Compositions and methods for the treatment of alopecia areata

Abstract

[Solution] The present application provides a storage stable squaric acid ester composition (SAE). The present application further provides a system and method for delivering the SAE composition to a subject to treat alopecia areata. The system includes a reservoir compartment containing the SAE and excipients, and an applicator unit for topically administering the SAE composition.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 235,999, filed August 23, 2021, U.S. Provisional Patent Application No. 63 / 284,231, filed November 30, 2021, and U.S. Provisional Patent Application No. 63 / 286,987, filed December 7, 2021, which are incorporated by reference in their entireties herein. Summary of the Invention

[0002] An embodiment of the present application is directed to a system for delivering a squaric acid ester (SAE) composition to a subject, the system comprising a storage compartment containing a composition having at least about 2.5% (weight / volume) SAE and excipients, and an applicator unit, the applicator unit delivering a volume of about 1 milliliter of the SAE composition.

[0003] Embodiments of the present application are directed to a method of delivering a squaric acid ester (SAE) composition to a subject to treat a condition susceptible to treatment with the SAE composition, comprising providing an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and delivering the SAE composition from the storage compartment through the applicator to the subject.

[0004] A further embodiment of the present application is directed to a kit for administering a squaric acid ester (SAE) composition to a subject, comprising an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, the kit further comprising instructions for administering the SAE composition to treat a condition susceptible to treatment with the SAE composition.

[0005] A further embodiment of the present application is directed to a composition comprising a squaric acid ester (SAE) and an excipient, wherein the composition is essentially free of water and DMSO, and wherein the composition has a total volume of 1 milliliter. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 is a schematic diagram of one embodiment of a system for delivering a squaric acid ester (SAE) composition to a subject. Detailed Description of the Invention

[0007] The present disclosure is not limited to the specific systems, apparatus, and methods described, as these may vary. The terms used herein are only for describing a particular implementation or embodiment, and are not intended to limit the scope. Such aspects of the present disclosure may be embodied in many different forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0008] The present disclosure is not limited in terms of the specific embodiments described in this application, which are intended as examples of various aspects. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from the spirit and scope thereof. In addition to those enumerated herein, functionally equivalent methods and apparatuses within the scope of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be included within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0009] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used herein, the term "comprising" means "including, but not limited to."

[0010] Although various compositions, methods, and devices are described in terms "comprising" (which should be interpreted as meaning "including, but not limited to") various components or steps, the compositions, methods, and devices can also "consist essentially of" or "consist of" the various components and steps, and such terms should be interpreted as defining an essentially closed group of members.

[0011] With respect to the use of virtually any plural and / or singular term herein, those of skill in the art can interpret the plural to the singular and / or the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly provided herein for clarity.

[0012] In general, those skilled in the art will understand that the terms used in this specification, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "includes" should be interpreted as "includes but is not limited to", etc.). Those skilled in the art will further understand that if a specific number of claims introduced are intended, such an intention will be explicitly set forth in the claim, and in the absence of such a setting, no such intention exists. For example, as an aid to understanding, the following appended claims may use the introductory phrases "at least one" and "one or more" to introduce the claims. However, the use of such phrases should not be construed as meaning that the introduction of a claim repetition with the indefinite article "a" or "an" limits a particular claim that includes such introduced claim repetition to embodiments containing only one such repetition, even if the same claim includes the introductory phrases "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"). Similarly, the use of definite articles used at the beginning of a claim.Moreover, even if a particular number of repetitions of an introduced claim are explicitly recited, one of ordinary skill in the art will recognize that such recitation should be interpreted to mean at least the number recited (e.g., the mere recitation of "two enumerations" without other qualifiers means at least two enumerations, or two or more enumerations). Furthermore, when a phrase similar to "at least one of A, B, and C, etc." is used, such a configuration is generally intended in the sense that one of ordinary skill in the art would understand the phrase (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, and C, etc.). When a convention similar to "at least one of A, B, or C, etc." is used, such a configuration is generally intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, and C, etc.). One of ordinary skill in the art will further understand that virtually any conjunctive word and / or phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B," or "A and B."

[0013] In addition, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0014] All percentages, parts and ratios are based on the total weight of the composition and all measurements made at about 25° C. unless otherwise specified.

[0015] As will be appreciated by those of skill in the art, all ranges disclosed herein encompass all possible subranges and combinations of subranges for any purpose, including in terms of providing a written description. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. As will also be appreciated by those of skill in the art, all phrases such as "up to," "at least," etc. refer to ranges that are inclusive of the recited numbers and that can then be broken down into subranges as described above. Finally, as will be appreciated by those of skill in the art, ranges include individual members. Thus, for example, a group having 1-3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to a group having 1, 2, 3, 4, 5 cells, etc.

[0016] The term "about" as used herein refers to variations in numerical quantities that may occur, for example, due to real-world measurement or handling procedures, due to unintentional errors in these procedures, due to differences in the manufacture, source, or purity of the composition or reagent, and the like. In general, the term "about" as used herein means greater or smaller than the stated value or range of values ​​by 1 / 10 of the stated value, e.g., ±10%. The term "about" also refers to variations that would be recognized as equivalent by one of ordinary skill in the art, unless they encompass known values ​​implemented by the prior art. Each value or range of values ​​preceded by the term "about" is also intended to encompass embodiments of the stated absolute value or range of values. Quantitative values ​​referred to in this disclosure, whether or not modified by the term "about", include equivalents to the stated value, e.g., variations in numerical quantities of such values ​​that may occur but would be recognized as equivalents by one of ordinary skill in the art. If the context of this disclosure indicates otherwise or is inconsistent with such an interpretation, the above interpretation can be modified as would be readily apparent to one of ordinary skill in the art. For example, in a list of numerical values ​​such as "about 49, about 50, about 55," "about 50" means less than half the interval between the preceding and succeeding values, e.g., a range extending from greater than 49.5 to less than 52.5. Additionally, the expressions "less than about" or "greater than about" should be understood in light of the definition of the term "about" provided herein.

[0017] As used herein, the term "substantially free" or "essentially free" indicates that the particular material being referenced is present in an amount of 10% by weight or 10% by volume or less of the total composition. As used herein, the term "essentially free of water" indicates that the composition is essentially free of any source of water, including atmospheric water.

[0018] When a range of values ​​is listed, each intervening value between the upper and lower limits of that range, as well as other stated or intervening values ​​within that listed range, are intended to be encompassed within the scope of the disclosure. For example, if a range of 1 μm to 8 μm is listed, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also intended to be expressly disclosed, as are ranges of values ​​equal to or greater than 1 μm and ranges of values ​​equal to or less than 8 μm.

[0019] The terms "patient" and "subject" are intended to be interchangeable and mean any living organism that can be treated with the compounds of the present invention. Thus, the terms "patient" and "subject" include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, a "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. In some embodiments, the patient or subject is an adult, child, or infant. In some embodiments, the patient or subject is a human.

[0020] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrate animals, such as wild animals, domestic animals, and farm animals.

[0021] In this disclosure, the term "disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0022] As used herein, the terms "administer," "administering," or "administration" refer to the direct administration of a compound (also referred to as a substance of interest) or a pharma- ceutically acceptable salt or composition of a compound (substance of interest) to a subject.

[0023] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to reduce the frequency or delay the onset of symptoms of a medical condition, to enhance the texture, appearance, color, feel, or hydration of the intended tissue treatment area of ​​a tissue surface in a subject compared to subjects not administered the compound or composition, or to otherwise obtain a beneficial or desired clinical result. For purposes of this invention, beneficial or desired clinical results include reversal, alleviation or amelioration of the symptoms of a condition, reduction in the extent of a condition, disorder or disease, stabilization of a condition (i.e., does not worsen), stabilization (i.e., does not worsen) of the state of the condition, disorder or disease, delay in the onset or slowing of progression of the condition, disorder or disease, improvement in the state of the condition, disorder or disease, and remission (whether partial or total), whether detectable or undetectable, or enhancement or amelioration of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0024] In some embodiments, the compounds and methods disclosed herein can be utilized in conjunction with or on a subject in need of such treatment, which can also be referred to as being "in need thereof." As used herein, the phrase "in need of" means that a subject has been identified as having a need for a particular method or treatment, and the treatment has been administered to the subject for that particular purpose.

[0025] As used herein, the term "therapeutic" or "therapeutic agent" or "pharmaceutical active agent" means an agent that is utilized to treat, combat, ameliorate, prevent or ameliorate an unwanted condition or disease in a patient.

[0026] As used herein, the term "composition" refers to a combination or mixture of two or more different components, ingredients, or substances.

[0027] As used herein, the term "controlled delivery" refers to the delivery of an SAE composition to a specific location or for a specific time on the skin of a patient. As used herein, the term "precise" refers to the delivery of an SAE composition to a precise location or precise amount of composition. The term "precise" refers to a location or time that has a deviation of within 10% from the desired location or amount.

[0028] The term "therapeutically effective" is intended to define the amount of active ingredient (i.e., a compound or derivative thereof) used to treat a disease or disorder or effect a clinical endpoint.

[0029] A "therapeutically effective amount" or "effective amount" of a compound or composition is a predetermined amount calculated to inhibit, block, or reverse the desired effect, i.e., cell activation, migration, or proliferation. The activity contemplated by the method includes both medical and / or prophylactic treatment, as appropriate. The specific dose of the compound administered in accordance with the present invention to obtain a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide dosage range. However, it will be understood that the above dosage ranges are not intended to limit the scope of the invention in any way, since the effective amount administered will be determined by the physician in light of the relevant circumstances, including the condition being treated, the choice of compound to be administered, and the chosen route of administration. A therapeutically effective amount of a compound of the present invention is typically an amount sufficient to achieve an effective systemic concentration or a local concentration in tissues when administered in a physiologically acceptable excipient composition.

[0030] As used herein, the term "responder" refers to a subject or a population of subjects who show improvement in symptoms after treatment with a therapeutically effective amount of an SAE composition. As used herein, the term "partial responder" refers to a subject or a population of subjects who experience any amount of measurable hair growth with a SALT score of less than about 50% at the end of 4 months of treatment.

[0031] As used herein, the term "non-responder" refers to a subject or population of subjects who do not show improvement in symptoms following treatment with a therapeutically effective amount of an SAE composition.

[0032] The term "inhibiting" includes administering a compound of the invention to prevent the onset of the symptoms, alleviate the symptoms, relieve the symptoms, slow or reduce the progression of the disease and / or its symptoms, or eliminate the disease, condition, or disorder.

[0033] As used herein, the phrase "essentially no water" refers to an amount of water that would not result in hydrolysis of the SAE composition to the clinically inactive free acid form. "Essentially no atmospheric water" is defined as about 10% water or less.

[0034] As used herein, the term "excipients" includes carriers and diluents, which means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in carrying or transporting a pharmaceutical, cosmetic, or other agent across a tissue layer, such as the stratum corneum or stratum spinosum.

[0035] As used herein, the terms "topically" and "topical" refer to the application of a composition to the surface of skin, mucosal cells, keratin, and tissue. Examples of keratin are nails and hair.

[0036] As used herein, the term "skin" refers to the thin layer of tissue that naturally covers the human or animal body. Skin is composed of the epidermis and the dermis. As used herein, the stratum corneum is the outermost layer of the epidermis and the papillary dermis is the top layer of the dermis. As used herein, the term "scalp" refers to the skin on a patient's head.

[0037] As used herein, the term "stable" refers to a formulation that retains the same properties and characteristics after storage of the formulation as when it was manufactured. The properties are chemical, physical, microbiological, therapeutic, and toxicological. A stable formulation retains 90% of the original desired properties after storage.

[0038] As used herein, the term "shelf stable" refers to a formulation that is stable for up to about 60 months under standard environmental and atmospheric conditions, including temperatures ranging from 4° C. to about 50° C.

[0039] The term "room temperature" as used herein refers to a "controlled room temperature" between 20°C and 25°C, which corresponds to 68°F to 77°F, with deviations between 15°C and 30°C, which corresponds to 59°F to 86°F, being allowed for an average temperature range of about 68°F to 77°F.

[0040] Less than the full scale of the disclosure may be claimed for any reason, by reserving the right to exclude or exclude by proviso any individual member of such group, including any subrange or combination of subranges within such group that may be claimed according to ranges or similar methods hereby. Furthermore, less than the full scale of the disclosure may be claimed for any reason, by reserving the right to exclude or exclude individual substituents, structures, or members of the group or groups claimed herein. Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entireties into this disclosure in order to more fully describe the state of the art as of the date of this disclosure to those skilled in the art. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall govern.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention.

[0042] System for delivering SAE compositions - Patent application An embodiment of the present application is directed to a system for delivering a squaric acid ester (SAE) composition to a subject, the system comprising: a storage compartment containing the composition having at least about 2.5% (wt / vol) SAE and excipients; and an applicator unit, the applicator unit delivering a volume of about 1 milliliter of the SAE composition.

[0043] In some embodiments, the SAE composition comprises squaric acid dibutyl ester (SADBE). In some embodiments, the SAE composition comprises squaric acid diethyl ester (SADEE). In some embodiments, the SAE composition comprises a single SAE. In some embodiments, the SAE composition comprises a combination of SAEs. In some embodiments, the SAE composition comprises SADBE and SADEE.

[0044] In some embodiments, the system for delivering an SAE composition to a subject comprises at least about 2.5% (wt / vol) SAE. In some embodiments, the system for delivering an SAE composition to a subject comprises at least about 5% (wt / vol) SAE. In some embodiments, the system for delivering an SAE composition to a subject comprises at least about 7% (wt / vol) SAE. In some embodiments, the system for delivering an SAE composition to a subject comprises at least about 10% (wt / vol) SAE. In some embodiments, the system for delivering an SAE composition to a subject comprises at least about 1% to about 20%, about 1% to about 18%, about 1% to about 16%, about 1% to about 15%, about 1% to about 14%, about 1% to about 12%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% Including an SAE range of about 2%, about 2% to about 20%, about 3% to about 20%, about 4% to about 20%, about 5% to about 20%, about 6% to about 20%, about 7% to about 20%, about 8% to about 20%, about 9% to about 20%, about 10% to about 20%, about 12% to about 20%, about 14% to about 20%, about 15% to about 20%, about 16% to about 20%, about 18% to about 20%, or values ​​within these ranges. Specific examples include about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or a range between any two of these values.

[0045] Some embodiments disclosed herein also include pharmaceutical compositions that include, as an active ingredient, one or more of the compounds disclosed herein in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the excipients are selected from at least one of ketones, alcohols, and other organic solvents.

[0046] In some embodiments, the system for delivering the SAE composition to a subject comprises delivering a therapeutically effective volume of the SAE composition. In some embodiments, the system for delivering the SAE composition to a subject comprises delivering an effective volume of the SAE composition. In some embodiments, the system for delivering the SAE composition to a subject comprises delivering about 1 milliliter of the SAE composition. In some embodiments, the system for delivering the SAE composition to a subject comprises delivering about 0.8 milliliters of the SAE composition. In some embodiments, the system for delivering the SAE composition to a subject comprises delivering about 1.2 milliliters of the SAE composition. In some embodiments, the system for delivering the SAE composition to a subject comprises delivering a range of about 0.7 milliliters to about 1.3 milliliters of the SAE composition.In some embodiments, the system for delivering the SAE composition to a subject comprises a volume of about 0.1 milliliters to about 2 milliliters, about 0.1 milliliters to about 1.9 milliliters, about 0.1 milliliters to about 1.8 milliliters, about 0.1 milliliters to about 1.7 milliliters, about 0.1 milliliters to about 1.6 milliliters, about 0.1 to about 1.5 milliliters, about 0.1 milliliters to about 1.4 milliliters, about 0.1 milliliters to about 1.3 milliliters, about 0.1 milliliters to about 1.5 ... liters to about 1.2 milliliters, about 0.1 milliliters to about 1.1 milliliters, about 0.1 milliliters to about 1.0 milliliters, about 0.1 milliliters to about 0.9 milliliters, about 0.1 milliliters to about 0.8 milliliters, about 0.1 milliliters to about 0.7 milliliters, about 0.1 milliliters to about 0.6 milliliters, about 0.1 milliliters to about 0.5 milliliters, about 0.1 milliliters to about 0.4 milliliters, about 0.1 milliliters to about 0.3 milliliters about 0.1 milliliters to about 0.2 milliliters, about 0.2 milliliters to about 2 milliliters, about 0.3 milliliters to about 2 milliliters, about 0.4 milliliters to about 2 milliliters, about 0.5 milliliters to about 2 milliliters, about 0.6 milliliters to about 2 milliliters, about 0.7 milliliters to about 2 milliliters, about 0.8 milliliters to about 2 milliliters, about 0.9 milliliters to about 2 milliliters, about 1.0 milliliters to about 2.0 milliliters, about 1.1 milliliters 1.5 to about 2.0 milliliters, about 1.6 to about 2.0 milliliters, about 1.7 to about 2.0 milliliters, about 1.8 to about 2.0 milliliters, about 1.9 to about 2.0 milliliters, or a range of values ​​within these ranges.Specific examples include about 0.1 milliliters, about 0.2 milliliters, about 0.3 milliliters, about 0.4 milliliters, about 0.5 milliliters, about 0.6 milliliters, about 0.7 milliliters, about 0.8 milliliters, about 0.9 milliliters, about 1.0 milliliters, about 1.1 milliliters, about 1.2 milliliters, about 1.3 milliliters, about 1.4 milliliters, about 1.5 milliliters, about 1.6 milliliters, about 1.7 milliliters, about 1.8 milliliters, about 1.9 milliliters, about 2.0 milliliters, or a range between any two of these values.

[0047] In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE is storage stable. In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature. In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature of about 23° C. In some embodiments, the SAE compositions described herein are stable at a temperature range of about 20° C. to about 23° C. In some embodiments, the SAE compositions described herein are stable at a temperature range of about 20° C. to about 25° C. In some embodiments, the SAE compositions described herein are stable at a temperature range of about 25° C. to about 50° C. In some embodiments, the SAE compositions described herein are stable at a temperature range of about 5° C. to about 50° C., about 5° C. to about 40° C., about 5° C. to about 30° C., about 5° C. to about 28° C., about 5° C. to about 26° C., about 5° C. to about 25° C., about 5° C. to about 24° C., about 5° C. to about 22° C., about 5° C. to about 20° C., about 5° C. to about 18° C., about 5° C. to about 16° C., about 5° C. to about 14° C., about 5° C. to about 12° C., about 5° C. to about 10° C., about 5° C. to about 8° C., about 5° C. to about 6° C., or values ​​within these ranges. Specific examples include about 5°C, about 10°C, about 15°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 28°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or a range between any two of these values.

[0048] In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 12 months. In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 6 months to about 24 months. In some embodiments, the system for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month and the system is stable at room temperature for about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or values ​​within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0049] In some embodiments, the system for delivering an SAE composition to a subject, the SAE composition is shelf stable for about 12 months. In some embodiments, the system for delivering an SAE composition to a subject, the SAE composition is shelf stable for about 6 months to about 24 months. In some embodiments, the system for delivering an SAE composition to a subject, the SAE composition is shelf stable for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month to about 28 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month to about 36 ... The system has storage stability of about 1 month to about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or values ​​within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0050] In some embodiments, a system for delivering an SAE composition to a subject includes an applicator unit. In some embodiments, a system for delivering an SAE composition to a subject includes an applicator unit, the applicator unit including a storage compartment, an airtight seal, a connection area, and an applicator. In some embodiments, the storage compartment holds the SAE composition. In some embodiments, the storage unit includes an airtight seal at an end having the connection area. In some embodiments, the applicator unit includes an absorbent membrane located at a distal end of the storage unit. In some embodiments, the applicator unit includes an absorbent membrane, the absorbent membrane being soaked with the SAE composition after the airtight seal is broken on the storage compartment.

[0051] FIG. 1 is a schematic diagram of one embodiment of a system for delivering a squaric acid ester (SAE) composition to a subject. The system includes an applicator for storing and applying the SAE. The applicator 100 includes an open proximal end 110 of the applicator, an applicator tip 120, a glass ampoule 130 containing the composition, a distal filter 140, a closed distal end 150 of the applicator, and a vent hole 160 located at the closed distal end 150 of the applicator. To apply the composition to a subject in need thereof, the glass ampoule 130 is broken by applying pressure to the applicator 100, and the composition saturates the applicator tip 120. The applicator tip 120 contacts the skin of the subject to apply the composition. The distal filter 140 prevents backflow of the glass and composition through the vent hole 160 at the distal end of the applicator after the ampoule is broken.

[0052] In some embodiments, the applicator for delivering the SAE composition comprises an applicator tip. In some embodiments, the applicator tip is a filter. In some embodiments, the applicator tip is polyester; laminated foam plastic; cotton; porous polyethylene; wool; gauze or other similar absorbent material; polyolefin, nylon, polycarbonate, poly(ethersulfone), and mixtures thereof; and fluoropolymers such as polyvinylidene fluoride (PVDF) and polytetrafluoroethylene (PTFE).

[0053] In some embodiments, the applicator for delivery of the SAE composition includes a glass ampoule for storage of the SAE composition. In some embodiments, the glass ampoule is borosilicate glass. In some embodiments, the glass ampoule protects the SAE composition from changes in temperature. In some embodiments, the glass ampoule protects the SAE composition from light. In some embodiments, the glass ampoule protects the SAE composition from atmospheric oxygen. In some embodiments, the SAE composition in the glass ampoule is storage stable.

[0054] In some embodiments, the applicator for delivery of the SAE composition includes a distal filter. In some embodiments, the distal filter is a material selected from porous polyethylene; wool; gauze or other similar absorbent materials; polyolefins, nylon, polycarbonate, poly(ethersulfone), and mixtures thereof; and fluoropolymers such as polyvinylidene fluoride (PVDF) and polytetrafluoroethylene (PTFE).

[0055] In some embodiments, the applicator for delivery of the SAE composition comprises a vent.

[0056] In some embodiments, the system for delivering the SAE composition to a subject includes a storage compartment, the storage compartment protecting the SAE composition from atmospheric water. In some embodiments, the system for delivering the SAE composition to a subject, the SAE composition is essentially free of water. In some embodiments, the system for delivering the SAE composition to a subject, the SAE composition is essentially free of water. In some embodiments, the system for delivering the SAE composition to a subject, the SAE composition is essentially free of water and DMSO.

[0057] In some embodiments, a system for delivering an SAE composition to a subject provides controlled delivery of the SAE composition to a subject. In some embodiments, the system for delivering an SAE composition to a subject distributes the SAE composition evenly across the area of ​​skin to be treated. In some embodiments, the area of ​​skin to be treated is variable in size. In some embodiments, the maximum area of ​​skin to be treated is about 800 cm. 2 In some embodiments, the controlled delivery of an SAE composition to a subject provides a precise volume of the SAE composition. In some embodiments, the controlled delivery of an SAE composition to a subject occurs at a predetermined rate. In some embodiments, the controlled delivery of an SAE composition to a subject protects the SAE composition from water prior to administration to the subject.

[0058] In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to a subject in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered topically to a subject in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to the skin of a subject in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to the scalp of a subject in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered adjacent to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to an area of ​​skin determined to be optimal by a physician. In some embodiments, a system for delivering an SAE composition to a subject, where the SAE composition is selectively administered to areas of the skin in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, where the SAE composition does not contact any unintended areas of the skin. In some embodiments, a system for delivering an SAE composition to a subject, where the SAE composition is contained entirely within a reservoir unit and an applicator unit.

[0059] In some embodiments, the system is for delivering the SAE composition to a subject with skin disease.In some embodiments, the system is for delivering the SAE composition to a subject with alopecia.In some embodiments, the system is for delivering the SAE composition to a subject with alopecia areata.In some embodiments, the system is for delivering the SAE composition to a subject for treating a condition selected from viral warts, herpes simplex virus, molluscum contagiosum, and cutaneous T-cell lymphoma.

[0060] In some embodiments, a system for delivering a therapeutically effective amount of an SAE composition to a subject. In some embodiments, the therapeutically effective amount is an amount disclosed herein. In some embodiments, the system for delivering an SAE composition to a subject results in the elimination of the condition being treated. In some embodiments, the system for delivering an SAE composition to a subject results in the restoration of hair loss. In some embodiments, the system for delivering an SAE composition to a subject results in hair growth in an area of ​​skin that is in direct contact with the SAE composition. In some embodiments, the system for delivering an SAE composition to a subject results in hair growth in an area of ​​skin adjacent to the site of administration of the SAE composition.

[0061] In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in a one-point improvement in any ordinal or interval rating scale, such as Physician Global Assessment or Investigator Global Assessment.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in about 100% hair growth recovery in the area where the patch is administered.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in at least about 50% increase in hair growth in the area where the patch is administered, as defined by the number of hair follicles with actively growing hair shafts, as seen by clinical, trichological, or histopathological evaluation. In some embodiments, successful treatment of alopecia areata with an SAE composition may result in increased hair growth at the site where the composition was administered, such as about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about An increase of 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or a value within these ranges. Specific examples include increasing hair growth, as defined by the number of hair follicles with actively growing hair shafts as seen by clinical, trichiscopic, or histopathological evaluation, by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0062] In some embodiments, successful treatment of alopecia areata with the SAE composition may indicate a Severity Alopecia Tool (SALT) score at the site where the patch was administered of about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 9 ... % to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or values ​​within these ranges. Specific examples include improving Severity Alopecia Tool (SALT) score by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0063] In some embodiments, the system is for delivering an SAE composition to a subject, the SAE composition being delivered to the subject once a month. In some embodiments, the system is for delivering an SAE composition to a subject, the SAE composition being delivered to the subject once a month for 4 months. In some embodiments, the system is for delivering an SAE composition to a subject, the SAE composition being delivered to the subject once a month for 1-12 months, 1-11 months, 1-10 months, 1-9 months, 1-8 months, 1-7 months, 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, or values ​​within these ranges. Specific examples include 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or ranges between any two of these values.

[0064] In some embodiments, a system for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. In some embodiments, a system for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. Subjects who experience hair growth at the end of four months of treatment are referred to as "responders." Subjects who do not experience hair growth at the end of four months of treatment are referred to as "non-responders." Subjects who experience measurable hair growth at any amount less than about 50% SALT score at the end of four months of treatment are referred to as "partial responders." In some embodiments, a system for delivering an SAE composition to a subject, wherein the subject is a responder. In some embodiments, a system for delivering an SAE composition to a subject, wherein the subject is a non-responder. In some embodiments, a system for delivering an SAE composition to a subject, wherein the subject is a partial responder. In some embodiments, a system for delivering an SAE composition to a non-responder, where the SAE composition is delivered every two weeks. In some embodiments, a system for delivering an SAE composition to a partial responder, where the SAE composition is delivered every two weeks. In some embodiments, a system for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every week. In some embodiments, a system for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered twice a week. In some embodiments, a system for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every three weeks.

[0065] Methods for delivering SABDE compositions Embodiments of the present application are directed to a method of delivering a squaric acid ester (SAE) composition to a subject to treat a condition susceptible to treatment with the SAE composition, comprising providing an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and delivering the SAE composition from the storage compartment through the applicator to the subject.

[0066] In some embodiments, the SAE composition comprises squaric acid dibutyl ester (SADBE). In some embodiments, the SAE composition comprises squaric acid diethyl ester (SADEE). In some embodiments, the SAE composition comprises a single SAE. In some embodiments, the SAE composition comprises a combination of SAEs. In some embodiments, the SAE composition comprises SADBE and SADEE.

[0067] In some embodiments, the method is for delivering an SAE composition to a subject, the SAE composition comprising at least about 2.5% (w / v) SAE. In some embodiments, the method is for delivering an SAE composition to a subject, the SAE composition comprising at least about 5% (w / v) SAE. In some embodiments, the method is for delivering an SAE composition to a subject, the SAE composition comprising at least about 7% (w / v) SAE. In some embodiments, the method is for delivering an SAE composition to a subject, the SAE composition comprising at least about 10% (w / v) SAE. In some embodiments, the method includes delivering an SAE composition to a subject, the SAE composition being between about 1% and about 20%, about 1% and about 18%, about 1% and about 16%, about 1% and about 15%, about 1% and about 14%, about 1% and about 12%, about 1% and about 10%, about 1% and about 9%, about 1% and about 8%, about 1% and about 7%, about 1% and about 6%, about 1% and about 5%, about 1% and about 4%, about 1% and about 3%, about 1% and about 5%, about 1% and about 6%, about 1% and about 7%, about 1% and about 8%, about 1% and about 9%, about 1% and about 10 ... In some embodiments, the method comprises an SAE ranging from about 2% to about 2%, about 2% to about 20%, about 3% to about 20%, about 4% to about 20%, about 5% to about 20%, about 6% to about 20%, about 7% to about 20%, about 8% to about 20%, about 9% to about 20%, about 10% to about 20%, about 12% to about 20%, about 14% to about 20%, about 15% to about 20%, about 16% to about 20%, about 18% to about 20%, or a value within these ranges. Specific examples include about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or a range between any two of these values.

[0068] Some embodiments disclosed herein also include pharmaceutical compositions that include, as an active ingredient, one or more of the compounds disclosed herein in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the excipients are selected from at least one of ketones, alcohols, and other organic solvents.

[0069] In some embodiments, the method for delivering an SAE composition to a subject comprises delivering a therapeutically effective volume of the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject comprises delivering an effective volume of the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject comprises delivering about 1 milliliter of the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject comprises delivering about 0.8 milliliters of the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject comprises delivering about 1.2 milliliters of the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject comprises delivering a range of about 0.7 milliliters to about 1.3 milliliters of the SAE composition.In some embodiments, the method for delivering the SAE composition to a subject comprises delivering from about 0.1 milliliters to about 2 milliliters, from about 0.1 milliliters to about 1.9 milliliters, from about 0.1 milliliters to about 1.8 milliliters, from about 0.1 milliliters to about 1.7 milliliters, from about 0.1 milliliters to about 1.6 milliliters, from about 0.1 to about 1.5 milliliters, from about 0.1 milliliters to about 1.4 milliliters, from about 0.1 milliliters to about 1.3 milliliters, or from about 0.1 milliliters. to about 1.2 milliliters, about 0.1 milliliters to about 1.1 milliliters, about 0.1 milliliters to about 1.0 milliliters, about 0.1 milliliters to about 0.9 milliliters, about 0.1 milliliters to about 0.8 milliliters, about 0.1 milliliters to about 0.7 milliliters, about 0.1 milliliters to about 0.6 milliliters, about 0.1 milliliters to about 0.5 milliliters, about 0.1 milliliters to about 0.4 milliliters, about 0.1 milliliters to about 0.3 milliliters , about 0.1 milliliters to about 0.2 milliliters, about 0.2 milliliters to about 2 milliliters, about 0.3 milliliters to about 2 milliliters, about 0.4 milliliters to about 2 milliliters, about 0.5 milliliters to about 2 milliliters, about 0.6 milliliters to about 2 milliliters, about 0.7 milliliters to about 2 milliliters, about 0.8 milliliters to about 2 milliliters, about 0.9 milliliters to about 2 milliliters, about 1.0 milliliters to about 2.0 milliliters, about 1.1 milliliters The method includes delivering a range of about 1.2 to about 2.0 milliliters, about 1.3 to about 2.0 milliliters, about 1.4 to about 2.0 milliliters, about 1.5 to about 2.0 milliliters, about 1.6 to about 2.0 milliliters, about 1.7 to about 2.0 milliliters, about 1.8 to about 2.0 milliliters, about 1.9 to about 2.0 milliliters, or a range of values ​​within these ranges.Specific examples include about 0.1 milliliters, about 0.2 milliliters, about 0.3 milliliters, about 0.4 milliliters, about 0.5 milliliters, about 0.6 milliliters, about 0.7 milliliters, about 0.8 milliliters, about 0.9 milliliters, about 1.0 milliliters, about 1.1 milliliters, about 1.2 milliliters, about 1.3 milliliters, about 1.4 milliliters, about 1.5 milliliters, about 1.6 milliliters, about 1.7 milliliters, about 1.8 milliliters, about 1.9 milliliters, about 2.0 milliliters, or a range between any two of these values.

[0070] In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE is storage stable. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature of about 23° C. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature range of about 20° C. to about 23° C. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature range of about 20° C. to about 25° C. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature range of about 25° C. to about 50° C. In some embodiments, there is provided a method for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature range of about 5° C. to about 50° C., about 5° C. to about 40° C., about 5° C. to about 30° C., about 5° C. to about 28° C., about 5° C. to about 26° C., about 5° C. to about 25° C., about 5° C. to about 24° C., about 5° C. to about 22° C., about 5° C. to about 20° C., about 5° C. to about 18° C., about 5° C. to about 16° C., about 5° C. to about 14° C., about 5° C. to about 12° C., about 5° C. to about 10° C., about 5° C. to about 8° C., about 5° C. to about 6° C., or values ​​within these ranges. Specific examples include about 5°C, about 10°C, about 15°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 28°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or a range between any two of these values.

[0071] In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 12 months. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 6 months to about 24 months. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month to about 28 ... the method is stable at room temperature for about 1 month to about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or values ​​within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0072] In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is shelf stable for about 12 months. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is shelf stable for about 6 months to about 24 months. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is shelf stable for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month to about 28 ... the method is stable at room temperature for about 1 month to about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or values ​​within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0073] In some embodiments, the method for delivering an SAE composition to a subject includes an applicator unit. In some embodiments, the method for delivering an SAE composition to a subject includes an applicator unit, the applicator unit including a storage compartment, an airtight seal, a connection area, and an applicator. In some embodiments, the storage compartment holds the SAE composition. In some embodiments, the storage unit includes an airtight seal at an end having the connection area. In some embodiments, the applicator unit includes an absorbent membrane located at a distal end of the storage unit. In some embodiments, the applicator unit includes an absorbent membrane, the absorbent membrane being soaked with the SAE composition after the airtight seal is broken on the storage compartment.

[0074] In some embodiments, a method for delivering an SAE composition to a subject using an applicator unit, the applicator unit comprising a storage compartment. In some embodiments, a method for delivering an SAE composition to a subject using an applicator unit, the applicator unit comprising a storage compartment for protecting the SAE composition from atmospheric water. In some embodiments, a method for delivering an SAE composition to a subject, the SAE composition being essentially free of water. In some embodiments, a method for delivering an SAE composition to a subject, the SAE composition being essentially free of water. In some embodiments, a method for delivering an SAE composition to a subject, the SAE composition being essentially free of water and DMSO.

[0075] In some embodiments, a method for delivering an SAE composition to a subject provides for controlled delivery of the SAE composition to the subject. In some embodiments, the method for delivering an SAE composition to a subject distributes the SAE composition evenly across the area of ​​skin to be treated. In some embodiments, the area of ​​skin to be treated is variable in size. In some embodiments, the maximum area of ​​skin to be treated is about 800 cm. 2In some embodiments, the controlled delivery of an SAE composition to a subject provides a precise volume of the SAE composition. In some embodiments, the controlled delivery of an SAE composition to a subject occurs at a predetermined rate. In some embodiments, the controlled delivery of an SAE composition to a subject protects the SAE composition from water prior to administration to the subject.

[0076] In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered to a subject in need thereof. In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered topically to a subject in need thereof. In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered to the skin of a subject in need thereof. In some embodiments, a system for delivering an SAE composition to a subject, wherein the SAE composition is administered to the scalp of a subject in need thereof. In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered adjacent to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, a method for delivering an SAE composition to a subject, wherein the SAE composition is administered to an area of ​​skin determined to be optimal by a physician. In some embodiments, the method for delivering an SAE composition to a subject is one in which the SAE composition is administered selectively to areas of the skin in need thereof. In some embodiments, the method for delivering an SAE composition to a subject is one in which the SAE composition does not contact any unintended areas of the skin. In some embodiments, the method for delivering an SAE composition to a subject is one in which the SAE composition is contained entirely within a reservoir unit and an applicator unit.

[0077] In some embodiments, the system is for delivering the SAE composition to a subject with skin disease.In some embodiments, the method is for delivering the SAE composition to a subject with alopecia.In some embodiments, the method is for delivering the SAE composition to a subject with alopecia areata.In some embodiments, the method is for delivering the SAE composition to a subject to treat a condition selected from viral warts, herpes simplex virus, molluscum contagiosum, and cutaneous T-cell lymphoma.

[0078] In some embodiments, a method for delivering a therapeutically effective amount of an SAE composition to a subject. In some embodiments, the therapeutically effective amount is an amount disclosed herein. In some embodiments, the method for delivering an SAE composition to a subject results in the elimination of the condition being treated. In some embodiments, the method for delivering an SAE composition to a subject results in the restoration of hair loss. In some embodiments, the method for delivering an SAE composition to a subject results in hair growth in an area of ​​skin that is in direct contact with the SAE composition. In some embodiments, the method for delivering an SAE composition to a subject results in hair growth in an area of ​​skin adjacent to the site of administration of the SAE composition.

[0079] In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in a one-point improvement in any ordinal or interval rating scale, such as Physician Global Assessment or Investigator Global Assessment.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in about 100% hair growth recovery in the area where the patch is administered.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in at least about 50% increase in hair growth in the area where the patch is administered, as defined by the number of hair follicles with actively growing hair shafts, as seen by clinical, trichological, or histopathological evaluation. In some embodiments, successful treatment of alopecia areata with an SAE composition may result in increased hair growth at the site where the composition was administered, such as about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about An increase of 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or a value within these ranges. Specific examples include increasing hair growth, as defined by the number of hair follicles with actively growing hair shafts as seen by clinical, trichiscopic, or histopathological evaluation, by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0080] In some embodiments, successful treatment of alopecia areata with the SAE composition may indicate a Severity Alopecia Tool (SALT) score at the site where the patch was administered of about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 9 ... % to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or values ​​within these ranges. Specific examples include improving Severity Alopecia Tool (SALT) score by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0081] In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month for 4 months. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month for 1-12 months, 1-11 months, 1-10 months, 1-9 months, 1-8 months, 1-7 months, 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, or values ​​within these ranges. Specific examples include 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or ranges between any two of these values.

[0082] In some embodiments, the method is for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. Subjects who experience hair growth at the end of four months of treatment are referred to as "responders." Subjects who do not experience hair growth at the end of four months of treatment are referred to as "non-responders." Subjects who experience measurable hair growth at any amount less than about 50% SALT score at the end of four months of treatment are referred to as "partial responders." In some embodiments, the method is for delivering an SAE composition to a subject, wherein the subject is a responder. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the subject is a non-responder. In some embodiments, the method is for delivering an SAE composition to a subject, wherein the subject is a partial responder. In some embodiments, the method is for delivering an SAE composition to a non-responder, where the SAE composition is delivered every two weeks. In some embodiments, the method is for delivering an SAE composition to a partial responder, where the SAE composition is delivered every two weeks. In some embodiments, the method is for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every week. In some embodiments, the method is for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered twice a week. In some embodiments, the method is for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every three weeks.

[0083] Kits for delivering SAE compositions An embodiment of the present application is directed to a kit for administering a squaric acid ester (SAE) composition to a subject, the kit comprising an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and an SAE composition comprising at least 5% SAE, the kit further comprising instructions for administering the SAE composition to treat a condition susceptible to treatment with the SAE composition.

[0084] In some embodiments, the SAE composition comprises squaric acid dibutyl ester (SADBE). In some embodiments, the SAE composition comprises squaric acid diethyl ester (SADEE). In some embodiments, the SAE composition comprises a single SAE. In some embodiments, the SAE composition comprises a combination of SAEs. In some embodiments, the SAE composition comprises SADBE and SADEE.

[0085] In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition comprising at least about 2.5% (w / v) SAE. In some embodiments, the method is for delivering an SAE composition to a subject, the SAE composition comprising at least about 5% (w / v) SAE. In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition comprising at least about 7% (w / v) SAE. In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition comprising at least about 10% (w / v) SAE. In some embodiments, there is provided a kit for delivering an SAE composition to a subject, the SAE composition comprising about 1% to about 20%, about 1% to about 18%, about 1% to about 16%, about 1% to about 15%, about 1% to about 14%, about 1% to about 12%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9%, about 1% to about 9%, about 1% to about 10 ... %, about 1% to about 2%, about 2% to about 20%, about 3% to about 20%, about 4% to about 20%, about 5% to about 20%, about 6% to about 20%, about 7% to about 20%, about 8% to about 20%, about 9% to about 20%, about 10% to about 20%, about 12% to about 20%, about 14% to about 20%, about 15% to about 20%, about 16% to about 20%, about 18% to about 20%, or an SAE range of values ​​within these ranges. Specific examples include about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or a range between any two of these values.

[0086] Some embodiments disclosed herein also include pharmaceutical compositions that include, as an active ingredient, one or more of the compounds disclosed herein in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the excipients are selected from at least one of ketones, alcohols, and other organic solvents.

[0087] In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering a therapeutically effective volume of the SAE composition. In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering an effective volume of the SAE composition. In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering about 1 milliliter of the SAE composition. In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering about 0.8 milliliters of the SAE composition. In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering about 1.2 milliliters of the SAE composition. In some embodiments, the kit for delivering an SAE composition to a subject comprises delivering a range of about 0.7 milliliters to about 1.3 milliliters of the SAE composition.In some embodiments, the kit for delivering the SAE composition to a subject comprises a volume of about 0.1 milliliters to about 2 milliliters, about 0.1 milliliters to about 1.9 milliliters, about 0.1 milliliters to about 1.8 milliliters, about 0.1 milliliters to about 1.7 milliliters, about 0.1 milliliters to about 1.6 milliliters, about 0.1 to about 1.5 milliliters, about 0.1 milliliters to about 1.4 milliliters, about 0.1 milliliters to about 1.3 milliliters, about 0.1 milliliters to about 1.5 ... about 0.1 to about 1.2 milliliters, about 0.1 to about 1.1 milliliters, about 0.1 to about 1.0 milliliters, about 0.1 to about 0.9 milliliters, about 0.1 to about 0.8 milliliters, about 0.1 to about 0.7 milliliters, about 0.1 to about 0.6 milliliters, about 0.1 to about 0.5 milliliters, about 0.1 to about 0.4 milliliters, about 0.1 to about 0.3 milliliters , about 0.1 milliliters to about 0.2 milliliters, about 0.2 milliliters to about 2 milliliters, about 0.3 milliliters to about 2 milliliters, about 0.4 milliliters to about 2 milliliters, about 0.5 milliliters to about 2 milliliters, about 0.6 milliliters to about 2 milliliters, about 0.7 milliliters to about 2 milliliters, about 0.8 milliliters to about 2 milliliters, about 0.9 milliliters to about 2 milliliters, about 1.0 milliliters to about 2.0 milliliters, about 1.1 milliliters 1.5 to about 2.0 milliliters, about 1.6 to about 2.0 milliliters, about 1.7 to about 2.0 milliliters, about 1.8 to about 2.0 milliliters, about 1.9 to about 2.0 milliliters, or a range of values ​​within these ranges.Specific examples include about 0.1 milliliters, about 0.2 milliliters, about 0.3 milliliters, about 0.4 milliliters, about 0.5 milliliters, about 0.6 milliliters, about 0.7 milliliters, about 0.8 milliliters, about 0.9 milliliters, about 1.0 milliliters, about 1.1 milliliters, about 1.2 milliliters, about 1.3 milliliters, about 1.4 milliliters, about 1.5 milliliters, about 1.6 milliliters, about 1.7 milliliters, about 1.8 milliliters, about 1.9 milliliters, about 2.0 milliliters, or a range between any two of these values.

[0088] In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE is storage stable. In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature. In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE composition is stable at a temperature of about 23° C. In some embodiments, the SAE composition described herein is stable at a temperature range of about 20° C. to about 23° C. In some embodiments, the SAE composition described herein is stable at a temperature range of about 20° C. to about 25° C. In some embodiments, the SAE composition described herein is stable at a temperature range of about 25° C. to about 50° C. In some embodiments, the SAE compositions described herein are stable at a temperature range of about 5° C. to about 50° C., about 5° C. to about 40° C., about 5° C. to about 30° C., about 5° C. to about 28° C., about 5° C. to about 26° C., about 5° C. to about 25° C., about 5° C. to about 24° C., about 5° C. to about 22° C., about 5° C. to about 20° C., about 5° C. to about 18° C., about 5° C. to about 16° C., about 5° C. to about 14° C., about 5° C. to about 12° C., about 5° C. to about 10° C., about 5° C. to about 8° C., about 5° C. to about 6° C., or values ​​within these ranges. Specific examples include about 5°C, about 10°C, about 15°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 28°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or a range between any two of these values.

[0089] In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 12 months. In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 6 months to about 24 months. In some embodiments, the kit is for delivering an SAE composition to a subject, wherein the SAE composition is stable at room temperature for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month the kit is stable at room temperature for about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or values ​​within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0090] In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition being shelf stable for about 12 months. In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition being shelf stable for about 6 months to about 24 months. In some embodiments, the kit is for delivering an SAE composition to a subject, the SAE composition being shelf stable for about 1 month to about 60 months, about 1 month to about 57 months, about 1 month to about 54 months, about 1 month to about 51 months, about 1 month to about 48 months, about 1 month to about 45 months, about 1 month to about 42 months, about 1 month to about 39 months, about 1 month to about 36 months, about 1 month to about 33 months, about 1 month to about 30 months, about 1 month to about 27 months, about 1 month to about 28 ... the kit has a storage stability of about 1 month to about 24 months, about 1 month to about 21 months, about 1 month to about 18 months, about 1 month to about 15 months, about 1 month to about 12 months, about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, or a value within these ranges. Specific examples include about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, about 36 months, about 39 months, about 42 months, about 45 months, about 48 months, about 51 months, about 54 months, about 57 months, about 60 months, or a range between any two of these values.

[0091] In some embodiments, a kit for delivering an SAE composition to a subject includes an applicator unit. In some embodiments, a kit for delivering an SAE composition to a subject includes an applicator unit, the applicator unit including a storage compartment, an airtight seal, a connection area, and an applicator. In some embodiments, the storage compartment holds the SAE composition. In some embodiments, the storage unit includes an airtight seal at an end having the connection area. In some embodiments, the applicator unit includes an absorbent membrane located at a distal end of the storage unit. In some embodiments, the applicator unit includes an absorbent membrane, the absorbent membrane being soaked with the SAE composition after the airtight seal is broken on the storage compartment.

[0092] In some embodiments, a kit for delivering an SAE composition to a subject has an applicator unit, the applicator unit including a storage compartment. In some embodiments, a kit for delivering an SAE composition to a subject has an applicator unit, the applicator unit including a storage compartment for protecting the SAE composition from atmospheric water. In some embodiments, a kit for delivering an SAE composition to a subject, the SAE composition is essentially free of water. In some embodiments, a kit for delivering an SAE composition to a subject, the SAE composition is essentially free of water. In some embodiments, a kit for delivering an SAE composition to a subject, the SAE composition is essentially free of water and DMSO.

[0093] In some embodiments, a kit for delivering an SAE composition to a subject is provided, the kit providing controlled delivery of the SAE composition to the subject. In some embodiments, the kit for delivering an SAE composition to a subject distributes the SAE composition evenly across the area of ​​skin to be treated. In some embodiments, the area of ​​skin to be treated is variable in size. In some embodiments, the maximum area of ​​skin to be treated is about 800 cm. 2In some embodiments, the controlled delivery of an SAE composition to a subject provides a precise volume of the SAE composition. In some embodiments, the controlled delivery of an SAE composition to a subject occurs at a predetermined rate. In some embodiments, the controlled delivery of an SAE composition to a subject protects the SAE composition from water prior to administration to the subject.

[0094] In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered to a subject in need thereof. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered topically to a subject in need thereof. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered to the skin of a subject in need thereof. In some embodiments, the system is for delivering an SAE composition to a subject, where the SAE composition is administered to the scalp of a subject in need thereof. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered adjacent to a skin lesion of a patient in need thereof to treat a skin condition. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered to an area of ​​the skin determined to be optimal by a physician. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is administered selectively to areas of the skin in need thereof. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition does not contact any unintended areas of the skin. In some embodiments, the kit is for delivering an SAE composition to a subject, where the SAE composition is contained entirely within a reservoir unit and an applicator unit.

[0095] In some embodiments, the system is for delivering the SAE composition to a subject with skin disease.In some embodiments, the kit is for delivering the SAE composition to a subject with alopecia.In some embodiments, the kit is for delivering the SAE composition to a subject with alopecia areata.In some embodiments, the system is for delivering the SAE composition to a subject to treat a condition selected from viral warts, herpes simplex virus, molluscum contagiosum, and cutaneous T-cell lymphoma.

[0096] In some embodiments, the kit is for delivering a therapeutically effective amount of the SAE composition to a subject. In some embodiments, the therapeutically effective amount is an amount disclosed herein. In some embodiments, the kit is for delivering a SAE composition to a subject to cause the disappearance of the condition being treated. In some embodiments, the kit is for delivering a SAE composition to a subject to cause the restoration of hair loss. In some embodiments, the kit is for delivering a SAE composition to a subject to cause hair growth in an area of ​​skin that is in direct contact with the SAE composition. In some embodiments, the kit is for delivering a SAE composition to a subject to cause hair growth in an area of ​​skin adjacent to the site of administration of the SAE composition.

[0097] In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in a one-point improvement in any ordinal or interval rating scale, such as Physician Global Assessment or Investigator Global Assessment.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in about 100% hair growth recovery in the area where the patch is administered.In some embodiments, the subject is diagnosed with alopecia areata, and successful treatment of this condition results in at least about 50% increase in hair growth in the area where the patch is administered, as defined by the number of hair follicles with actively growing hair shafts, as seen by clinical, trichological, or histopathological evaluation. In some embodiments, successful treatment of alopecia areata with an SAE composition may result in increased hair growth at the site where the composition was administered, such as about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about An increase of 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or a value within these ranges. Specific examples include increasing hair growth, as defined by the number of hair follicles with actively growing hair shafts as seen by clinical, trichiscopic, or histopathological evaluation, by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0098] The Severity Alopecia Tool (SALT) score at the site where the patch was administered was approximately 50% to approximately 100%, approximately 50% to approximately 95%, approximately 50% to approximately 90%, approximately 50% to approximately 85%, approximately 50% to approximately 80%, approximately 50% to approximately 75%, approximately 50% to approximately 70%, approximately 50% to approximately 65%, approximately 50% to approximately 60%, approximately 50% to approximately 55%, approximately 60% to approximately 100%, approximately 60% to approximately 95%, approximately 60% to approximately 90%, approximately 60% to approximately 85%, approximately 60% to approximately 8 ... % to about 75%, about 60% to about 70%, about 60% to about 65%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 90% to about 100%, about 90% to about 95%, or values ​​within these ranges. Specific examples include improving Severity Alopecia Tool (SALT) score by about 100%, about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, or a range between any two of these values.

[0099] In some embodiments, a kit for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month. In some embodiments, a kit for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month for 4 months. In some embodiments, a kit for delivering an SAE composition to a subject, wherein the SAE composition is delivered to the subject once a month for 1-12 months, 1-11 months, 1-10 months, 1-9 months, 1-8 months, 1-7 months, 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, or values ​​within these ranges. Specific examples include 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or ranges between any two of these values.

[0100] In some embodiments, a kit for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. In some embodiments, a kit for delivering an SAE composition to a subject, wherein the subject is evaluated for hair growth at the end of four months of treatment. Subjects who experience hair growth at the end of four months of treatment are referred to as "responders." Subjects who do not experience hair growth at the end of four months of treatment are referred to as "non-responders." Subjects who experience measurable hair growth at any amount below about 50% SALT score at the end of four months of treatment are referred to as "partial responders." In some embodiments, a kit for delivering an SAE composition to a subject, wherein the subject is a responder. In some embodiments, a kit for delivering an SAE composition to a subject, wherein the subject is a non-responder. In some embodiments, a kit for delivering an SAE composition to a subject, wherein the subject is a partial responder. In some embodiments, a kit for delivering an SAE composition to a non-responder, where the SAE composition is delivered every two weeks. In some embodiments, a kit for delivering an SAE composition to a partial responder, where the SAE composition is delivered every two weeks. In some embodiments, a kit for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every week. In some embodiments, a kit for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered twice a week. In some embodiments, a kit for delivering an SAE composition to a non-responder or partial responder, where the SAE composition is delivered every three weeks.

[0101] In the above detailed description, reference is made to the accompanying drawings, which form a part of this specification. In the drawings, similar reference numerals generally identify similar components unless otherwise indicated by the context. The exemplary embodiments described in this disclosure are not meant to be limiting. Other embodiments may be used and other changes may be made without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the various features of the present disclosure, as generally described herein and illustrated in the figures, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0102] The present disclosure is not limited in terms of the specific embodiments described in this application, which are intended as illustrations of various features. Instead, the present application is intended to cover any variations, uses, or adaptations of the present teachings and to use their general principles. Moreover, the present application is intended to cover departures from the present disclosure as are within known or customary practice in the art to which these teachings pertain. As will be apparent to those skilled in the art, many modifications and variations can be made to the specific embodiments described without departing from the spirit and scope of the present disclosure. Functionally equivalent methods and apparatuses within the scope of the present disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description. It is to be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0103] The various features and functions disclosed above, or alternatives thereof, may be combined into many other different systems or applications. Various alternatives, modifications, variations, or improvements not presently foreseen or anticipated, may subsequently be made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments.

[0104] Further embodiments: Provided herein is embodiment A: a composition comprising a squaric acid ester (SAE) and an excipient, the composition being essentially free of water and DMSO, the composition having a volume of 1 milliliter.

[0105] Embodiment B: The composition of embodiment A, wherein the composition is shelf-stable for up to about 60 months.

[0106] Embodiment C: The composition of embodiment B, wherein the SAE is squaric acid dibutyl ester (SADBE) or squaric acid diethyl ester (SADEE).

[0107] Embodiment D: The composition of embodiment B, wherein the SAE is in an amount of at least about 5% (weight / volume) of SAE.

[0108] Embodiment E: The composition of embodiment B, wherein the SAE is in an amount of at least about 10% (weight / volume) SAE.

[0109] Embodiment F: The composition of embodiment B, wherein the composition is stored at room temperature.

[0110] Provided herein is embodiment G: a system for delivering a squaric acid ester (SAE) composition to a subject, the system comprising: a storage compartment containing the composition having at least about 2.5% (weight / volume) SAE and excipients; and an applicator unit, the applicator unit delivering a volume of about 1 milliliter of the SAE composition.

[0111] Embodiment H: The system of embodiment G, wherein the applicator unit includes a storage compartment, an airtight seal, a connection area, and an applicator.

[0112] Embodiment I: The system of embodiment H, wherein the storage compartment protects the SAE composition from atmospheric water.

[0113] Embodiment J: The system of embodiment H, wherein the absorbent membrane is disposed at a distal end of the storage unit.

[0114] Embodiment K: The system of embodiment J, wherein the absorbent membrane is soaked with the SAE composition after the airtight seal is broken on the storage compartment.

[0115] Embodiment L: The system of embodiment G, wherein the system provides controlled delivery of the SAE composition to the subject.

[0116] Embodiment M: The system of embodiment G, wherein the SAE composition is administered locally to a subject in need thereof.

[0117] Provided herein is embodiment N: a method of delivering a squaric acid ester (SAE) composition to a subject to treat a condition susceptible to treatment with the SAE composition, comprising providing an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and delivering the SAE composition from the storage compartment through the applicator to the subject.

[0118] Embodiment O: The method of embodiment N, wherein the subject is diagnosed with a skin disease.

[0119] Embodiment P: The method of embodiment N, wherein the subject is diagnosed with alopecia areata.

[0120] Embodiment Q: The method of embodiment N, wherein the composition is delivered to the scalp of a subject for the treatment of hair loss.

[0121] Embodiment R: The method of embodiment N, wherein delivering to a subject results in hair growth.

[0122] Embodiment S: The method of embodiment N, wherein the delivering step comprises delivering about 1 milliliter of the SAE composition.

[0123] Embodiment T: The method of embodiment N, wherein the SAE composition comprises at least about 5% (weight / volume).

[0124] Embodiment U: The method of embodiment N, wherein the SAE composition comprises at least about 7% (weight / volume).

[0125] Embodiment V: The method of embodiment N, wherein the SAE composition comprises at least about 10% (weight / volume).

[0126] Embodiment W: The method of embodiment N, wherein the step of delivering the SAE composition to a subject is controlled delivery.

[0127] Embodiment X: The method of embodiment N, wherein the step of delivering the SAE composition to a subject is controlled delivery.

[0128] Embodiment Y: The method of embodiment N, wherein the SAE composition is delivered to the subject once a month.

[0129] Embodiment Z: The method of embodiment N, wherein the SAE composition is delivered to the subject once a month for four months.

[0130] Embodiment AA: The method of embodiment Z, wherein the subjects are evaluated for hair growth at the end of said four months, and subjects who experience hair growth are responders.

[0131] Embodiment AB: The method of embodiment Z, wherein the subject is evaluated for hair growth at the end of said four months, and subjects who do not grow hair are non-responders.

[0132] Embodiment AC: The method of embodiment AB, wherein the SAE composition is delivered to the non-responder every two weeks.

[0133] Provided herein is embodiment AD: a kit for administering a squaric acid ester (SAE) composition to a subject, comprising an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and the SAE composition comprising at least 5% SAE, the kit further comprising instructions for administering the SAE composition to treat a condition susceptible to treatment with the SAE composition.

[0134] Working Example The following are provided for illustrative purposes only and are not intended to limit the scope of the embodiments broadly described above. Example 1

[0135] Example 1: Stability of SADBE The stability of SADBE was tested in ethyl acetate-added solvent for 3 months. The characteristics of the SADBE formulation are shown in Table 1. TIFF2024530719000002.tif63141

[0136] The formulations shown in Table 1 were filled into Type 1 glass vials and closed with butyl rubber stoppers and aluminum crimp seals. The initial and 3-month test results are summarized in Table 2 (NT = not tested, * a colorless, transparent solution with no precipitate or deposition on the vial walls). TIFF2024530719000003.tif128141

[0137] After 3 months storage at 40°C, all three formulations experienced significant increases in assays. This increase in assays was consistent with weight loss from the vials. Ethyl acetate is a volatile solvent and the container / closure was not optimized for this component. No new impurities were detected and there was no change in appearance. All data to date indicates that SADBE is stable in solvent 9 and solvent 10 at 40°C for up to 3 months.

[0138] Preferences and options with respect to a given aspect, feature, embodiment, or parameter of the invention should be considered as disclosed in combination with all preferences and options with respect to all other aspects, features, embodiments, and parameters of the invention, unless the context dictates otherwise.

[0139] While the present disclosure has been disclosed with reference to various embodiments, it will be apparent that other embodiments and variations thereof may be devised by those skilled in the art without departing from the true spirit and scope of the present disclosure, and it is intended that the appended claims be construed to include all such embodiments and equivalent variations.

Claims

1. 1. A composition comprising: Squaric acid esters (SAEs), an excipient; Including, the composition is essentially free of water and DMSO; The composition has a volume of 1 milliliter.

2. 10. The composition of claim 1, wherein the composition is shelf stable for up to about 60 months.

3. 3. The composition of claim 2, wherein the SAE is squaric acid dibutyl ester (SADBE) or squaric acid diethyl ester (SADEE).

4. 3. The composition of claim 2, wherein the SAE is in an amount of at least about 5% (wt / vol) of the SAE.

5. 3. The composition of claim 2, wherein the SAE is in an amount of at least about 10% (wt / vol) of the SAE.

6. 3. The composition of claim 2, wherein the composition is stored at room temperature.

7. 1. A system for delivering a squaric acid ester (SAE) composition to a subject, comprising: a storage compartment containing the composition having at least about 2.5% (wt / vol) of an SAE and excipients; an applicator unit that delivers a volume of about 1 milliliter of the SAE composition; Including, the system.

8. The system of claim 7 , wherein the applicator unit includes a storage compartment, an airtight seal, a connection area, and an applicator.

9. 9. The applicator unit of claim 8, wherein the storage compartment protects the SAE composition from atmospheric water.

10. The applicator unit of claim 8, wherein the absorbent membrane is disposed at a distal end of the reservoir unit.

11. 11. The absorbent membrane of claim 10, wherein the absorbent membrane is saturated with the SAE composition after the airtight seal is broken on the storage compartment.

12. 8. The system of claim 7, wherein the system provides controlled delivery of the SAE composition to the subject.

13. 8. The system of claim 7, wherein the SAE composition is administered locally to a subject in need thereof.

14. A squaric acid ester (SAE) composition for treating a condition susceptible to treatment with the SAE composition, wherein the SAE composition is delivered to a subject by an applicator device comprising a storage compartment, an airtight seal, a connection area, and an applicator, and the SAE composition is delivered from the storage compartment through the applicator to the subject.

15. 15. The SAE composition of claim 14, wherein the subject is diagnosed with a skin disorder.

16. 15. The SAE composition of claim 14, wherein the subject is diagnosed with alopecia areata.

17. 15. The SAE composition of claim 14, wherein the composition is delivered to the scalp of a subject for the treatment of hair loss.

18. 15. The SAE composition of claim 14, wherein delivery to the subject results in hair growth.

19. 15. The SAE composition of claim 14, wherein said delivering comprises delivering about 1 milliliter of said SAE composition.

20. 15. The SAE composition of claim 14, wherein the SAE composition comprises at least about 5% (wt / vol).

21. 15. The SAE composition of claim 14, wherein the SAE composition comprises at least about 7% (wt / vol).

22. 15. The SAE composition of claim 14, wherein the SAE composition comprises at least about 10% (wt / vol).

23. 15. The SAE composition of claim 14, wherein delivery of the SAE composition to a subject is controlled delivery.

24. 15. The SAE composition of claim 14, wherein the SAE composition is delivered to a subject once a month.

25. 15. The SAE composition of claim 14, wherein the SAE composition is delivered to a subject once a month for four months.

26. 26. The SAE composition of claim 25, wherein the subject is evaluated for hair growth at the end of said four months, and subjects who experience hair growth are responders.

27. 26. The SAE composition of claim 25, wherein the subject is evaluated for hair growth at the end of the four-month period, and subjects who do not grow hair are designated non-responders.

28. 28. The SAE composition of claim 27, wherein the SAE composition is delivered to the non-responder every two weeks.

29. 1. A kit for administering a squaric acid ester (SAE) composition to a subject, comprising: an applicator device including a storage compartment, an airtight seal, a connection area, and an applicator; the SAE composition comprising at least 5% SAE; Including, The kit further comprises instructions for administering the SAE composition to treat a condition susceptible to treatment with the SAE composition.

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