or degrade skin structure but whose presence or level nonetheless correlates with increased penetration of an agent of interest across skin, as compared with that observed in its absence. In some embodiments, co-peptides, carrier molecules, and carrier peptides may be penetration enhancing agents which do not damage, disrupt, and / or degrade skin structure(s). In some embodiments, co-peptides, carrier molecules, and carrier peptides may be penetration enhancing agents which do not irritate the skin. The term “penetration enhancing agent” does not encompass mechanical devices (e.g., needles, scalpels, etc.), or equivalents thereof (e.g., other damaging treatments). Also, those skilled in the art will appreciate that a structure such as a nanoparticle or an emulsion is not a chemical agent and therefore not a chemical penetration enhancing agent even if its presence correlates with enhanced skin penetration of an agent of interest that may be associated with the structure. In some embodiments, penetration enhancing agents is or comprises alcohol.

[0236] In some embodiments, penetration enhancing treatment modalities is or comprises microneedling. In some embodiments, penetration enhancing treatment modalities is or comprises laser treatment. In some embodiments, penetration enhancing treatment modalities is or comprises physical massage. For example, in some embodiments, the composition may be administered before or after a performing laser treatment of the site. In some embodiments, penetration enhancing treatment modalities is or comprises administration of an electric or magnetic field.Microneedling:

[0237] In some particular embodiments, microneedle (MN) arrays for use in accordance with the present disclosure are or share features with minimally invasive systems, developed to overcome some of the disadvantages commonly associated with the use of hypodermic and subcutaneous needles, as well as improve patient comfort and compliance. Such disadvantages include, for example, potential for needle tip misplacement with a hypodermic needle because a health professional cannot visualize where exactly the needle is going; such needle misplacement can result in adverse reactions when injectedAttorney Docket No. : 2012317-0366incorrectly. MN would be less prone to such a problem. Other advantages of MN are that they may not cause bleeding, minimize introduction of pathogens through MN produced holes, and eliminate transdermal dosing variability. Other advantages are the possibility of self-administration, reduce risk of accidental needle stick injuries, reduce risk of transmitting infection, and ease of disposal. In some embodiments, MN are multiple microscopic projections assembled on one side of a support, such as a patch or a device (e.g., stamp, roller, array, applicator, pen).

[0238] In some embodiments, MN for use in accordance with the present disclosure may be designed and / or constructed in arrays in order to improve skin contact and facilitate penetration into the skin. In some embodiments, utilized MN are of suitable length, width, and shape to minimize contact with nerves when inserted into the skin, while still creating efficient pathways for drug delivery. Alkilani, A. Z., et al., “Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum comeum.” Pharmaceutics. 7:438-470 (2015).

[0239] In some embodiments, a suitable MN may be solid, coated, porous, dissolvable, hollow, or hydrogel MN. Solid MN create microholes in the skin, thereby increasing transport of a drug formulation (e.g., “poke and patch” methods). Coated MN allow for rapid dissolution of a coated drug into the skin (e.g., “coat and poke” methods). Dissolvable MN allow for rapid and / or controlled release of a drug incorporated within the microneedles. Hollow MN may be used to puncture the skin and enable release of a composition following active infusion or diffusion of a formulation through a microneedle’s bores (e.g., “poke and flow” methods”). In the case of dissolvable MN, MN can act as a drug depot, holding a drug composition until released by dissolution in the case of dissolvable MN or swelling in the case of hydrogel MN (e.g., “poke and release” methods). However, as already described herein, in many embodiments, the active agent is not delivered by injection via one or more microneedles. That is, in many embodiments, any microneedle utilized in accordance with such embodiments is not coated, loaded, or fabricated with the PAI-1 inhibitor in any way that would achieve delivery of the PAI-1 inhibitor. Alternatively, in some embodiments, as described herein, a MN, utilized in accordance with the present disclosure (whether in MSC or otherwise), may comprise and / or deliver a PAI-1 inhibitor, if the PAI-1 inhibitor is formulated in a macro- or nano- emulsion composition as described herein. Thus, as will be appreciated by those skilled in the art reading the specification described herein, treatment of skin with microneedle(s) that deliverAttorney Docket No. : 2012317-0366the PAI-1 inhibitor (e.g., by injection through a microneedle, by the release of a microneedle coating or by the release from a dissolving microneedle) is not microneedle skin conditioning.

[0240] In some embodiments, a microneedle has a diameter which is consistent throughout the microneedle’s length. In some embodiments, the diameter of a microneedle is greatest at the microneedle’s base end. In some embodiments, a microneedle tapers to a point at the end distal to the microneedle’s base. In some embodiments, a microneedle may be solid. In some embodiments, a microneedle may be hollow. In some embodiments a microneedle may be tubular. In some embodiments, a microneedle may be sealed on one end. In some embodiments, a microneedle is part of an array of microneedles. In some embodiments, a microneedle may have a length of between about 1 pm to about 4,000 pm. In some embodiments, a microneedle may have a length of between about 1 pm to about 2,000 pm. In some embodiments, a microneedle may have a length of between about 50 pm to about 400 pm. In some embodiments, a microneedle may have a length of between about 800 pm to about 1500 pm.

[0241] In some embodiments, MN for use in accordance with the present disclosure may be fabricated from different materials, using technologies including, but not limited to micro-molding processes or lasers. In some embodiments, MN may be manufactured using various types of biocompatible materials including polymers, metal, ceramics, semiconductors, organics, composites, or silicon. Unless they are designed to break off into the skin and dissolve, in some embodiments, microneedles have the mechanical strength to remain intact and to deliver drugs, or collect biological fluid, while being inserted into the skin and / or removed from the skin after insertion. In some embodiments MN are capable of remaining in place for up to a number of days before intact removal. In some embodiments, microneedles may be sterilizable using standard technologies. In some embodiments, MN are biodegradable. In some embodiments, MN comprise a polymeric material. In some embodiments the polymeric material comprises poly-L-lactic acid, poly-glycolic acid, polycarbonate, poly-lactic-co-glycolic acid (PLGA), polydimethylsiloxane, polyvinylpyrrolidone (PVP), a copolymer of methyl vinyl ether and maleic anhydride, sodium hyaluronate, carboxymethyl cellulose, maltose, dextrin, galactose, starch, gelatin, or a combination thereof.Attorney Docket No. : 2012317-0366

[0242] Suitable MN arrays and MSC devices for use in combination with compositions comprising PAI-1 inhibitors for transdermal delivery of PAI- 1 inhibitors include devices such as those described in e.g., U.S. Patents 6,334,856; 6,503,231;6,908,453; 8,257,324; and 9,144,671.Combination Therapy or Treatment

[0243] According to the present invention, compositions and formulations as described herein (e.g. 5% w / w ET-02) may be topically administered in combination with one or more additional treatments. In some embodiments the one or more additional treatments is or comprises other active agents and / or therapeutic modalities (e.g. one or more PAI-inhibitors, or other agents), such as known therapeutic agents and / or independently active PAI-1 inhibitors. In some embodiments, for example, compositions and formulations as described herein include one or more such other active agents; in some embodiments, such other active agents are provided as part of distinct compositions. In some embodiments, combination therapy involves simultaneous administration of one or more doses or units of two or more other active agents and / or therapeutic modalities; in some embodiments, combination therapy involves simultaneous exposure to two or more other active agents and / or therapeutic modalities, for example through overlapping dosing regimens.

[0244] In some embodiments, compositions and formulations as described herein include or are administered in combination with one or more other active agents useful for the treatment of the relevant specific type of hair loss (e.g. androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia), for example as discussed herein in the context of the relevant disease, disorder, and / or condition.Kits

[0245] In some embodiments, the present invention provides pharmaceutical packs or kits including one or more emulsion compositions comprising one or more PAI-1 inhibitors (e.g. ET-02) and / or one or more microneedle devices according to the present invention. In some embodiments, pharmaceutical packs or kits include preparations or pharmaceutical compositions containing provided compositions in one or more containersAttorney Docket No. : 2012317-0366filled with optionally one or more additional ingredients of pharmaceutical compositions. In some embodiments, a pharmaceutical pack or kit includes an additional approved therapeutic agent for use in combination therapies. In some embodiments, optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.

[0246] Kits are provided that include therapeutic reagents and / or active agents, such as PAI-1 inhibitors (e.g. ET-02). As but one non-limiting example, provided compositions can be provided as topical formulations and administered as therapy. Pharmaceutical doses or instructions therefor may be provided in a kit for administration to an individual suffering from or at risk for conditions or disorders, e.g., those associated with the dermal level of the skin.

[0247] In some embodiments, a kit may comprise (i) a provided composition (e.g.5% w / w ET-02); and (ii) a device for topical administration of the composition (e.g. bottle with dropper attachment); and optionally (iii) instructions for use (e.g., of instructions for topical application less frequently than twice a day and / or instructions for topical application over a period of time that is at least seven days, and / or in an amount of approximately ImL, etc.)

[0248] In some embodiments, a kit may comprise (i) a provided composition (e.g.5% w / w ET-02); and (ii) a device that delivers the composition as a foam; and optionally (iii) instructions for use (e.g. instructions for topical application less frequently than twice a day and / or instructions for topical application over a period of time that is at least seven days, and / or in an amount of approximately ImL, etc.)

[0249] In some embodiments, a kit may comprise (i) a provided composition (e.g.5% w / w ET-02); and (ii) at least one pharmaceutically acceptable excipient; and optionally (iii) at least one syringe, spatula, swab for administration to skin; and (iv) instructions for use.

[0250] In some embodiments, a kit may comprise (i) a provided composition (e.g.5% w / w ET-02); and (ii) at least one pharmaceutically acceptable excipient; and optionally (iii) a device for injection (e.g., syringe and needle, microneedle array, hair brush, etc.); and (iv) instructions for use.Attorney Docket No. : 2012317-0366

[0251] It will be appreciated by those of ordinary skill in the art that inventive compositions and formulations for topical administration may have a cosmetic formulation such as skin softener, nutrition lotion type emulsion, cleansing lotion, cleansing cream, skin milk, emollient lotion, massage cream, emollient cream, make-up base, facial pack or facial gel, cleaner formulation such as shampoos, rinses, body cleanser, hair-tonics, or soaps, or dermatological composition such as lotions, ointments, gels, creams, patches or sprays. In some embodiments, compositions and formulations for topical administration are not formulated for administration to mucous membranes (e.g., are inappropriate for administration to mucous membranes and / or are not formulated to deliver an appropriate amount of large agent to or across mucous membranes).EXEMPLIFICATIONExample 1: Safety of topical PAI-1 inhibitor formulations

[0252] The present example demonstrates that topical application of PAI- 1 inhibitor formulations can result in no adverse effects in a population.

[0253] A double-blind clinical trial was conducted to assess the safety of topical application of PAI- 1 inhibitor formulations in humans. The study included three groups. Group A received vehicle treatment (N=8). Group B received 1.25% ET-02 treatment (N=8). Group C received 1.25% ET-02 treatment (N=8). The scalp of each subject was treated one daily topically with ImL of vehicle or ET-02 treatment over 28 days. Safety was assessed by monitoring of abnormal health events including skin abnormalities, blood work, and EKGs.

[0254] No adverse events were related to ET-02. No patients withdrew from the clinical trial due to adverse events. No skin reactions or irritations, including skin itching, burning, dryness, erythema, or scaling, were reported. No clinically significant lab or EKG abnormalities were reported.

[0255] This study described in this example documents the unexpected result, described herein, that topical administration of 5% ET-02 results in no adverse events related to ET-02 in a population.Example 2: Effects of topical PAI-1 inhibitor formulation on hair loss (Alopecia) and hair widthAttorney Docket No. : 2012317-0366

[0256] The present example demonstrates that a topical PAI-1 inhibitor formulation can cause hair re-growth after topical administration of a topical formulation of PAI- 1 inhibitor (e.g., see Table 1) in man is performed. The study is designed to test whether the topical formulation of PAI- 1 inhibitor significantly reduces hair loss in man with specific types of alopecia, namely androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia, by measuring hair follicle density following topical treatment with a PAI-1 inhibitor.

[0257] A clinical trial was conducted to assess the effects of a topical PAI-1 inhibitor formulation on scalp of man. The study included two groups. Group A received either vehicle or 1.25% ET-02 treatment (N=12). Group B received 5% ET-02 treatment (N=8). The scalp of each subject was treated once daily topically with 1 mL of vehicle or ET-02 formulation over 28 days. The results of the clinical trial were compared to other hair loss treatments.

[0258] Hair count was measured using automated image analysis of scalp photography. Hair count (total as well as non-vellus) was measured per square centimeter, in the same location for each measurement.

[0259] As shown in FIG. 1, 5% ET-02 treatment resulted in a 13% increase in non-vellus (or normal) hair count from baseline. Vehicle and 1.25% ET-02 treatment resulted in a 2% increase in non-vellus hair count from baseline.

[0260] As shown in FIG. 2, no subjects treated with 5% ET-02 exhibited hair loss.25% of subjects treated with Vehicle and 1.25% ET-02 exhibited hair loss.

[0261] As shown in FIG. 3, 5% ET-02 treatment resulted in similar or superior increase in non-vellus hair count over a shorter time frame than other hair loss treatments.5% Minoxidil foam over 15 weeks resulted in a 12% increase in non-vellus hair count. 5% Minoxidil topical over 48 weeks resulted in a 12% increase in non-vellus hair count. Img oral Finasteride over 26 weeks resulted in an 11% increase in non-vellus hair count. 5% ET-02 treatment at week 5 resulted in a 13% increase in non-vellus hair count.

[0262] As shown in FIG. 4, 5% ET-02 treatment resulted in a 9% increase in non-vellus hair width from baseline. Vehicle and 1.25% ET-02 treatment resulted in approximately a 1% decrease in hair width from baseline.Attorney Docket No. : 2012317-0366

[0263] This study described in this example documents the unexpected result, described herein, that topical administration of 5% ET-02 over 28 days results in hair regrowth, no hair loss, and increased hair thickness in subject. Further, the study described in this example documents the unexpected result, described herein, that topical administration of 5% ET-02 over 28 days results in comparable or superior hair re-growth to other hair regrowth treatments over a shorter period of time that could not be achieved by these other treatments in a briefer (5-week) period.Example 3: Effects of topical PAI-1 inhibitor formulation on hair darkness score

[0264] The present example demonstrates that a topical PAI-1 inhibitor formulation can impact hair darkness score in man.

[0265] A clinical trial was conducted to assess the effects of a topical PAI-1 inhibitor formulation on scalp of man. The study included two groups. Group A received either vehicle or 1.25% ET-02 treatment (N=12). Group B received 5% ET-02 treatment (N=8). The scalp of each subject was treated one daily topically with ImL vehicle or ET-02 formulation over 28 days.

[0266] Hair darkness was measured using automated image analysis of scalp photography. Hair darkness in non-vellus hair was measured at week 5.

[0267] As shown in FIG. 5, 5% ET-02 resulted in an 8% increase in hair darkness score at week 5 over baseline. Vehicle and 1.25% ET-02 treatment resulted in a 2% decrease in hair darkness score at week 5 over baseline. Those skilled in the art will be familiar with hair darkness score systems, and their use to assess hair color (and changes thereof) in man. As noted, the present Example documents an increase in hair darkness score in the present study. Those skilled in the art will understand that at least some hair darkness scores increase with decreasing hair color.

[0268] The study described in this example documents the unexpected result, described herein, that topical administration of 5% ET-02 over 28 days results in increased hair darkness score. Further, the study described in this example documents the unexpected result, described herein, that topical administration of 5% ET-02 over 28 days impacts hair graying (i.e., alters hair darkness score). For completeness, the present disclosure notes that, in some embodiments, provided technologies may achieve a decrease in hair darkness score;Attorney Docket No. : 2012317-0366in other embodiments, provided technologies may not significantly impact hair darkness score. Thus, in some embodiments, provided technologies can achieve improvement(s) in hair loss independent of any particular impact on hair graying.EQUIVALENTS

[0269] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims:

Claims

Attorney Docket No. : 2012317-0366CLAIMSWe claim:

1. A method of treating and / or reducing hair loss and / or graying, the method comprising:topically administering a composition that comprises or delivers a Plasminogen Activator Inhibitor- 1 (PAI-1) inhibitor to a site of the subject, so that the PAI-1 inhibitor is delivered to the subject,wherein the site contains or did contain a plurality of hair follicles,wherein the weight percentage of the PAI-1 inhibitor in the composition is at least 2%,wherein the administering occurs less frequently than twice a day, and wherein the administering occurs for a period of time that is least seven days.

2. The method of claim 1, wherein the PAI-1 inhibitor is selected from a group consisting of: 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid, 5-Chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, a butadiene, spironolactone, imidapril, an angiotensin converting enzyme inhibitor (ACEI, captopril, or enalapril), an angiotensin II receptor antagonist (AURA), a defibrotide (a polydeoxyribonucleotide), and any combination thereof.

3. The method of claim 1, wherein the PAI-1 inhibitor is 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid (ET-02).

4. The method of claim 1, wherein the subject is suffering from androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, senescent alopecia, and / or combinations thereof.

5. The method of any one of the preceding claims, wherein the site is the scalp.

6. The method of any one of claims 1-4, wherein the site is on the face.

7. The method of any one of claims 1-4, wherein the site is on the chest.

8. The method of any one of claims 1-4, wherein the site is on the crotch.Attorney Docket No. : 2012317-03669. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.

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

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

12. The method of claim 11, wherein the emulsion comprises a nanoemulsion.

13. The method of claim 11, wherein the emulsion comprises a macroemulsion.

14. The method of any one of the preceding claims, wherein the weight percentage is at least 3%.

15. The method of any one of the preceding claims, wherein the weight percentage is at least 4%.

16. The method of any one of the preceding claims, wherein the weight percentage is 5%.

17. The method of any one of the preceding claims, wherein the administering occurs once a day.

18. The method of any one of the preceding claims, wherein the administering occurs once every other day.

19. The method of any one of the preceding claims, wherein the administering occurs twice a week.Attorney Docket No. : 2012317-036620. The method of any one of the preceding claims, wherein the administering occurs once a week.

21. The method of any one of the preceding claims, wherein the administering occurs over a period of time that is at least two weeks.

22. The method of any one of the preceding claims, wherein the administering occurs over a period of time that is at least one month.

23. The method of any one of the preceding claims, wherein the administering occurs over a period of time that is at least six months.

24. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is substantially free of ETOH.

25. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is substantially free of all alcohols.

26. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is substantially free of sorbitol.

27. The method of any one of the preceding claims, wherein the composition comprising the PAI-1 inhibitor is substantially free of all alcohols.

28. The method of any one of the preceding claims, wherein not more than 35% of the composition by weight is comprised of a penetration enhancer.

29. The method of claim 28, wherein the penetration enhancer is one or more of glycerin, isopropyl myristate and / or propylene glycol.

30. The method of any one of the preceding claims, wherein the composition includes Steareth 20 in an amount that is greater than 1% but no more than 3% by weight of the composition.Attorney Docket No. : 2012317-036631. The method of any one of the preceding claims, wherein the composition includes propyl paraben in an amount that is greater than 0.05% but no more than 0.15% by weight of a composition.

32. The method of any one of the preceding claims, wherein the composition includes butylated hydroxyl toluene in an amount that is greater than 0.05% but no more than 0.15% by weight of a composition.

33. The method of any one of the preceding claims, wherein the composition includes water in an amount that is greater than 15% but no more than 70% by weight of the composition.

34. The method of any one of the preceding claims, wherein the composition comprises xanthan gum.

35. The method of any one of the preceding claims, wherein the composition includes methyl paraben in an amount that is greater than 0.1% but no more than 0.3% by weight of the composition.

36. The method of any one of the preceding claims, wherein the composition includes edetate di sodium.

37. A method of reducing hair loss by: topically administering to a population of subjects suffering from hair loss a composition comprising a PAI-1 inhibitor in a weight percentage of at least 2% according to a regimen demonstrated to achieve greater than 10% hair count increase from baseline on average in the population.

38. A method of reducing hair loss by: topically administering to a population of subjects suffering from hair loss a composition comprising a PAI-1 inhibitor in a weight percentage of at least 2% according to a regimen demonstrated to achieve greater than 8% hair thickness increase from baseline on average in the population.Attorney Docket No. : 2012317-036639. The method of claim 37 or 38, wherein the regimen is demonstrated to result in no adverse events in the population related to the PAI-1 inhibitor.

40. The method of claim 37 or 38, wherein the regimen is demonstrated to result in no instances of skin irritation in the population.

41. The method of claim 37 or 38, wherein the regimen is demonstrated to result in no hair graying in the population.

42. A method of reducing hair graying by: topically administering to a population of subjects suffering from hair graying a composition comprising a PAI-1 inhibitor in a weight percentage of at least 2% according to a regimen demonstrated to achieve greater than 7% of hair darkening on average in the population.

43. The method of any one of claims 37-42, wherein the PAI-1 inhibitor is selected from a group consisting of: 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid, 5-Chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, a butadiene, spironolactone, imidapril, an angiotensin converting enzyme inhibitor (ACEI, captopril, or enalapril), an angiotensin II receptor antagonist (AURA), a defibrotide (a polydeoxyribonucleotide), and any combination thereof.

44. The method of any one of claims 37-42 wherein the PAI-1 inhibitor is ET-02.

45. The method of any one of claims 37-42 wherein the weight percentage of the PAI-1 inhibitor is 5%.

46. A kit comprising a composition comprising a PAI-1 inhibitor in a weight percentage of at least 2%, a bottle with a dropper applicator for administering the composition to a site on a subject, and optionally instructions for administering the composition to the site.

47. The kit of claim 46, wherein the composition comprising the PAI-1 inhibitor is or comprises a suspension.Attorney Docket No. : 2012317-036648. The kit of claim 46, wherein the composition comprising the PAI-1 inhibitor is or comprises a foam.

49. The kit of claim 46, wherein the composition comprising the PAI-1 inhibitor is or comprises an emulsion.

50. The kit of claim 46, wherein the composition comprising the PAI-1 inhibitor is or comprises a nanoemulsion.

51. The kit of any one of claims 46-50 wherein the composition comprising the PAI-1 inhibitor is formulated as a suspension, a foam, a lotion, a cream, a powder, an ointment, a liniment, a gel, or drops.

52. The kit of any one of claims 46-51, wherein the PAI-1 inhibitor is selected from a group consisting of: 5-Chloro-2-[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy)acetyl]amino benzoic acid, 5-Chloro-2-{[{[3-(furan-3-yl)phenyl]amino}(oxo)acetyl]amino}benzoic acid, a benzopyran compound, a butadiene, spironolactone, imidapril, an angiotensin converting enzyme inhibitor (ACEI, captopril, or enalapril), an angiotensin II receptor antagonist (AURA), a defibrotide (a polydeoxyribonucleotide), and any combination thereof.

53. The kit of any one of claims 46-51, wherein the PAI-1 inhibitor is ET-02.

54. The kit of any one of claims 46-53, wherein the weight percentage is 5%.

55. The method of any one of claims 1, 4-42, or 45, or the kit of any one of claims 46- 51, or 54 wherein the PAI-1 inhibitor is a 2-aminobenzoic acid analog.

56. The method of any one of claims 1, 4-42, or 45, or the kit of any one of claims 46-51, or 54, wherein the PAI-1 inhibitor is a 5-chloro-2-aminobenzoic acid analog.Attorney Docket No. : 2012317-036657. The composition of any one of claims 1, 4-42, or 45, or the kit of any one of claims 46-51, or 54, wherein the PAI-1 inhibitor is a compound of Formula (1)Formula (1)wherein,Ri and R2 are the same or different, and each represents hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl, hydroxyl, alkoxy, cycloalkoxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyl, aralkyloxy, heterocyclic- alkyl, heterocyclicalkyloxy, aryl optionally having one or two substituents, 5- to 6- membered ring heteroaryl optionally having one or two substituents, or benzo-fused heteroaryl optionally having one or two substituents, amino or carbomyl, each of which is optionally substituted with one or two substituents, or cyano, carboxy, oralkoxy carbonyl; and Ri and R2 are optionally adjoined with each other toform a ring;R3 is hydrogen, alkyl, cycloalkyl, or aryl optionally having one or two substituents;X is -C(RS)=C(R6)-, -C(R? ) N-, or -N=C (Rs)-, wherein R5 , Re , R7 and Rs each represents hydrogen, halogen, alkyl optionally having one or two substituents, or alkoxy; L is alkylene (some carbon atoms in the alkylene optionally form a cycloalkyl ring), alkenylene, alkynylene, cycloalkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene, or alkylene-SCh-alkylene, each of which is optionally substituted with one or two substituents, or alkylene-N(R9)-alkylene optionally substituted with one or two substituents, wherein R9 represents hydrogen, or alkyl optionally having one or two substituents;p represents an integer of 0 or 1 ;A is a group represented by any one of the following Formulae (2), (3) or (4):Formula (2)Attorney Docket No. : 2012317-0366wherein,Rio and Rn are the same or different, and each represents hydrogen or straight- or branched-chain alkyl; and m represents an integer of 0 to 10,Formula (3)wherein,R12 and R13 are the same or different, and each represents hydrogen, halogen, or alkyl optionally having one or two substituents, cycloalkyl optionally having one or two substituents, or alkoxy optionally having one or two substituents;Y represents CH or nitrogen;Z represents CH2 , oxygen, orN-alkyl;n represents an integer of 0 to 3;U represents alkylene; andt represents an integer of 0 or 1,Formula (4)wherein,R14 and R15 are the same or different, and each represents hydrogen, halogen, or alkyl optionally having one or two substituents, cycloalkyl optionally having one or two substituents, or alkoxy optionally 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; andAr represents aryl having one or two substituents (the one or two substituents optionally form a ring with a part of carbon atoms in the aryl group), 5- to 6-membered ring aryl group having one or two identical or different heteroatoms optionally having one or two substituents, or benzo-fused heteroaryl optionally having one to three substituents; andAttorney Docket No. : 2012317-0366B represents COORie, wherein Ri6 represents hydrogen, alkyl, aryl or aralkyl, a group represented by CH(Rn)O — CORis or — CH(Rn) — O — CO — ORis, wherein R17 is hydrogen or alkyl, and Ris is alkyl or cycloalkyl; a (5-alkyl-2-oxo-l,3-dioxolen-4- yl)methyl group represented by the following Formula (5):Formula (5)wherein, R' represents alkyl, or a heterocyclic group: a lH-tetrazol-5-yl group, a 4,5- dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl group, a 4,5-dihydro-5-thioxo-4H-l,2,4- oxadiazol-3-yl group, or a 4,5-dihydro-5-oxo-l,2,4-thiadiazol-3-yl group, represented by the following Formulae (6), (7), (8) (sequentially from the left), (9) (bottom):Formulae (6), (7), (8) (sequentially from the left), (9) (bottom).

58. The method of any one of claims 1, 4-42, or 45, or the kit of any one of claims 46- 51, or 54, wherein the PAI-1 inhibitor is a compound of Formula (10)Formula (10)wherein,Ri and R2 are the same or different, and each represents hydrogen, halogen, alkyl, or aryl optionally having one or two substituents;R3 is hydrogen or alkyl;R14 and R15 are the same or different, and each represents hydrogen, alkyl, or halogen;Attorney Docket No. : 2012317-0366V is alkylene, oxyalkylene, or oxygen;Ar is aryl optionally having one or two substituents, aryl group having one or two identical or different heteroatoms optionally having one or two substituents, or benzofused heteroaryl optionally having one or three substituents;L is alkylene, alkyleneoxyalkylene, alkylenethioalkylene, alkylene-SO-alkylene, alkylene-SCh-alkylene; andq, U, t, p, and B are as defined in claim 57.

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