Topical compositions of substituted diazepines and uses thereof

Abstract

The present disclosure relates in some aspects to compositions, such as pharmaceutical compositions for topical administration, which are useful for treating or preventing hair loss, hair graying, and dermatological conditions in a subject, such as comprising a substituted diazepine, for example olanzapine. Also provided are kits comprising the compositions, and methods of using the compositions for treating or preventing hair loss, hair graying, and dermatological conditions.

Description

[0001] 2025-12-29

[0002] TOPICAL COMPOSITIONS OF SUBSTITUTED DIAZEPINES AND USES THEREOF

[0003] Aonia Traxler

[0004] CROSS-REFERENCE

[0005]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional App. No.

[0006] 63 / 739,550, filed December 28, 2024, and incorporated by reference for all purposes as if fully set forth herein. This application is timely filed on the first working day following Sunday, December 28, 2025, pursuant to PCT Rule 80.5 and MPEP §710.05.

[0007] FIELD OF THE INVENTION

[0008]

[0002] The present disclosure relates in some aspects to pharmaceutical compositions useful for treating or preventing hair loss and dermatological conditions in a subject, such as comprising a substituted diazepine. Also disclosed are kits comprising the compositions, and methods of their use for treating or preventing hair loss and dermatological conditions.

[0009] BACKGROUND

[0010]

[0003] Androgenetic alopecia, commonly referred to as pattern hair loss, is a prevalent condition that impacts up to 50% of men and 25% of women by the time they reach 50 years old (Vary, JC, The Medical Clinics of North America (Review), 99(6): 1195-1211). While the exact causes are not fully understood, factors such as oxidative stress and hormonal imbalances are believed to play a role. These and other similar underlying factors are also implicated in dermatological conditions such as impaired wound healing, uneven skin tone, and the loss of elasticity or structure.

[0011]

[0004] Current treatments for hair loss and other skin-related concerns are often limited in efficacy and associated with undesirable side effects. For example, therapies for hair loss typically target hormonal pathways or follicular stimulation, while skin treatments focus on repair or rejuvenation using compounds that can cause irritation or offer only modest results. As a result, there is still a significant unmet need for effective and well-tolerated treatments for pattern hair loss, such as addressed through the compositions and methods of this disclosure.

[0012] INCORPORATION BY REFERENCE

[0013]

[0005] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference is from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission2025-12-29 that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art.

[0014] BRIEF SUMMARY OF THE INVENTION

[0015]

[0006] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. It is not an extensive overview of the invention, nor intended to identify key or critical elements of the invention or to delineate its full scope. Its sole purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the detailed description below.

[0016]

[0007] In one aspect, provided is a topical composition for treating or preventing hair loss, comprising olanzapine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, the composition comprises the olanzapine at a concentration of between about 0.1 pM and about 5 mM.

[0017]

[0008] In embodiments, the topical delivery vehicle comprises a solvent system. In embodiments, the solvent system comprises any one or more solvents selected from the group consisting of polar aprotic solvents, water, alcohols, oils, and silicones. In embodiments, the solvent system comprises a polar aprotic solvent. In embodiments, the solvent system comprises one or more alcohols. In embodiments, the one or more alcohols are selected from the group consisting of ethanol, isopropanol, glycerin, butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, and diglycerin. In embodiments, the composition comprises one or more oils. In embodiments, the one or more oils are selected from the group consisting of fatty alcohols, fatty acids, waxes, triglycerides, hydrogenated oils, vegetable oils, mineral oil, squalane, isopropyl myristate, and esters thereof. In embodiments, the composition comprises one or more silicones. In embodiments, the one or more silicones are selected from the group consisting of cyclomethicone, cyclopentasiloxane, cyclohexasiloxane, dimethicone, dimethiconol, and phenyltrimethicone.

[0018]

[0009] In embodiments, the topical delivery vehicle comprises one or more pharmaceutically acceptable excipients. In embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, viscosity modifying agents, adhesion modifying agents, preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, or gelling agents.

[0019]

[0010] In embodiments, the topical delivery vehicle is a hydroalcoholic solution or gel, an aqueous gel, an aqueous solution, an anhydrous solution or gel, an emulsion, a microemulsion, a nanoemulsion, a solid lipid nanoparticle, a nanostructured lipid carrier, an ethosome, a transethosome, a silicone composition, a foam, a film-forming composition, an aqueous cyclodextrin inclusion system, or a depot vehicle.

[0020]

[0011] In embodiments, the topical delivery vehicle is selected from the group consisting of:2025-12-29 i. an anhydrous solution or gel comprising: one or more polar aprotic solvents; and optionally, one or more pharmaceutically acceptable excipients.

[0021] ii. a hydroalcoholic solution or gel comprising: water; one or more alcohols; and optionally, one or more pharmaceutically acceptable excipients;

[0022] iii. an aqueous gel comprising: water; a humectant; a gelling agent; optionally, a buffering agent; and optionally, a solubilizing agent;

[0023] iv. an emulsion comprising: water; one or more oils; and one or more emulsifiers;

[0024] v. a microemulsion or nanoemulsion comprising: water; one or more additional solvents; one or more oils; and one or more surfactants;

[0025] vi. a solid lipid nanoparticle or nanostructured lipid carrier comprising: one or more lipids; one or more surfactants; and optionally one or more antioxidants;

[0026] vii. an ethosome or transethosome comprising liposomes;

[0027] viii. an aqueous solution comprising one or more mineral salts or phytocomplexes;

[0028] ix. an aqueous cyclodextrin inclusion system comprising water and one or more cyclodextrins; or

[0029] x. a silicone composition comprising a silicone and one or more solvents.

[0030]

[0012] In embodiments, the anhydrous solution or gel comprises propylene carbonate and dimethyl isosorbide.

[0031]

[0013] In embodiments, the topical delivery vehicle is selected from the group consisting of an anhydrous polar cosolvent liquid, an oil-dominant anhydrous liquid, a non-aqueous nanosuspension, an aqueous cyclodextrin inclusion system, a liposomal or lipid-vesicle dispersion, a hydroalcoholic solution or gel, an aqueous gel, an emulsion, a microemulsion or nanoemulsion, solid lipid nanoparticles or nanostructured lipid carriers, ethosomes or transethosomes, niosomes, bilosomes, invasomes, a commercial or proprietary topical base, a foam or foamable scalp vehicle, an anhydrous organogel or structured oil, a micellar solution, deformable liposomes, liquid-crystalline lipid nanoparticles, a wash-off scalp vehicle, biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, an aqueous drug nanocrystal or nanosuspension, an ointment or pomade scalp vehicle, a solid stick or wax-stick applicator, a patch, laminate, or strip sustained-release scalp system, a microneedle-enabled scalp delivery system, microencapsulation systems, polymer-coated or layer-by-layer vesicles, an ionic-liquid or deep-eutectic-solvent carrier system, silicone-based topical compositions, film-forming topical compositions, depot or residence-time-extender topical vehicles, foam or mousse formulations, or a combination or hybrid vehicle system.

[0032]

[0014] Also provided are such other compositions and methods as will be described and enabled herein.2025-12-29

[0015] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims.

[0033]

[0016] The headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035]

[0017] While various features of certain aspects and embodiments are summarized above, the following detailed description illustrates exemplary aspects and embodiments in further detail to enable one of skill in the art to practice such aspects and embodiments, and in so doing to make and use the full scope of the invention.

[0036]

[0018] The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. It will be understood that many modifications, substitutions, changes, and variations in the described aspects, embodiments, applications, examples, and details can be made by one of skill without departing from the spirit of the invention, or the scope of the invention as described in the appended claims, and the general principles defined herein may be applied to a wide range of aspects. Thus, the invention is not intended to be limited to the aspects and embodiments presented, but is to be accorded the widest scope consistent with the principles and novel features disclosed, including their equivalents. The description will make such aspects and embodiments apparent to one of skill, in that such aspects and embodiments will be readily cognizable and readily creatable without undue experimentation, solely using the teachings herein and the general knowledge of the art.

[0037]

[0019] While the methods described and illustrated herein may include particular steps, it should be apparent that other methods including fewer, more, or different steps than those described and shown are also within the spirit and scope of the invention. The methods and uses of any compound or composition discussed, and any associated steps shown herein, therefore should be understood as being provided for purposes of illustration, not limitation. It should be further understood that the specific order or hierarchy of steps in the methods and uses of any compound or composition disclosed are only exemplary approaches. All methods described herein can be performed in any suitable order unless otherwise2025-12-29 indicated herein or otherwise clearly contradicted by context. The specific order or hierarchy of steps in any methods thus may be rearranged according to ordinary skill, while remaining within the spirit and scope of the disclosure. Any presented claims also will present elements of the steps in a sample and exemplary order, and are not meant to be limited to the specific order presented.

[0038]

[0020] Unless otherwise stated, all measurements, values, ratings, positions, dimensions, magnitudes, sizes, locations, orientations, configurations, and other specifications that are set forth (either expressly or impliedly) in this specification, including in the figures and in the claims, are approximate, and not exact. They are intended to have a reasonable range that is consistent with the functions to which they relate and with what is customary in the art to which they pertain. Moreover, the recitation of ranges of values is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated, each individual value is incorporated into the specification as if it were individually recited herein.

[0039]

[0021] The use of any and all examples, or exemplary language provided with respect to an embodiment, is intended merely to better illuminate certain non-limiting aspects of the invention and does not pose a limitation on the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0040]

[0022] While the invention and its various aspects are described in terms of particular embodiments and applications, it is not intended that these descriptions in any way limit its scope to any such embodiments and applications, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims.

[0041] A. General Definitions and Terms

[0042]

[0023] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. While the term “one or more” or “many” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple components in particular embodiments.

[0043]

[0024] The terms “comprising,” “including,” “such as,” and “having” are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). Thus, the term “including” means, and is used interchangeably with, the phrase “including but not limited to.” The term “or” is used herein to mean, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0044]

[0025] A shorthand may be used for some terms and, unless context clearly indicates otherwise, will have the same meaning as the full term. For example, a “pharmaceutical composition” may be referred2025-12-29 to simply as a “composition,” and other such shorthand terms will be readily appreciated in view of the disclosure.

[0045]

[0026] Unless context indicates a distinction relevant to a described or claimed embodiment, “composition” and “formulation” are used interchangeably and equivalently herein.

[0046]

[0027] “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.”

[0047]

[0028] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, relative amounts, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers will be understood as not being modified by the term “about.”

[0048]

[0029] In some embodiments (equivalently, and only for shorthand, “in embodiments”), the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus one percent (±1%) of the recited unit of measure. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure.

[0049]

[0030] The term “substantially,” where it is applied to modify a parameter or characteristic herein, will be read in the context of the invention and in light of the knowledge in the art to provide certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of substantially as a term of degree, or by ascertaining the scope as would one of skill in the art. Where no such certainty can be established from the context, the term may be understood as also meaning “about,” e.g., within ±1%, within ±5%, or within ±10%.

[0050]

[0031] Where “about” is used to modify one number in a series or range, it is understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range; thus, the term “about 1 , 2, or 3” is understood to mean “about 1 , about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.”

[0051]

[0032] In embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.2025-12-29

[0033] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs, who as shorthand may be referred to simply as “one of skill” or “one in the art.”

[0052]

[0034] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, such as biology, biochemistry, dermatology, pharmacology, and medical science, and are those that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0053]

[0035] Where definitions are included herein, they are for purposes of assisting the reader in understanding the disclosed embodiments; however, it will be appreciated that any such definitions are not intended to limit the scope of the invention, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0054]

[0036] Further definitions follow, to assist a reader in understanding the embodiments.

[0055]

[0037] “Treat,” “treated,” “treating,” “treatment," and like terms refer to treating a condition in a subject, and include causing a desired biological or pharmacological effect that: (a) inhibits a condition, i.e. , arrests its development; (b) relieves a condition, i.e., causes regression thereof; (c) protects from or relieves a symptom or pathology caused by or related to a condition; (d) reduces, decreases, inhibits, ameliorates, or prevents the severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a condition; or (e) prevents or inhibits a worsening or progression of one or more symptoms or pathologies associated with a condition or comorbid with a condition.

[0056]

[0038] “Prevent,” “prevented,” “preventing,” “prevention,” and like terms refer to preventing a condition in a subject, and include causing a desired biological or pharmacological effect that: (a) prevents a condition from occurring in a subject; (b) prevents one or more symptoms or pathologies associated with a condition from occurring in a subject; or (c) delays the onset of one or more symptoms or pathologies associated with a condition.

[0057]

[0039] A “condition,” unless context clearly indicates a more specific meaning, broadly includes any disease, disorder, illness, injury, disability, symptom, set of symptoms, or other medical or health condition that the disclosed methods are useful to treat.

[0058]

[0040] An “effective amount,” a “therapeutically effective amount,” or “a pharmacologically effective amount” refers to an amount of an active agent or composition disclosed herein that is sufficiently non-toxic and effective to provide a desired therapeutic effect with performance at a reasonable benefit / risk ratio attending any medical treatment. The effective amount may vary depending upon the subject, the2025-12-29 weight and age thereof, the severity of the symptoms or degree of health benefit sought, the manner of administration, and the like, all of which can readily be determined by one of skill in the art.

[0059]

[0041] “Therapeutic effect” or “therapeutic efficacy” means the response(s) in a subject after treatment that are judged to be desirable and beneficial. Hence, depending on the symptoms to be treated, or improvement in health or functioning sought, and depending on the particular constituent(s) of the methods of the disclosure under consideration, those responses shall differ, but would be readily understood by those of skill.

[0060]

[0042] The terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to a human, a mammal, or any other animal susceptible to a condition (e.g., hair loss, a hair loss condition, or a dermatological condition). In embodiments, the subject is a human. The subject may be a human infant, a human child, a human adult, or an elderly human. Such terms will be understood to include one who has an indication for which a method described herein may be efficacious, or who otherwise may benefit by the invention. In general, all of the disclosed methods will be appreciated to work for all subjects, although individual variation is to be expected, and will be understood.

[0061]

[0043] Still additional definitions and abbreviations are provided elsewhere herein.

[0062] B. Pharmaceutical Compositions

[0063]

[0044] The present disclosure relates in some aspects to compositions, such as pharmaceutical compositions, useful for treating hair loss and dermatological conditions.

[0064]

[0045] “Compositions” and “pharmaceutical compositions” herein may be used equivalently and interchangeably, and a composition may be a “pharmaceutical” composition independent of and without reference to any specific regulatory regime, or any specific approval therein, and without commercialization as a “pharmaceutical” or for “pharmaceutical” use. In some embodiments however, disclosed compositions may be, or be used as, “pharmaceuticals."

[0065]

[0046] A “composition” herein generally refers to composition of matter suitable for administration to an animal, such as a human. For example, a composition may comprise a disclosed compound, e.g., an active agent (or “active ingredient”), such as a substituted diazepine, for administration to an animal, such as a human. In embodiments, a composition comprises a disclosed compound, such as a substituted diazepine, together with a, preferably pharmaceutically acceptable, carrier, diluent, or excipient.

[0066]

[0047] Herein, an “excipient” may refer generically to a carrier, diluent, or excipient, unless context clearly indicates otherwise. For example, some disclosed embodiments may separately comprise a “carrier.” In embodiments, an excipient, or an ingredient that may act as an excipient, may be referred to by a specific term for purposes of clarity or convenience. For example, some disclosed embodiments comprise a “solvent system.”

[0067]

[0048] In embodiments, more than one carrier, diluent, or excipient may be used, and therefore in some embodiments reference to “an embodiment” may refer to one or more excipients, two excipients, or2025-12-29 greater than two excipients. Although certain excipients may be disclosed or claimed in some embodiments, any such excipients are exemplary only unless stated otherwise. In embodiments, a disclosed compound, such as a substituted diazepine, may be administered without an excipient, or without a specific disclosed excipient, such as without hydroxypropyl cellulose or without another hydroxyalkylcellulose.

[0068]

[0049] Useful features of the compositions include curing or alleviating the symptoms of a subject suffering from a hair loss condition (e.g., androgenetic alopecia), or a dermatological condition (e.g., impaired wound healing, rhytids).

[0069]

[0050] Without being bound by theory, a disclosed composition may stimulate hair growth by prolonging anagen, stimulating keratinocyte proliferation, and / or upregulating keratin production, upon administration to human scalp hair follicles.

[0070]

[0051] In one aspect, provided is a composition comprising a therapeutically effective amount of a substituted diazepine.

[0071]

[0052] In embodiments, the composition comprises (i) a substituted diazepine; (ii) a pharmaceutically acceptable excipient; and (ill) a solvent system. In embodiments, the composition contains a substituted diazepine as the only active ingredient. Hence, also provided is a composition comprising: (I) a substituted diazepine as the only active ingredient; and (ii) a pharmaceutically acceptable excipient. In embodiments, the composition comprises: (I) a substituted diazepine as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (Hi) a solvent system. In embodiments, the composition consists essentially of: (I) a substituted diazepine; and (ii) a pharmaceutically acceptable excipient. In embodiments, the composition consists essentially of: (I) a substituted diazepine; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0072]

[0053] In one aspect, provided is a composition comprising a therapeutically effective amount of olanzapine, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises (i) olanzapine, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In embodiments, the composition contains olanzapine as the only active ingredient. Hence, also provided is a composition comprising: (i) olanzapine as the only active ingredient; and (ii) a pharmaceutically acceptable excipient. In embodiments, the composition comprises: (I) olanzapine as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In embodiments, the composition consists essentially of: (i) olanzapine, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient. In embodiments, the composition consists essentially of: (i) olanzapine, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0073]

[0054] In embodiments, a disclosed composition is for treating hair loss. In embodiments, a disclosed composition is for preventing hair loss.2025-12-29

[0055] In embodiments, a disclosed composition is for treating hair graying. In embodiments, a disclosed composition is for preventing hair graying.

[0074]

[0056] In embodiments, a disclosed composition is for treating a dermatological condition. In embodiments, a disclosed composition is for preventing a dermatological condition.

[0075] a. Substituted Diazepines

[0076]

[0057] In embodiments, a disclosed composition comprises a substituted diazepine. A “substituted diazepine” refers to a compound comprising a diazepine ring (e.g., a 1 ,4-diazepine ring) that is fused with one or more aryl and / or heteroaryl rings, and which is optionally substituted with one or more substituents.

[0077]

[0058] Substituted diazepines useful in disclosed compositions and methods include benzodiazepines, thienodiazepines, thienobenzodiazepines, thienotriazolodiazepines, imidazo-benzodiazepines, oxazolobenzodiazepines, pyridodiazepines, pyrazolodiazepines, and other like chemophores known to those of skill in the art.

[0078]

[0059] “Substituted diazepine” as used herein also includes derivatives of substituted diazepine, such as compounds derived (e.g., synthesized) from substituted diazepine (e.g., benzodiazepines, thienodiazepines, thienobenzodiazepines, thienotriazolodiazepines, imidazo-benzodiazepines, oxazolobenzodiazepines, pyridodiazepines, pyrazolodiazepines) as the starting material, such as by the modification, addition, or subtraction of one or more functional groups, atoms, or moieties. Substituted diazepine derivatives also include compounds not synthesized from a substituted diazepine as the starting material, but whose structures include a diazepine moiety.

[0079]

[0060] In embodiments, the substituted diazepine is diazepam, lorazepam, clonazepam, midazolam, remimazolam, alprazolam, triazolam, estazolam, temazepam, oxazepam, lormetazepam, nitrazepam, flunitrazepam, chlordiazepoxide, medazepam, prazepam, halazepam, quazepam, phenazepam, delorazepam, gidazepam, pinazepam, camazepam, ketazolam, cinolazepam, mexazolam, zolazepam, clobazam, sulazepam, clorazepate, clotiazepam, brotizolam, etizolam, cloxazolam, flutazolam, tofisopam, imidazenil, bretazenil, flumazenil, olanzapine, or clozapine.

[0080]

[0061] In embodiments, the substituted diazepine is a thienobenzodiazepine. In embodiments, the substituted diazepine is a substituted thienobenzodiazepine. In embodiments, the substituted diazepine is a thienobenzodiazepine substituted with any one or more of an optionally substituted alkyl, an optionally substituted alkylene-heterocyclyl, and an optionally substituted heterocyclyl (e.g., piperazinyl).

[0081]

[0062] In embodiments, the substituted diazepine is olanzapine. Olanzapine (also marketed and sold using the tradename ZYPREXA®) has the IUPAC name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, and the chemical structure:2025-12-29

[0082]

[0083]

[0063] In embodiments, the substituted diazepine is provided as a salt. Herein, unless context clearly demands otherwise, a “substituted diazepine” or reference to any particular substituted diazepine, such as olanzapine, will be understood to include its salts.

[0084]

[0064] A substituted diazepine salt includes any salt prepared from a non-toxic acid or base, such as synthesized by conventional chemical methods. Generally, a substituted diazepine salt can be prepared by reacting the free acid or base forms of the substituted diazepine with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. One of skill can select from among a wide variety of available counterions. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.

[0085]

[0065] Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxy- benzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, diphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate,2025-12-29 tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, and the like (see, e.g., Berge. J Pharmaceutical Sciences. 1977;66(1):1-19).

[0086] b. Formulations and Excipients

[0087]

[0066] In embodiments, the composition is suitable for topical or transdermal administration. In embodiments, the composition is formulated for topical administration. In embodiments, the composition is formulated for transdermal administration. In embodiments, the composition suitable for topical or transdermal administration comprises a pharmaceutically acceptable excipient.

[0088]

[0067] In embodiments, a composition is formulated for injection. Formulations for injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile solutions or dispersions, and also may comprise additives such as solubilizers, stabilizers, and suspending, preserving, wetting, emulsifying, dispensing, and isotonic agents.

[0089]

[0068] In embodiments, a composition is formulated into a topical dosage form. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Topical dosage forms may comprise a penetrant or carrier. Penetrants include, for transmucosal administration, detergents, bile salts, fusidic acid derivatives, and combinations thereof. Carriers include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof.

[0090]

[0069] In embodiments, a composition is formulated for transdermal application. In general, transdermal delivery involves contacting the formulations with a subject’s skin under conditions effective for the active agent(s) to penetrate the skin and cause an effect. Transdermal formulations include ointments, creams, suspensions, lotions, pastes, gels, sprays, foams, oils, and combinations thereof. An exemplary transdermal delivery form is a transdermal “patch,” which may be used to provide continuous or discontinuous infusion of active agent(s) in controlled amounts. Patches may be constructed for continuous, gradual, pulsatile, or on demand delivery of the agents. In embodiments, a patch is a medicated adhesive patch, a single-layer or multi-layer drug-in-adhesive patch, a “matrix” (or “monolithic”) patch, or a “reservoir” patch. In embodiments, a patch is part of a delivery system, such as used with an electronic device coupled to a subject’s mobile device, and / or coupled with a mobile app (e.g., to control a delivery rate from a reservoir, and / or to provide information about delivery to the app or user). Various such technologies will be known and may be used.

[0091]

[0070] In another aspect, provided is a topical composition comprising: a substituted diazepine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, a composition comprises: (i) a substituted diazepine; (ii) a pharmaceutically acceptable excipient; and (ill) a solvent system. In embodiments, a composition comprises olanzapine, or a2025-12-29 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, a composition comprises: (i) olanzapine, or a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable excipients and / or one or more solvents.

[0092]

[0071] In embodiments, the composition comprises a substituted diazepine at a concentration of between about 0.01 pM and 5 mM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 0.01 pM and 1 mM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 0.1 pM and 500 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 1 pM and 100 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 1 pM and 50 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 20 pM and 60 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of between about 20 pM and 50 pM.

[0093]

[0072] In embodiments, the composition comprises a substituted diazepine at a concentration of between about 0.1 pM and about 500 pM, including about 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM, 10 pM, 11 pM, 12 pM, 13 pM, 14 pM, 15 pM, 16 pM, 17 pM, 18 pM, 19 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, 45 pM, 50 pM, 55 pM, 60 pM, 65 pM, 70 pM, 75 pM, 80 pM, 85 pM, 90 pM, 95 pM, 100 pM, 105 pM, 110 pM, 115 pM, 120 pM, 125 pM, 130 pM, 135 pM, 140 pM, 145 pM, 150 pM, 155 pM, 160 pM, 165 pM, 170 pM, 175 pM, 180 pM, 185 pM, 190 pM, 195 pM, 200 pM, 210 pM, 220 pM, 230 pM, 240 pM, 250 pM, 260 pM, 270 pM, 280 pM, 290 pM, 300 pM, 320 pM, 340 pM, 360 pM, 380 pM, 400 pM, 420 pM, 440 pM, 460 pM, 480 pM, and 500 pM, including amounts and open- and closed-ended ranges between these concentrations.

[0094]

[0073] In embodiments, the composition comprises a substituted diazepine at a concentration of less than about 0.1 pM (including concentrations between about 1 nM and 0.1 pM, about 10 nM and about 0.1 pM, and about 50 nM and about 0.1 pM). In embodiments, the composition comprises a substituted diazepine at a concentration of greater than about 500 pM (including concentrations between about 500 pM and about 1 mM, about 1 mM and about 100 mM, and about 100 mM and about 1 M). In embodiments, the composition comprises a substituted diazepine at a concentration of about 1 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of about 20 pM. In embodiments, the composition comprises a substituted diazepine at a concentration of about 50 pM.

[0095]

[0074] In embodiments, the composition comprises olanzapine, or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof, in an amount of between about 0.000001% and about 5% by weight of the composition. In embodiments, the composition comprises olanzapine in an amount of between about 0.00001% and about 0.1% by weight of the composition. In embodiments, the composition2025-12-29 comprises olanzapine in an amount selected from about 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, and 5%, including amounts and ranges between these values.

[0096]

[0075] In embodiments, a disclosed composition is formulated for topical administration (e.g., as a topical dosage form), such as through the use of one or more pharmaceutically acceptable excipients. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Pharmaceutically acceptable excipients for such compositions include penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, oils, silicones, solubilizing agents, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients generally known to one of skill.

[0097]

[0076] “Pharmaceutically acceptable” as used in connection with an excipient or other ingredient herein means that the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, or complication, and commensurate with a reasonable risk / benefit ratio. In embodiments, “pharmaceutically acceptable” means that a particular ingredient has been approved by the FDA for topical use, such as in cosmetic products. Such excipients may also be referred to as “cosmetically” or “dermatologically” acceptable, and are known in the art.

[0098]

[0077] In embodiments, a composition comprises a topical delivery vehicle. A “topical delivery vehicle” is as generally known in the art, and refers to a component of a composition for delivering one or more active agents to a subject via topical administration. Exemplary such vehicles include hydroalcoholic solutions and gels, aqueous gels, aqueous solutions, anhydrous gels, emulsions, microemulsions, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, ethosomes, transethosomes, silicone compositions, foams, film-forming compositions, and depot vehicles.

[0099]

[0078] In embodiments, disclosed compositions are formulated as a unit dosage form, each dosage containing an effective amount of the active ingredient(s), for example in the dose amounts disclosed herein. “Unit dosage form” refers to a physically discrete unit suited as unitary dosages to be consumed by the individual, each unit containing a predetermined quantity of active material calculated to produce the desired effect(s). Unit dosage forms are often used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof, of the composition.

[0100]

[0079] In embodiments, the composition comprises a penetration enhancer. Without being bound by theory, penetration enhancers are generally characterized by their ability to increase the permeability of biological barriers, such as scalp skin. In embodiments, including a penetration enhancer in the composition increases the bioavailability of the active agent(s) by improving the ability of the active2025-12-29 agent(s) to diffuse into the skin tissue. Penetration enhancers include, for example, fatty acids and oils such as castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petroleum jelly, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof.

[0101]

[0080] In embodiments, the penetration enhancer is 1,2-lauryl ether, aprotinin, azone, benzalkonium chloride, benzalkonium bromide, cetylpyridinium chloride, cetyltrimethyl ammonium, cyclodextrin, dextran sulfate, ethanol, isopropanol, glycol, lauric acid, propylene glycol, lysophosphatidylcholine, menthol, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, chitosan, sodium glycocholate, sodium deoxyglycocholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, dimethyl sulfoxide, dimethyl isosorbide, propylene carbonate, or a combination thereof. In embodiments, the penetration enhancer is selected from a group comprising lower chain alcohol with a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, polyoxyethylene-9-lauryl ether, polyoxythylene-20-cetyiether, benzalkonium chloride, cetylpyridinium chloride, vitamin E TPGS, caprylocaproyl polyoxylglycerides, stearoyl macrogolglycerides, propylene glycol dicaprylocaprate, or mixtures thereof. Penetration enhancers may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of penetration enhancers in the composition divided by the total weight of the composition).

[0102]

[0081] In embodiments, the base may further include a conditioning agent to prevent drying of the skin and hair. Representative conditioning agents may include, but are not limited to, glycerin, propylene glycol, alpha hydroxyl acids, urea, lactic acid, oils, lanolin and silicone and its derivatives. In embodiments, conditioning agents are physically and chemically compatible with the essential components of the composition, and do not otherwise unduly impair product stability, aesthetics or performance. In embodiments, the concentration of the conditioning agent in the composition is sufficient to provide the desired conditioning benefits, as will be apparent to one of ordinary skill in the art. The concentration may vary with the conditioning agent, the conditioning performance desired, the average size of the conditioning agent particles, the type and concentration of other components, and other like factors.

[0103]

[0082] In embodiments, the composition comprises a carrier. Carriers can be designed to give controlled release profiles, improved circulation times and better penetration across the epithelium. In embodiments, the carrier is a hydrophobic drug carrier. Hydrophobic drug carriers can have the advantage of exhibiting slow sustained release and may adhere well to biological surfaces. Hydrophobic drug carriers can have slow (i.e., extended) release kinetics, or may be constructed to have a rapid or immediate release profile. Non-limiting examples of hydrophobic carriers include squalane (and / or squalene), medium-chain triglycerides (MCT; e.g., caprylic / capric triglycerides), isopropyl myristate, mineral oil,2025-12-29 hydrogenated polyisobutene, and / or other saturated oils. In embodiments, the carrier comprises a lipid-based particulate carrier (e.g., liposomes / lipid vesicles) and / or an oil-based nanosuspension carrier. Techniques include using hydrophilic coatings on hydrophobic nanoparticles to improve their transport across tissue surfaces while retaining the slow-release profiles. These include polyethylene glycol and chitosan coatings (see, e.g., de la Fuente, et al. Nanomedicine 2008;3:845-857).

[0104]

[0083] Any of a variety of pharmaceutically acceptable carriers may be used including aqueous media such as water, saline, glycine, hyaluronic acid and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et aL, eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et aL, eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). Carriers may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of carriers in the composition divided by the total weight of the composition).

[0105]

[0084] In embodiments, the composition comprises an emulsifier. The emulsifier may be an anionic, cationic, or neutral emulsifier. Emulsifiers include anionic emulsifiers, such as alkyl sulfate, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulphonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarcosinates, isethionates, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarcosinate. Exemplary non-ionic or neutral emulsifiers include sorbitan ester, ethoxylated sorbitan ester, ethoxylated alkyl ether, ethoxylated fatty acid ether, fatty alcohol, ethoxylated fatty alcohol, and esters of glycerin and fatty acids. Emulsifiers also include synthetic and natural polymers. In embodiments, an emulsifier is a silicone (e.g., dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone, etc.). Emulsifiers may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of emulsifiers in the composition divided by the total weight of the composition).

[0106]

[0085] In embodiments, the composition comprises an anti-dandruff agent or other ingredients which are commonly applied to the scalp or hair, including antimicrobial agents, where desirable, generally in amounts found useful in topical applications. One of skill can determine the type and amount of anti-dandruff agents useful in disclosed compositions?2025-12-29

[0086] In embodiments, the composition comprises an antioxidant. Antioxidants include amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof peptides, such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes (e.g., 0-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (e.g., dihydroliponic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thiorodoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, y-linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., buthionine sulfoximines, homocysteine sulfoximines, buthionine sulfones, penta, hexa and heptathionine sulfoximine), in very low tolerated doses (e.g., pmol to pmol / kg), and furthermore (metal)chelators (e.g., a-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extracts, bilirubin, biliverdin, EDTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., y-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof vitamin C and derivatives thereof (e.g., sodium ascorbate, ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate, tocotrienol), vitamin A and derivatives (vitamin A palmitate) and coniferyl benzoate of benzoic resin, rutinic acid and derivatives thereof, a-glycosylrutin, ferulaic acid, furfurylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguajak resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, zinc and derivatives thereof (e.g., ZnO, ZnSO4), selenium and derivatives thereof (e.g., selenium methionine), stilbenes and derivatives thereof (e.g., stilbene oxide, trans-stilbene oxide).

[0107]

[0087] In embodiments, the antioxidant is a lipophilic antioxidant selected from the group consisting of tocopherols, tocopherol derivatives, butylhydroxytoluene, butylhydroxyanisole, ascorbyl palmitate, and combinations thereof. In embodiments, where the composition comprises an aqueous phase, the antioxidant comprises a water-phase antioxidant selected from ascorbic acid, sodium ascorbate, erythorbate, sulfites, bisulfites, and combinations thereof. In embodiments, the antioxidant is selected based on compatibility with the solvent system and whether the composition is aqueous, non-aqueous, or biphasic. In embodiments, an antioxidant is present in an amount of between about 0% and about 2% by weight of the composition, including between about 0.0001% and about 1%, and including subranges such as between about 0.0001% and about 0.1%, and between about 0.01% and about 1%. Antioxidants may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of antioxidants in the composition divided by the total weight of the composition).2025-12-29

[0088] In embodiments, the composition comprises a thickener. Thickeners include crosslinked polyacrylic acids and derivatives thereof, polysaccharides and derivatives thereof, such as xanthan gum, agar agar, alginates or tyloses, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and polyvinylpyrrolidone. Thickeners may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of thickeners in the composition divided by the total weight of the composition).

[0108]

[0089] In embodiments, the composition comprises a cosmetically and / or demno-cosmetically active substance. Cosmetically and / or dermo-cosmetically active substances include color-imparting active substances, skin- and hair-pigmenting compositions, tinting compositions, tanning compositions, bleaches, keratin-hardening substances, antimicrobial active substances, light filter active substances, repellent active substances, substances having hyperemic activity, substances having keratolytic and keratoplastic activity, antiphlogistic agents, substances having keratinizing activity, antioxidant active substances or substances active as free radical scavengers, skin-moisturizing substances or skin humectants, refatting active substances, substances having antierythematous or antiallergic activity, branched fatty acids, and mixtures thereof. Cosmetically and / or dermo-cosmetically active substances may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of cosmetically and / or dermo-cosmetically active substances in the composition divided by the total weight of the composition).

[0109]

[0090] In embodiments, the composition comprises a fragrance. Fragrances include natural fragrances, such as extracts of blossoms (lily, lavender, rose, jasmine, neroli, ylang-ylang), stalks and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guajak wood, cedar wood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Fragrances also include synthetic fragrance compounds, such as synthetic esters, ethers, aldehydes, ketones, alcohols, and hydrocarbons. Fragrances also include essential oils and perfume oils, such as sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, lime tree blossom oil, juniper oil, vetiver oil, oliban oil, galbanum oil, labolanum oil, lavandin oil, Bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, a-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, BOISAMBRENE® Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allylamyl glycolate, cyclovertal, lavandin oil, muscatel sage oil, G39 damascone, Bourbon geranium oil, cyclohexyl salicylate, Vertofix® Coeur, ISO-E-SUPER®, FIXOLIDE® NP, evemyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romillate, irotyl and floramat. Fragrances may be included in a composition in an amount ranging from2025-12-29 about 0.1 wt% to about 10 wt% (calculated as the total weight of fragrances in the composition divided by the total weight of the composition).

[0110]

[0091] In embodiments, the composition comprises a hydroxyalkyl cellulose. Hydroxyalkyl celluloses can have multiple functions when included as an excipient. For example, a hydroxyalkyl cellulose may act as any of a penetration enhancer, carrier, emulsifier, stabilizer, viscosity modifying agent, adhesion modifying agent, antioxidant, adhesive polymer, solubilizing agent, binder, humectant, and / or gelling agent In embodiments, the composition comprises hydroxymethylcellulose. In embodiments, the composition comprises hydroxyethylcellulose. In embodiments, the composition comprises hydroxypropylcellulose.

[0111]

[0092] In embodiments, the composition comprises a solvent, and optionally a cosolvent. Any solvent(s) and cosolvent(s) may be collectively referred to as a “solvent system.” Without being bound by theory, the solvent system chosen can affect the stability, bioavailability, and overall efficacy of the composition. In embodiments, the solvent system is capable of dissolving or solubilizing the active ingredients and any included excipients at the desired concentration(s), and should be stable and compatible with components of the composition. In embodiments, wherein the solvent system comprises more than one solvent, the ratio of cosolvents is optimized, for example to increase the penetration or bioavailability of an active ingredient. Preferred solvent systems are also safe and non-toxic for human consumption. In embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized during selection of solvents included in a solvent system of the disclosure. Solvents that may be included in disclosed compositions may include, without limitations, water, ethanol, isopropanol, polyhydric alcohols (e.g., glycerin), 1 ,3-butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars which are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof. Solvents may be present, individually or in total (if more than one solvent is included), in the composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solvents in the composition divided by the total weight of the composition).

[0112]

[0093] In embodiments, the solvent system is an aqueous solvent system. In embodiments, the solvent system comprises water. In embodiments, the solvent system comprises ethanol. In embodiments, the solvent system comprises propylene glycol.

[0113]

[0094] In embodiments, the solvent system comprises an oil. Oils suitable for inclusion in compositions, such as topical compositions (e.g., comprising a topical delivery vehicle such as an emulsion, nanoemulsion, microemulsion, and the like) are known to those of skill in the art and include, for example, solid lipids (e.g., fatty alcohols, fatty acids, waxes, triglycerides, and hydrogenated oils) and liquid lipids (e.g., medium-chain triglycerides, long-chain triglycerides, vegetable oils, mineral oil, squalane, isopropyl myristate, and esters thereof).2025-12-29

[0095] In embodiments, the solvent system comprises a silicone. Silicones suitable for inclusion in compositions, such as topical compositions (e.g., comprising a topical delivery vehicle such as a volatile silicone-assisted delivery system) are known to those of skill in the art and include, for example, volatile silicones (e.g., cyclomethicone, cyclopentasiloxane, cyclohexasiloxane), non-volatile silicones (e.g., dimethicone, dimethiconol), silicone elastomers, and mixtures thereof.

[0114]

[0096] In embodiments, the composition comprises a viscosity modifying agent. In embodiments, the viscosity modifying agent is a thickener. Common thickeners include acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, hydroxyalkylcelluloses, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffins, and petroleum jelly. In embodiments, the viscosity modifying agent is a carbohydrate. Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Exemplary polysaccharides include cellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Exemplary glycerides includes hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixture thereof. In embodiments, the viscosity modifying agent is a polymer. The polymer may be a natural or synthetic polymer. Natural polymers include polysaccharides, nucleic acid, and proteins. Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohol, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidone, etc. Exemplary thickening agents include alginate derivatives, preneutralized carbomer 430, hydrophilic silicas, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, polyvinylpyrrolidone, and salts. Viscosity modifying agents may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of viscosity modifying agents in the composition divided by the total weight of the composition).

[0115]

[0097] For example, in some embodiments, a disclosed composition comprises hydroxypropylcellulose as a viscosity modifying agent. It will be appreciated, however, that hydroxypropylcellulose or another disclosed excipient may perform multiple functions when included in a composition, as noted elsewhere herein. In embodiments, a disclosed composition comprises between about 1% (w / v) and about 10% (w / v) of hydroxypropylcellulose. In embodiments, a disclosed composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about2025-12-29 9%, or about 10% (w / v) of hydroxypropylcellulose. In embodiments, a disclosed composition comprises about 2% (w / v) of hydroxypropylcellulose. In embodiments, the composition comprises less than about 1% (w / v) of hydroxypropylcellulose, such as about 0.75%, 0.5%, or 0.125% (w / v) of hydroxypropylcellulose. In embodiments, the composition comprises less than about 0.1% (w / v) of hydroxypropylcellulose, such as about 0.075%, 0.065%, 0.05%, or 0.0125% (w / v) of hydroxypropylcellulose.

[0116]

[0098] In embodiments, the composition comprises an adhesion modifying agent. In embodiments, the composition comprises an adhesive polymer. Adhesive polymers have physicochemical properties that allow prolonged binding to tissue surfaces. In embodiments, inclusion of an adhesive polymer in the composition increases the amount of time that an active agent is in contact with, and can diffuse across, a barrier (e.g., skin). Adhesive polymers include chitosan, gelatin guar gum, lectins, sodium alginate, soluble starch, tragacanth, xanthan gum deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropylmethyl- cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In embodiments, the adhesion modifying agent is a tackifier. Tackifiers include gums, resins (natural or modified), carbomers, or other natural or synthetic polymers. Adhesion modifying agents may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of adhesion modifying agents in the composition divided by the total weight of the composition).

[0117]

[0099] In embodiments, the composition comprises a preservative. Preservatives can be used to inhibit microbial growth or increase stability of the composition, thereby prolonging the shelf life of the composition. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates (e.g., sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin E, and tocopherol. Preservatives may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of preservatives in the composition divided by the total weight of the composition).

[0118]

[0100] In embodiments, the composition may include one or more vitamins. Any vitamin having a property, for example, to nourish the hair, nourish the skin, inhibit hair loss, and / or enhance hair growth may be used. Vitamins include essential B vitamins such as thiamine, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, biotin and pantothenic acid. In embodiments, the concentration of the vitamin in the composition is sufficient to provide a desired benefit (e.g., for treating hair loss, promoting hair growth, treating a dermatological condition) while remaining compatible with components of disclosed compositions. Such concentration can vary with the vitamin selected, the effect desired and the type and concentration of other components, and other like factors. Representatively, the composition may include between 1 mg and 200 mg of a vitamin(s), and in some embodiments between 50 mg and 250 mg of the vitamin(s).2025-12-29

[0101] In embodiments, the composition comprises a solubilizing agent. Solubilizing agents may form complexes with active ingredients which can have different physicochemical properties than the active ingredient alone. The properties of the complexes can increase the solubility of the active agent(s) in the composition. Solubilizing agents include water-soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids, cyclodextrins, and phospholipids. In embodiments the solubilizing agent is a water-soluble enhancing agent. Water-soluble enhancing agents include polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. In embodiments the solubilizing agent is a non-ionic surfactant. Non-ionic surfactants include Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750. In embodiments the solubilizing agent is an organic liquid. Organic liquids include beeswax, d-alpha-tocopherol, oleic acid, and medium-chain mono-or diglycerides. In embodiments the solubilizing agent is a cyclodextrin. In embodiments the solubilizing agent is a phospholipid. Phospholipids include hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, and L-alpha-dimyristoyl-phosphatidylglycerol. In embodiments, the solubilizing agent is lecithin. Solubilizing agents may be included in a composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solubilizing agents in the composition divided by the total weight of the composition).

[0119]

[0102] In embodiments, the composition comprises a colorant. Colorants include pigments such as, e.g., titanium dioxide, chromium oxide greens, ultramarine blues and pinks, and ferric oxides. Colorants may be present, individually or in total (if more than one colorant is included), in disclosed compositions in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants in the composition divided by the total weight of the composition).

[0120]

[0103] In embodiments, the composition comprises a binder. Binders include polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starches, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropyl- methylcellulose, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, and salts thereof (e.g., carmellose sodium). Binders also include natural gums such as karaya, xanthan, carrageenans, gellan gum, locust bean gum, gum arable and tragacanth, chitosan, colloidal magnesium aluminum silicate, and colloidal silica. Binders may be present, individually or in total (if more than one binder is included), in disclosed compositions in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of binders in the composition divided by the total weight of the composition).

[0121]

[0104] In embodiments, the composition comprises a humectant. Humectants, such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12), may be present, individually or in total (if more2025-12-29 than one humectant is included), in the composition in an amount of up to about 10 wt%, up to about 5 wt%, up to about 3 wt%, up to about 1 wt%, or up to about 0.1 wt% (calculated as the total weight of humectants in the composition divided by the total weight of the composition).

[0122]

[0105] In embodiments, the composition comprises a surfactant. Surfactants include anionic, nonionic, and amphoteric compounds. Anionic surfactants include, for example, higher alkyl sulfates such as potassium or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates, such as salts of monosulfated monoglycerides of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecyl benzene sulfonate, higher fatty sulfoacetates, and higher fatty acid esters of 1 ,2 dihydroxypropane sulfonate. Nonionic surfactants include condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms); condensation products comprising hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides and other fatty moieties, and with propylene oxide and polypropylene oxides, e.g., Pluronic materials such as Pluronic F127. In embodiments, the surfactant is an alkyl polyglycoside (APG) surfactant, such as APG C8-C10, APG C10-C16, decyl glucoside, coco-glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric, CIO-16 glycosides, carboxymethyl ethers, sodium salts), C12-C16 fatty alcohol glycoside, PLANTAREN® 2000 N UP / MB, PLANTAPON® LGC Sorb, PLANTAREN® 1200 N UP / MB, and PLANTAREN® 818 UP / MB. Surfactants may be present, individually or in total (if more than one surfactant is included) in the composition in an amount ranging from about 0.01 wt% to about 10 wt% (calculated as the total weight of surfactants in the composition divided by the total weight of the composition).

[0123]

[0106] In embodiments, the composition comprises a gelling agent. Gelling agents include pectins, starches, and gelatin forms derived from animals (e.g., pork gelatin) or from plants. In embodiments, a pectin is an amidated pectin, non-amidated pectin, high methoxyl pectin, low methoxyl pectin, or a combination thereof. In embodiments, a gelatin is Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin), or a bone gelatin (e.g., calf bone, pig bone). Gelling agents may be present, individually or in total (if more than one gelling agent is included) in the composition in an amount ranging from about 0.1 wt% to about 20 wt% (calculated as the total weight of gelling agents in the composition divided by the total weight of the composition).

[0124]

[0107] Depending on unit dosage volume and total volume, the composition may be provided as a final packaged product (e.g., in a bottle or any other suitable container). In embodiments, the bottle is a dropper bottle, a fine mist spray bottle, a pump bottle, a glass bottle, or a plastic bottle. In embodiments, the bottle is a dropper bottle. In embodiments, the bottle is a fine mist spray bottle. In embodiments, the bottle is a pump bottle.2025-12-29

[0108] In embodiments, a disclosed excipient may perform more than one function when included in a composition. For example, hydroxypropylcellulose may function to modify the viscosity of the composition, while also affecting the composition’s adhesive properties, or stabilizing an active agent in the composition, promoting emulsification, or another function as described herein.

[0125]

[0109] One of ordinary skill in the art appreciates that the selection of a suitable excipient for use in a disclosed composition may depend on a variety of factors. Relevant factors in the selection of the appropriate excipient(s), include, for example, compatibility of the excipient with the other components of the compositions (e.g., active agents, other excipients), desired penetration kinetics of the active agents, processing parameters, biocompatibility, and user preferences.

[0126]

[0110] In embodiments, the composition comprises liposomes. In embodiments, the composition comprises liposomes, wherein the active agent(s) (e.g., a substituted diazepine and any additional active agents) and any excipients present are encapsulated within the liposomes. Such compositions (which are referred to herein as “liposomal compositions” as shorthand) may improve distribution, efficacy, bioavailability, and / or activity by improving delivery and skin penetration.

[0127]

[0111] A “liposome" refers to a vesicle comprising one or more concentrically ordered lipid bilayers encapsulating an aqueous phase. The formation of such vesicles requires the presence of “vesicle-forming lipids,” which are amphipathic lipids capable of assuming or being incorporated into a bilayer structure. This includes such lipids that are capable of forming a bilayer by themselves or in combination with another lipid or lipids.

[0128]

[0112] Suitable vesicle-forming lipids that may be incorporated into liposomes in liposomal compositions of the disclosure include natural phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, monoolein), hydrogenated or synthetic phospholipids (e.g., dioleoylphosphatidylethanolamine, hydrogenated phosphatidylcholine, dipalmitoylphosphatidyl- choline, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine), sphingolipids (e.g., sphingomyelin, ceramides), glycolipids, negatively charged lipids (e.g., dicetyl phosphate, phosphatidylglycerol, phosphatidylinositol), positively charged lipids (e.g., stearylamine, dimethyldioctadecylammonium bromide).

[0129]

[0113] In embodiments, a liposome comprises a polymer. Suitable polymers that may be incorporated into liposomes include natural and synthetic polymers, as well as polymer-conjugated lipids. Natural polymers include polysaccharides (e.g., chitosan, hyaluronic acid, alginate) and proteins (e.g., gelatin, albumin). Synthetic polymers include polyethylene glycol (PEG), polyvinyl alcohol (PVA), and poloxamers (e.g., PLURONIC® F127). Polymer- conjugated lipids include polyethylene glycol-lipid conjugates (e.g., distearoylphosphatidyl- ethanolamine-PEG, dipalmitoylphosphatidylethanolamine-PEG) and functionalized polymers (e.g., PEG-amine, PEG-maleimide).2025-12-29

[0114] Liposomes may also comprise any other excipient described herein, such as penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, gelling agents,

[0130]

[0115] Liposomes can be prepared according to conventional techniques known to those of skill in the art. These techniques include the ether injection method (Deamer et al. Acad. Sci. 1978;308:250), the surfactant method (Brunner et al. Biochim. Biophys. Acta. 1976;455:322), the freeze-thaw method (Pick et al. Arch. Biochim. Biophys. 1981 ;212:186), the reverse-phase evaporation method (Szoka et al. Biochim. Biophys. Acta 1980; 601:559-571), the ultrasonic treatment method (Huang et al. Biochemistry.

[0131] 1969;8:344), the ethanol injection method (Kremer et al. Biochemistry. 1977; 16:3932), the extrusion method (Hope et al., Biochim. Biophys. Acta. 1985;812:55-65), and the French press method (Barenholz et al. FEBS Lett. 1979;99:210). These processes can be used in combination or modified.

[0132] c. Topical Delivery Vehicles

[0133]

[0116] In embodiments, a composition comprises olanzapine and a topical delivery vehicle.

[0134]

[0117] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the vehicle is a hydroalcoholic solution or gel. In embodiments, the hydroalcoholic solution or gel comprises water; one or more alcohols; and optionally, one or more pharmaceutically acceptable excipients. In embodiments, the hydroalcoholic solution or gel comprises: water; ethanol; propylene glycol and / or butylene glycol; optionally, dimethyl isosorbide and / or diethyl phthalate; and optionally, a viscosity modifying agent (e.g., a thickener, such as a carbomer, a hydroxyalkylcelluose, or a combination thereof). An exemplary such vehicle comprises between about 10% and about 80% ethanol; between about 0% and about 60% propylene glycol and / or butylene glycol; water (qs); between about 0% and about 5% of a viscosity modifying agent (e.g., thickener); and between about 0% and about 40% of dimethyl isosorbide and / or diethyl phthalate.

[0135]

[0118] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is an aqueous gel. In embodiments, the aqueous gel is alcohol-free. In embodiments, the aqueous gel comprises water; one or more humectants; and one or more gelling agents. In embodiments, the aqueous gel further comprises a buffer system, wherein the pH is between about 4.5 and about 6.8. In embodiments, the aqueous gel further comprises an optional solubilization aid, such as hydroxypropyl-0-cyclodextrin and / or a cosolvent. An exemplary such vehicle comprises between about 0% and about 40% of one or more humectants; between about 0.1% and about 5% of one or more gelling agents; between about 0% and about 40% of hydroxypropyl-P-cyclodextrin and / or a cosolvent; and water (qs).

[0136]

[0119] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is an emulsion. In embodiments, the emulsion is an oil-in-water (O / W)2025-12-29 emulsion or a water-in-oil (W / O) emulsion. In embodiments, the emulsion comprises an oil phase; an aqueous phase; and an emulsifier system. In embodiments, the emulsion further comprises a viscosity modifying agent. An exemplary such vehicle comprises between about 5% and about 60% of an oil phase; between about 0.1% and about 10% of an emulsifier system; between about 0% and about 5% of a viscosity modifying agent; and an aqueous phase (qs).

[0137]

[0120] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is a microemulsion or a nanoemulsion. In embodiments, the microemulsion or nanoemulsion comprises oil; water; and a surfactant and / or co-surfactant system. In embodiments, the microemulsion or nanoemulsion further comprises an optional cosolvent, such as dimethyl isosorbide, diethyl phthalate, propylene glycol, or a combination thereof. An exemplary such vehicle comprises between about 1% and about 30% oil; between about 5% and about 60% of a surfactant and / or co-surfactant system; between about 0% and about 40% of a cosolvent; and water (qs).

[0138]

[0121] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle comprises lipid nanoparticles. In embodiments, the lipid nanoparticles comprise solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs). In embodiments, the lipid nanoparticles comprise one or more solid lipids; optionally one or more liquid lipids (for NLCs); and one or more surfactants, dispersed in an aqueous phase. In embodiments, the lipid nanoparticles further comprise an antioxidant. An exemplary such vehicle comprises between about 0.1% and about 20% of a lipid phase; between about 0.1% and about 10% of one or more surfactants; and water (qs), wherein the lipid nanoparticles have a particle size between about 50 nm and about 500 nm.

[0139]

[0122] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is an ethosome or a transethosome. In embodiments, the ethosome or transethosome comprises lipid vesicles containing ethanol. In embodiments, the ethosome or transethosome comprises between about 20% and about 45% ethanol. In embodiments, the ethosome or transethosome further comprises one or more phospholipids and water. In embodiments, the ethosome or transethosome is formulated to facilitate deformation of lipid bilayers and penetration into follicular ducts.

[0140]

[0123] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle comprises a commercially available hydrophilic base. In embodiments, the commercially available hydrophilic base is alcohol-free and propylene glycol-free. In embodiments, the commercially available hydrophilic base comprises water, mineral salts, and one or more phytocomplexes. In embodiments, the commercially available hydrophilic base is TrichoSol™.

[0141]

[0124] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is a foam or a quick-break scalp solution. In embodiments, the foam or quick-break scalp solution is formulated to improve coverage through hair upon topical administration. In2025-12-29 embodiments, the foam or quick-break scalp solution comprises one or more propellants or foaming agents and one or more volatile components formulated to evaporate upon application.

[0142]

[0125] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is an anhydrous gel or an organogel. In embodiments, the anhydrous gel or organogel comprises one or more hydrophobic liquids, such as squalane or medium-chain triglycerides, structured with one or more gelling agents. In embodiments, the gelling agent comprises a fumed silica or a derivative thereof. In embodiments, the anhydrous gel or organogel is formulated to reduce run-off and increase contact time following topical administration.

[0143]

[0126] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is a film-forming composition. In embodiments, the film-forming composition is formulated to form a thin film on the scalp following application. In embodiments, the film-forming composition comprises one or more film-forming polymers and is formulated to extend residence time of olanzapine at the site of application.

[0144]

[0127] In embodiments, a composition comprises olanzapine and a topical delivery vehicle, wherein the topical delivery vehicle is a depot scalp vehicle. In embodiments, the depot scalp vehicle is formulated to increase residence time within follicular infundibula following topical administration. In embodiments, the depot scalp vehicle is formulated to prolong contact time of olanzapine at the site of application.

[0145]

[0128] In embodiments, the topical delivery vehicle is an anhydrous polar cosolvent liquid, an oil-dominant anhydrous liquid, a non-aqueous soft nanosuspension, an aqueous cyclodextrin inclusion system, a liposomal or lipid-vesicle dispersion, a hydroalcoholic solution or gel, an aqueous gel, an emulsion, a microemulsion or nanoemulsion, solid lipid nanoparticles or nanostructured lipid carriers, ethosomes or transethosomes, niosomes, a commercial or proprietary topical base, a foam or foamable scalp vehicle, an anhydrous organogel or structured oil, a micellar solution, deformable liposomes including transfersomes or invasomes, liquid-crystalline lipid nanoparticles, a wash-off scalp vehicle, biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, an aqueous drug nanocrystal or nanosuspension, an ointment or pomade scalp vehicle, a solid stick or wax-stick applicator, a patch, laminate, or strip sustained-release scalp system, a microneedle-enabled scalp delivery system, microencapsulation systems including microsponges or porous beads, polymer-coated or layer-by-layer vesicles, an ionic-liquid or deep-eutectic-solvent carrier system, silicone-based topical compositions, film-forming topical compositions, depot or sustained-release topical vehicles, foam or mousse formulations, or a combination or hybrid vehicle systems.

[0146]

[0129] Exemplary Vehicle 1 : Anhydrous polar cosolvent liquid

[0147]

[0130] In one example, a topical delivery vehicle is an anhydrous polar cosolvent liquid comprising a cyclic carbonate solvent and a polar solubilizing agent In embodiments, the polar cosolvent2025-12-29 fraction is at least 50% by weight of the composition. In embodiments, the vehicle comprises between about 10% and about 90% of the cyclic carbonate solvent (e.g., propylene carbonate, butylene carbonate, glycerol carbonate, combinations thereof). In embodiments, the vehicle comprises a polar penetration enhancer and / or solubilizing agent (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether (Transcutol-type glycol ether), solketal, triethyl citrate, triacetin, propylene glycol, dipropylene glycol, butylene glycol, combinations thereof), in an amount of between about 10% and about 90% by weight of the composition.

[0148]

[0131] In embodiments, the cyclic carbonate solvent and the polar solubilizing agent are present at a weight ratio of between about 90:10 and about 10:90, including about 50:50, provided that the total polar cosolvent fraction remains at least 50% by weight of the composition. In embodiments, the vehicle further comprises one or more additional anhydrous cosolvents (e.g., ethanol, isopropanol, diethyl phthalate, dermatologically acceptable glycol ethers, combinations thereof), in an amount of between about 0% and about 40%, with the cyclic carbonate solvent and / or polar solubilizing agent reduced q.s.

[0149]

[0132] In embodiments, the vehicle further comprises a lipophilic antioxidant (e.g., a tocopherol or derivatives thereof), in an amount of between about 0% and about 1% by weight of the composition. In embodiments, the vehicle further comprises an oil phase (e.g., squalane, saturated hydrocarbons, esters, combinations thereof), in an amount of between about 0% and about 49%, provided that the polar cosolvent fraction remains at least 50% by weight of the composition. In embodiments, the vehicle further comprises a structurant suitable for forming an anhydrous gel or organogel (e.g., fumed silica, waxes, combinations thereof), in an amount of between about 0% and about 15%.

[0150]

[0133] Exemplary Vehicle 2: Oil-dominant anhydrous liquid

[0151]

[0134] In another example, a topical delivery vehicle is an oil-dominant anhydrous liquid comprising an oil phase and a polar solubilizing system. In embodiments, the oil phase is at least 40% by weight of the composition. In embodiments, the vehicle comprises an oil phase (e.g., squalane, isopropyl myristate, medium-chain triglycerides, hydrogenated polyisobutene, mineral oil, saturated hydrocarbons, esters, combinations thereof) in an amount of between about 20% and about 90% by weight of the composition.

[0152]

[0135] In embodiments, the vehicle further comprises a cyclic carbonate solvent (e.g., propylene carbonate, butylene carbonate, glycerol carbonate, combinations thereof) in an amount of between about 0% and about 60% by weight of the composition, and a polar penetration enhancer and / or solubilizing agent (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether (Transcutol-type glycol ether), solketal, triethyl citrate, triacetin, propylene glycol, dipropylene glycol, butylene glycol, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, where both a cyclic carbonate solvent and a polar solubilizing agent are present, they are present at a weight ratio of between about 90:10 and about 10:90, including about 50:50.2025-12-29

[0136] In embodiments, the vehicle further comprises one or more additional anhydrous cosolvents (e.g., ethanol, isopropanol, diethyl phthalate, dermatologically acceptable glycol ethers, combinations thereof) in an amount of between about 0% and about 40%, with the oil phase and / or polar solubilizing system reduced q.s. In embodiments, the vehicle further comprises a lipophilic antioxidant (e.g., a tocopherol or derivatives thereof) in an amount of between about 0% and about 1% by weight of the composition.

[0153]

[0137] In embodiments, the vehicle further comprises a structurant suitable for forming an anhydrous gel or organogel (e.g., fumed silica, waxes, combinations thereof) in an amount of between about 0% and about 15% by weight of the composition.

[0154]

[0138] Exemplary Vehicle 3: Non-aqueous “soft” nanosuspension

[0155]

[0139] In another example, a topical delivery vehicle is a non-aqueous “soft” nanosuspension comprising an oil carrier and a non-ionic surfactant system, wherein the active agent is present as suspended solid particles. In embodiments, the vehicle comprises an oil carrier (e.g., medium-chain triglycerides, including caprylic / capric triglycerides, fractionated coconut oil-derived triglycerides, combinations thereof) in an amount of between about 70% and about 99% by weight of the composition.

[0156]

[0140] In embodiments, the vehicle further comprises a sorbitan fatty acid ester surfactant (e.g., sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, combinations thereof) in an amount of between about 0.1% and about 30% by weight of the composition. In embodiments, the vehicle further comprises one or more additional non-aqueous carrier oils (e.g., squalane, isopropyl myristate, C12-15 alkyl benzoate, combinations thereof) in an amount of between about 0% and about 40%, with the oil carrier reduced q.s.

[0157]

[0141] In embodiments, the composition is substantially water-free, comprising no more than about 5% water, including no more than about 2%, about 1%, or about 0.5% water. In embodiments, the suspended solid particles have a particle size distribution characterized by a D90 of no more than about 2000 nm, including no more than about 1000 nm or no more than about 500 nm, and optionally a D50 of no more than about 500 nm.

[0158]

[0142] In embodiments, the vehicle further comprises a lipophilic antioxidant (e.g., a tocopherol or derivatives thereof) in an amount of between about 0% and about 1% by weight of the composition. In embodiments, the vehicle further comprises a co-surfactant and / or viscosity modifier (e.g., lecithin, phospholipids, polyglyceryl esters, glyceryl monostearate, fatty alcohols, fumed silica, combinations thereof) in an amount of between about 0% and about 10%.

[0159]

[0143] Exemplary Vehicle 4: Aqueous cyclodextrin inclusion system

[0160]

[0144] In another example, a topical delivery vehicle is an aqueous cyclodextrin inclusion system configured to solubilize the active agent. In embodiments, the vehicle comprises a cyclodextrin solubilizing agent (e.g., hydroxypropyl-p-cyclodextrin, sulfobutyl ether-p-cyclodextrin, methyl-p-cyclodextrin,2025-12-29 P-cyclodextrin, y-cyclodextrin, combinations thereof) in an amount of between about 1% and about 30% by weight of the composition.

[0161]

[0145] In embodiments, the vehicle further comprises an aqueous buffer system (e.g., acetate, citrate, phosphate, lactate, succinate, combinations thereof), with water q.s. to 100%, wherein the pH is maintained between about 4.0 and about 7.5. In embodiments, the vehicle further comprises a chelating agent (e.g., EDTA or derivatives thereof) in an amount of between about 0% and about 0.2% by weight of the composition.

[0162]

[0146] In embodiments, the vehicle further comprises a water-phase antioxidant (e.g., sodium ascorbate, ascorbic acid, erythorbate, combinations thereof) in an amount of between about 0% and about 2% by weight of the composition. In embodiments, the vehicle further comprises one or more cosolvents (e.g., propylene glycol, butylene glycol, dimethyl isosorbide, diethyl phthalate, combinations thereof) in an amount of between about 0% and about 40%, with water reduced q.s.

[0163]

[0147] Exemplary Vehicle 5: Liposomal or lipid-vesicle dispersion

[0164]

[0148] In another example, a topical delivery vehicle is an aqueous liposomal or lipid-vesicle dispersion comprising the active agent encapsulated in and / or associated with lipid vesicles. In embodiments, the vehicle comprises a lipid-forming component (e.g., phosphatidylcholines, including hydrogenated and / or saturated phosphatidylcholines such as HSPC, DPPC, DSPC, combinations thereof) in an amount of between about 0.05% and about 20% by weight of the composition.

[0165]

[0149] In embodiments, the vehicle further comprises a sterol component (e.g., cholesterol, phytosterols, combinations thereof) in an amount of between about 0% and about 50 mol% of the total lipid content. In embodiments, the vehicle further comprises a charged lipid (e.g., anionic phospholipids, cationic lipids, combinations thereof) in an amount of between about 0% and about 30 mol% of the total lipid content.

[0166]

[0150] In embodiments, the vehicle comprises an aqueous phase with water q.s. to 100%, optionally buffered (e.g., acetate, citrate, phosphate, lactate, succinate, combinations thereof) to a pH of between about 4.0 and about 7.5. In embodiments, the vehicle further comprises a chelating agent (e.g., EDTA or derivatives thereof) in an amount of between about 0% and about 0.2% by weight of the composition, and / or an antioxidant (e.g., sodium ascorbate, tocopherols, derivatives thereof) in an amount of between about 0% and about 2%.

[0167]

[0151] In embodiments, the lipid vesicles have a mean diameter of between about 30 nm and about 1000 nm, optionally between about 50 nm and about 500 nm, and optionally exhibit a polydispersity index of no more than about 0.4. In embodiments, the dispersion is prepared by film hydration, ethanol injection, extrusion, microfluidization, sonication, magnetic stirring, or combinations thereof.

[0168]

[0152] Exemplary Vehicle 6: Hydroalcoholic solution or gel2025-12-29

[0153] In another example, a topical delivery vehicle is a hydroalcoholic solution or gel comprising an alcohol, a polyol, and water. In embodiments, the vehicle comprises an alcohol (e.g., ethanol, isopropanol, n-propanol, t-butanol, combinations thereof) in an amount of between about 10% and about 80% by weight of the composition.

[0169]

[0154] In embodiments, the vehicle further comprises a polyol or humectant (e.g., propylene glycol, butylene glycol, dipropylene glycol, glycerin, pentylene glycol, combinations thereof) in an amount of between about 0% and about 60% by weight of the composition, with water q.s. to 100%. In embodiments, the vehicle further comprises a polymer thickener or gelling agent (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, combinations thereof) in an amount of between about 0% and about 5%.

[0170]

[0155] In embodiments, the vehicle further comprises one or more additional cosolvents and / or solubilizing agents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, diethyl phthalate, triacetin, ethyl lactate, combinations thereof) in an amount of between about 0% and about 40%, with the alcohol, polyol, and / or water reduced q.s. In embodiments, the vehicle is a solution when the polymer thickener is present at no more than about 1%, and a gel when the polymer thickener is present at no less than about 0.1%.

[0171]

[0156] Exemplary Vehicle 7: Aqueous gel

[0172]

[0157] In another example, a topical delivery vehicle is an aqueous gel comprising water, a humectant, and a polymeric gellant. In embodiments, the vehicle comprises water q.s. to 100% by weight of the composition, and a humectant (e.g., glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, sorbitol, combinations thereof) in an amount of between about 0% and about 40%.

[0173]

[0158] In embodiments, the vehicle further comprises a gellant or rheology modifier (e.g., carbomers, poloxamers, cellulose derivatives, xanthan gum, gellan gum, polyacrylamides, combinations thereof) in an amount of between about 0.05% and about 10%. In embodiments, the vehicle further comprises a buffer or pH adjuster (e.g., acetate, citrate, phosphate, lactate, succinate, combinations thereof) to maintain a pH of between about 4.0 and about 7.5.

[0174]

[0159] In embodiments, the vehicle further comprises a solubilizer system comprising one or more cosolvents and / or cyclodextrins (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, ethanol, triacetin, ethyl lactate, hydroxypropyl-0-cyclodextrin, combinations thereof) in an amount of between about 0% and about 40%, with water and / or humectant reduced q.s. In embodiments, the vehicle further comprises a chelating agent and / or antioxidant in amounts consistent with aqueous formulations.

[0175]

[0160] Exemplary Vehicle 8: Emulsion

[0176]

[0161] In another example, a topical delivery vehicle is an emulsion configured as an oil-in-water or water-in-oil system. In embodiments, the vehicle comprises an oil phase (e.g., squalane, isopropyl myristate, medium-chain triglycerides, hydrogenated polyisobutene, mineral oil, C12-15 alkyl benzoate,2025-12-29 dimethicone, combinations thereof) in an amount of between about 1% and about 80% by weight of the composition.

[0177]

[0162] In embodiments, the vehicle further comprises an aqueous phase with water q.s. to 100%, optionally comprising one or more humectants. In embodiments, the vehicle further comprises an emulsifier system (e.g., nonionic surfactants, sorbitan esters, polyglyceryl esters, lecithin, phospholipids, PEG-free emulsifiers, combinations thereof) in an amount of between about 0.05% and about 15%.

[0178]

[0163] In embodiments, the vehicle further comprises a co-emulsifier, viscosity modifier, structurant, antioxidant, and / or chelating agent, each present in amounts suitable for topical emulsions.

[0179]

[0164] Exemplary Vehicle 9: Microemulsion or nanoemulsion

[0180]

[0165] In another example, a topical delivery vehicle is a microemulsion or nanoemulsion comprising an oil phase, an aqueous phase, and a surfactant system. In embodiments, the vehicle comprises an oil phase (e.g., squalane, isopropyl myristate, medium-chain triglycerides, C12-15 alkyl benzoate, combinations thereof) in an amount of between about 0.1% and about 50% by weight of the composition.

[0181]

[0166] In embodiments, the vehicle further comprises a surfactant and / or co-surfactant system (e.g., polysorbates, sorbitan esters, polyglyceryl esters, lecithin, PEG-free surfactants, combinations thereof) in an amount of between about 1% and about 80%. In embodiments, the vehicle further comprises one or more cosolvents or solubilizing agents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, diethyl phthalate, propylene glycol, butylene glycol, ethanol, combinations thereof) in an amount of between about 0% and about 50%.

[0182]

[0167] In embodiments, the dispersed oil droplets have a mean diameter of between about 10 nm and about 1000 nm, including between about 20 nm and about 300 nm.

[0183]

[0168] Exemplary Vehicle 10: Solid lipid nanoparticles or nanostructured lipid carriers

[0184]

[0169] In another example, a topical delivery vehicle comprises solid lipid nanoparticles or nanostructured lipid carriers dispersed in an aqueous phase. In embodiments, the vehicle comprises a lipid phase (e.g., glyceryl behenate, glyceryl palmitostearate, cetyl palmitate, stearic acid, hydrogenated vegetable oils, combinations thereof, and optionally liquid lipids such as medium-chain triglycerides or squalane) in an amount of between about 0.05% and about 40% by weight of the composition.

[0185]

[0170] In embodiments, the vehicle further comprises a surfactant or stabilizer system (e.g., poloxamers, lecithin, phospholipids, sorbitan esters, polyglyceryl esters, combinations thereof) in an amount of between about 0.01% and about 20%, and an aqueous phase with water q.s. to 100%.

[0186]

[0171] In embodiments, the nanoparticles have a mean diameter of between about 20 nm and about 2000 nm. In embodiments, the vehicle further comprises a lipid-phase antioxidant and / or aqueous-phase chelating agent in amounts suitable for nanoparticle formulations.

[0187]

[0172] Exemplary Vehicle 11 : Ethosomes or transethosomes2025-12-29

[0173] In another example, a topical delivery vehicle is an ethosomal or transethosomal vesicular dispersion comprising an alcohol-rich aqueous phase and lipid vesicles. In embodiments, the vehicle comprises a phospholipid (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, saturated phosphatidylcholine, combinations thereof) in an amount of between about 0.1% and about 10% by weight of the composition.

[0188]

[0174] In embodiments, the vehicle further comprises an alcohol (e.g., ethanol, isopropanol, combinations thereof) in an amount of between about 10% and about 50% by weight of the composition. In embodiments, the vehicle further comprises water q.s. to 100%, optionally comprising one or more humectants (e.g., glycerin, propylene glycol, butylene glycol, combinations thereof).

[0189]

[0175] In embodiments, the vehicle further comprises a penetration enhancer and / or edge activator (e.g., diethylene glycol monoethyl ether, propylene glycol, surfactants, combinations thereof) in an amount of between about 0% and about 20%. In embodiments, the vesicles have a mean diameter of between about 30 nm and about 500 nm.

[0190]

[0176] In embodiments, the vehicle further comprises a chelating agent and / or antioxidant in amounts suitable for aqueous vesicular systems.

[0191]

[0177] Exemplary Vehicle 12: Silicone-based topical composition

[0192]

[0178] In another example, a topical delivery vehicle is a silicone-based composition comprising one or more volatile and / or non-volatile silicones. In embodiments, the vehicle comprises a silicone component (e.g., dimethicone, cyclomethicone, cyclopentasiloxane, phenyltrimethicone, combinations thereof) in an amount of between about 10% and about 95% by weight of the composition.

[0193]

[0179] In embodiments, the vehicle further comprises one or more non-silicone cosolvents or solubilizing agents (e.g., dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether, combinations thereof) in an amount of between about 0% and about 40%. In embodiments, the vehicle further comprises an oil phase (e.g., squalane, esters, hydrocarbons, combinations thereof) in an amount of between about 0% and about 40%.

[0194]

[0180] In embodiments, the vehicle further comprises a silicone elastomer, structurant, or rheology modifier (e.g., crosslinked siloxanes, silica, waxes, combinations thereof) in an amount effective to adjust viscosity or spreadability. In embodiments, the composition is anhydrous.

[0195]

[0181] Exemplary Vehicle 13: Foam or mousse formulation

[0196]

[0182] In another example, a topical delivery vehicle is a foam or foamable scalp vehicle configured for application to hair-bearing skin. In embodiments, the vehicle is a pump-foam formulation or a pressurized foam formulation that forms a foam upon dispensing. In embodiments, the vehicle comprises a liquid carrier system (e.g., aqueous, hydroalcoholic, or mixed solvent systems) suitable for topical scalp application.2025-12-29

[0183] In embodiments, the vehicle further comprises one or more foaming agents and / or surfactants (e.g., nonionic surfactants, amphoteric surfactants, zwitterionic surfactants, combinations thereof) in amounts effective to generate and stabilize a foam structure. In embodiments, the vehicle further comprises one or more solubilizing agents, penetration enhancers, humectants, viscosity modifiers, preservatives, antioxidants, or combinations thereof, in amounts suitable for scalp formulations.

[0197]

[0184] In embodiments, the foamable vehicle is dispensed using a mechanical pump foamer without a propellant. In embodiments, the foamable vehicle is dispensed using a pressurized container comprising one or more propellants (e.g., hydrocarbons, compressed gases, combinations thereof). In embodiments, the resulting foam is a fast-breaking foam or a stable foam that spreads easily across the scalp and hair follicles and leaves minimal residue after application.

[0198]

[0185] Exemplary Vehicle 14: Film-forming topical composition

[0199]

[0186] In another example, a topical delivery vehicle is a film-forming composition configured to form a continuous or semi-continuous film upon application to skin or scalp. In embodiments, the vehicle comprises a film-forming polymer (e.g., polyvinylpyrrolidone, polyvinyl alcohol, acrylates, methacrylates, cellulose derivatives, combinations thereof) in an amount of between about 0.1% and about 20% by weight of the composition.

[0200]

[0187] In embodiments, the vehicle further comprises a solvent system (e.g., water, alcohols, polyols, volatile silicones, combinations thereof) in an amount sufficient to dissolve or disperse the film-forming polymer. In embodiments, the vehicle further comprises a plasticizer (e.g., triethyl citrate, triacetin, glycerin, combinations thereof) in an amount effective to improve film flexibility.

[0201]

[0188] In embodiments, the formed film provides sustained or localized delivery of the active agent to the skin or scalp.

[0202]

[0189] Exemplary Vehicle 15: Depot or sustained-release topical vehicle

[0203]

[0190] In another example, a topical delivery vehicle is a depot or sustained-release formulation configured to retain the active agent at the site of application. In embodiments, the vehicle comprises a viscous or semi-solid matrix (e.g., waxes, fatty alcohols, high-molecular-weight polymers, combinations thereof).

[0204]

[0191] In embodiments, the vehicle further comprises a carrier phase (e.g., oils, silicones, polyols, combinations thereof) in which the active agent is dispersed or dissolved. In embodiments, the vehicle further comprises release-modifying agents (e.g., polymers, lipid matrices, combinations thereof) that slow diffusion of the active agent.

[0205]

[0192] In embodiments, the depot vehicle provides prolonged residence time on the skin or scalp relative to solution or lotion formulations.

[0206]

[0193] Exemplary Vehicle 16: Anhydrous organogel or structured oil2025-12-29

[0194] In another example, a topical delivery vehicle is an anhydrous organogel or structured oil comprising a hydrophobic liquid phase structured into a semi-solid or gel-like form. In embodiments, the vehicle comprises an oil phase (e.g., squalane, medium-chain triglycerides, isopropyl myristate, hydrogenated polyisobutene, mineral oil, silicone oils, combinations thereof) in an amount of between about 40% and about 99% by weight of the composition.

[0207]

[0195] In embodiments, the vehicle further comprises a structurant or gelling agent suitable for forming an anhydrous organogel (e.g., fumed silica, organoclays, fatty alcohols, waxes, hydrogenated oils, polymeric organogelators, combinations thereof) in an amount effective to impart a gel or structured semi-solid consistency. In embodiments, the vehicle is substantially water-free.

[0208]

[0196] In embodiments, the vehicle further comprises one or more solubilizing agents, penetration enhancers, or cosolvents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, propylene carbonate, combinations thereof) in amounts effective to solubilize or disperse the active agent within the structured oil matrix. In embodiments, the vehicle further comprises a lipophilic antioxidant (e.g., a tocopherol or derivatives thereof) in an amount suitable for anhydrous formulations.

[0209]

[0197] In embodiments, the anhydrous organogel provides prolonged residence time on the scalp or skin and reduced run-off relative to liquid anhydrous formulations.

[0210]

[0198] Exemplary Vehicle 17: Micellar solution

[0211]

[0199] In another example, a topical delivery vehicle is a micellar solution configured as an oil-free or substantially oil-free clear scalp tonic. In embodiments, the vehicle comprises water q.s. to 100% by weight of the composition and a micelle-forming surfactant system.

[0212]

[0200] In embodiments, the micellar system comprises one or more surfactants (e.g., nonionic surfactants, amphoteric surfactants, zwitterionic surfactants, combinations thereof) present at a concentration sufficient to form micelles that solubilize the active agent. In embodiments, the vehicle comprises no more than about 5% oil by weight of the composition, including no more than about 2%, about 1%, or about 0.5% oil, and in embodiments is substantially free of added oils.

[0213]

[0201] In embodiments, the vehicle further comprises one or more solubilizing agents or cosolvents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, propylene glycol, butylene glycol, combinations thereof) in amounts effective to enhance micellar solubilization of the active agent. In embodiments, the vehicle further comprises a buffer system to maintain a pH suitable for scalp application.

[0214]

[0202] In embodiments, the micellar solution is optically clear or translucent and is applied as a leave-on scalp tonic, spray, or dropper-applied liquid that dries rapidly and leaves minimal residue.

[0215]

[0203] Exemplary Vehicle 18: Deformable liposomes, transfersomes, or invasomes

[0216]

[0204] In another example, a topical delivery vehicle is a deformable phospholipid vesicle system comprising liposomes, transfersomes, invasomes, or related highly deformable lipid vesicles. In embodiments, the vehicle comprises a phospholipid component (e.g., phosphatidylcholine, hydrogenated2025-12-29 phosphatidylcholine, saturated phosphatidylcholine, combinations thereof) in an amount effective to form lipid vesicles.

[0217]

[0205] In embodiments, the vehicle further comprises one or more edge activators and / or membrane-softening agents (e.g., surfactants, bile salts, fatty acids, nonionic surfactants, combinations thereof) in amounts effective to impart enhanced vesicle deformability relative to conventional liposomes. In embodiments, the vesicles are capable of deforming and penetrating into skin microstructures under topical application conditions.

[0218]

[0206] In embodiments, the vehicle further comprises an aqueous phase with water q.s. to 100%, and optionally one or more alcohols or cosolvents (e.g., ethanol, isopropanol, propylene glycol, diethylene glycol monoethyl ether, combinations thereof) in amounts effective to enhance penetration and / or vesicle flexibility. In embodiments, the composition is an invasome formulation comprising both an alcohol and an edge activator.

[0219]

[0207] In embodiments, the deformable vesicles have a mean diameter of between about 50 nm and about 500 nm. In embodiments, the vehicle further comprises a chelating agent and / or antioxidant in amounts suitable for aqueous vesicular systems.

[0220]

[0208] Exemplary Vehicle 19: Liquid-crystalline lipid nanoparticles

[0221]

[0209] In another example, a topical delivery vehicle comprises liquid-crystalline lipid nanoparticles configured as cubosomes, hexosomes, or related non-lamellar lipid nanostructures. In embodiments, the vehicle comprises one or more lipid-forming components capable of forming liquid-crystalline phases (e.g., monoolein, phytantriol, glycerol monooleate, amphiphilic lipids, combinations thereof) in an amount effective to form a dispersed liquid-crystalline nanoparticle phase.

[0222]

[0210] In embodiments, the vehicle further comprises an aqueous phase with water q.s. to 100% by weight of the composition and one or more stabilizers (e.g., polymeric stabilizers, surfactants, combinations thereof) in amounts effective to maintain dispersion of the liquid-crystalline nanoparticles. In embodiments, the stabilizer comprises a nonionic polymeric stabilizer.

[0223]

[0211] In embodiments, the liquid-crystalline lipid nanoparticles have internal cubic or hexagonal nanostructures that provide high internal surface area and controlled release of the active agent. In embodiments, the nanoparticles have a mean diameter of between about 50 nm and about 500 nm.

[0224]

[0212] In embodiments, the vehicle further comprises one or more cosolvents, penetration enhancers, chelating agents, antioxidants, or combinations thereof, in amounts suitable for aqueous nanoparticle dispersions. In embodiments, the vehicle provides sustained or enhanced delivery of the active agent to the scalp or skin relative to simple solution formulations.

[0225]

[0213] Exemplary Vehicle 20: Wash-off scalp vehicle2025-12-29

[0214] In another example, a topical delivery vehicle is a wash-off scalp vehicle configured as a shampoo, conditioner, cleansing composition, or rinse-off treatment. In embodiments, the vehicle comprises an aqueous base with water q.s. to 100% by weight of the composition.

[0226]

[0215] In embodiments, the vehicle further comprises one or more surfactant systems suitable for scalp cleansing (e.g., anionic surfactants, amphoteric surfactants, nonionic surfactants, zwitterionic surfactants, combinations thereof) in amounts effective to provide cleansing, foaming, or conditioning performance. In embodiments, the surfactant system is selected to provide mild cleansing suitable for repeated scalp application.

[0227]

[0216] In embodiments, the vehicle further comprises one or more conditioning agents, humectants, thickeners, opacifiers, pearlizing agents, preservatives, antioxidants, chelating agents, fragrances, or combinations thereof, in amounts suitable for wash-off scalp formulations. In embodiments, the active agent is configured to deposit on the scalp and / or hair follicles during washing and rinsing.

[0228]

[0217] In embodiments, the wash-off scalp vehicle is applied to wet hair and scalp, massaged, and rinsed after a contact time sufficient to deliver the active agent.

[0229]

[0218] Exemplary Vehicle 21 : Biodegradable polymeric nanoparticles

[0230]

[0219] In another example, a topical delivery vehicle comprises biodegradable polymeric nanoparticles dispersed in an aqueous or mixed solvent medium. In embodiments, the vehicle comprises polymeric nanoparticles formed from one or more biodegradable polymers (e.g., poly(lactic-co-glycolic acid), poly(lactic acid), poly(caprolactone), poly(lactic-co-caprolactone), combinations thereof).

[0231]

[0220] In embodiments, the polymeric nanoparticles encapsulate or associate with the active agent within a polymeric matrix or core. In embodiments, the nanoparticles are dispersed in an aqueous phase with water q.s. to 100%, optionally comprising one or more stabilizers or surfactants (e.g., polymeric stabilizers, nonionic surfactants, combinations thereof) in amounts effective to maintain colloidal stability.

[0232]

[0221] In embodiments, the polymeric nanoparticles have a mean diameter of between about 50 nm and about 1000 nm. In embodiments, the nanoparticles are configured to provide controlled or sustained release of the active agent following topical application.

[0233]

[0222] In embodiments, the vehicle further comprises one or more penetration enhancers, humectants, chelating agents, antioxidants, buffers, or combinations thereof, in amounts suitable for polymeric nanoparticle dispersions intended for scalp or skin application.

[0234]

[0223] Exemplary Vehicle 22: Polymer-lipid hybrid nanoparticles

[0235]

[0224] In another example, a topical delivery vehicle comprises polymer-lipid hybrid nanoparticles configured as core-shell nanostructures. In embodiments, the vehicle comprises a polymeric core formed from one or more biodegradable polymers (e.g., poly(lactic-co-glycolic acid), poly(lactic acid), poly(caprolactone), poly(lactic-co-caprolactone), combinations thereof) and a lipid shell surrounding the polymeric core.2025-12-29

[0225] In embodiments, the lipid shell comprises one or more lipid components (e.g., phospholipids, fatty acids, cholesterol, glycolipids, combinations thereof) associated with or coating the polymeric core. In embodiments, the active agent is encapsulated within the polymeric core, associated with the lipid shell, or distributed between the core and shell.

[0236]

[0226] In embodiments, the polymer-lipid hybrid nanoparticles are dispersed in an aqueous phase with water q.s. to 100%, optionally comprising one or more stabilizers or surfactants in amounts effective to maintain colloidal stability. In embodiments, the nanoparticles have a mean diameter of between about 50 nm and about 1000 nm.

[0237]

[0227] In embodiments, the hybrid nanoparticles provide controlled release of the active agent and improved interaction with skin or scalp tissue relative to polymer-only or lipid-only nanoparticles.

[0238]

[0228] Exemplary Vehicle 23: Aqueous drug nanocrystals or nanosuspension

[0239]

[0229] In another example, a topical delivery vehicle is an aqueous drug nanocrystal or nanosuspension formulation comprising the active agent as suspended solid particles dispersed in a water-based medium. In embodiments, the vehicle comprises water q.s. to 100% by weight of the composition.

[0240]

[0230] In embodiments, the active agent is present as crystalline or partially amorphous solid particles stabilized against aggregation. In embodiments, the vehicle further comprises one or more stabilizers, surfactants, or dispersing agents (e.g., nonionic surfactants, polymeric stabilizers, amphoteric surfactants, combinations thereof) in amounts effective to maintain particle dispersion and physical stability.

[0241]

[0231] In embodiments, the suspended particles have a particle size distribution characterized by a mean diameter of between about 50 nm and about 2000 nm, including between about 100 nm and about 1000 nm. In embodiments, the formulation is substantially free of added oils and is configured as a low-viscosity liquid or lightly thickened dispersion.

[0242]

[0232] In embodiments, the vehicle further comprises one or more humectants, buffers, chelating agents, antioxidants, penetration enhancers, or combinations thereof, in amounts suitable for aqueous nanosuspension formulations intended for scalp or skin application.

[0243]

[0233] Exemplary Vehicle 24: Ointment or pomade scalp vehicle

[0244]

[0234] In another example, a topical delivery vehicle is an ointment or pomade scalp vehicle configured as a highly occlusive semisolid formulation. In embodiments, the vehicle comprises a hydrophobic base that is hydrocarbon-rich and / or silicone-rich.

[0245]

[0235] In embodiments, the vehicle comprises one or more hydrocarbons, oils, or waxy materials (e.g., petrolatum, mineral oil, paraffins, microcrystalline waxes, hydrogenated hydrocarbons, combinations thereof) and / or one or more silicones (e.g., dimethicone, cyclomethicone, phenyltrimethicone, combinations thereof) in amounts effective to form a semisolid, occlusive matrix.2025-12-29

[0236] In embodiments, the vehicle further comprises one or more structuring agents or viscosity modifiers (e.g., waxes, fatty alcohols, polymeric thickeners, combinations thereof) in amounts effective to impart pomade-like or ointment-like consistency. In embodiments, the composition is substantially water-free.

[0246]

[0237] In embodiments, the vehicle further comprises one or more solubilizing agents, penetration enhancers, antioxidants, or combinations thereof, in amounts suitable for incorporation of the active agent into the occlusive base. In embodiments, the ointment or pomade vehicle provides prolonged residence time on the scalp and reduced evaporation relative to non-occlusive formulations.

[0247]

[0238] Exemplary Vehicle 25: Solid stick or wax-stick applicator

[0248]

[0239] In another example, a topical delivery vehicle is a solid stick or wax-stick applicator configured as a doseable solid or semi-solid formulation for direct application to the scalp or skin. In embodiments, the vehicle is an anhydrous or substantially anhydrous composition.

[0249]

[0240] In embodiments, the vehicle comprises one or more structuring solids or waxes (e.g., beeswax, carnauba wax, candelilla wax, microcrystalline wax, fatty alcohols, hydrogenated oils, combinations thereof) in amounts effective to form a solid or semi-solid stick that retains its shape at room temperature.

[0250]

[0241] In embodiments, the vehicle further comprises one or more liquid carriers (e.g., oils, esters, silicones, combinations thereof) in amounts effective to modulate hardness, glide, and spreadability during application. In embodiments, the active agent is dissolved, dispersed, or suspended within the solid matrix.

[0251]

[0242] In embodiments, the solid stick vehicle allows controlled, localized delivery of the active agent with minimal mess and reduced risk of run-off relative to liquid formulations.

[0252]

[0243] Exemplary Vehicle 26: Patch, laminate, or strip sustained-release scalp system

[0253]

[0244] In another example, a topical delivery vehicle is a patch, laminate, or strip configured as an occlusive sustained-release scalp delivery system. In embodiments, the vehicle comprises a matrix layer containing the active agent and configured for prolonged contact with the scalp.

[0254]

[0245] In embodiments, the matrix layer comprises one or more polymers (e.g., pressure-sensitive adhesives, hydrogels, elastomers, polyacrylates, silicones, polyisobutylenes, combinations thereof) in which the active agent is dispersed or dissolved. In embodiments, the matrix is an anhydrous matrix or a hydrated matrix.

[0255]

[0246] In embodiments, the vehicle further comprises an adhesive layer configured to secure the patch, laminate, or strip to the scalp for a defined wear period. In embodiments, the adhesive layer is integral with the matrix layer or is provided as a separate layer.

[0256]

[0247] In embodiments, the vehicle further comprises a backing layer configured to provide mechanical support and optional occlusion. In embodiments, the backing layer is occlusive or2025-12-29 semi-occlusive. In embodiments, the system is configured to deliver the active agent over a period of hours to days while maintaining close contact with the scalp.

[0257]

[0248] Exemplary Vehicle 27: Microencapsulation, microsponges, or porous beads

[0258]

[0249] In another example, a topical delivery vehicle comprises microencapsulated active agent particles, microsponges, or porous beads configured for controlled release and reduced irritation upon topical application. In embodiments, the vehicle comprises microparticles formed from polymeric, lipidic, inorganic, or hybrid materials.

[0259]

[0250] In embodiments, the microencapsulated structures comprise porous or semi-porous particles (e.g., polymeric microsponges, silica-based porous beads, polymeric microspheres, combinations thereof) that physically entrap the active agent within internal pores or cavities. In embodiments, the active agent is released from the microparticles gradually upon contact with skin, moisture, sebum, or mechanical action.

[0260]

[0251] In embodiments, the microparticles have a mean particle size of between about 1 pm and about 200 pm. In embodiments, the microparticles are dispersed within a topical carrier system (e.g., aqueous gels, emulsions, anhydrous gels, lotions, creams, combinations thereof) suitable for scalp or skin application.

[0261]

[0252] In embodiments, the microencapsulation system reduces burst release, improves tolerability, and / or enhances stability of the active agent relative to non-encapsulated formulations.

[0262]

[0253] Exemplary Vehicle 28: Polymer-coated or layer-by-layer vesicles

[0263]

[0254] In another example, a topical delivery vehicle comprises polymer-coated vesicles or layer-by-layer-assembled vesicular systems. In embodiments, the vehicle comprises lipid vesicles (e.g., liposomes, deformable liposomes, phospholipid vesicles, combinations thereof) that are coated with one or more polymer layers.

[0264]

[0255] In embodiments, the polymer coating is formed from one or more polymers (e.g., chitosan, alginate, hyaluronic acid, poly(acrylic acid), poly(ethyleneimine), polyelectrolytes, combinations thereof) deposited onto the vesicle surface via electrostatic interaction, covalent attachment, adsorption, or layer-by-layer assembly. In embodiments, the polymer coating forms a shell around the vesicle, resulting in a double-layered or multi-layered vesicular structure.

[0265]

[0256] In embodiments, the polymer-coated vesicles encapsulate the active agent within the vesicle core and / or associate the active agent with the lipid bilayer. In embodiments, the polymer coating provides enhanced vesicle stability, controlled release, and / or modified interaction with the skin or scalp relative to uncoated vesicles.

[0266]

[0257] In embodiments, the polymer-coated vesicles are dispersed in an aqueous or mixed solvent medium suitable for topical application and further comprise one or more stabilizers, buffers, chelating agents, antioxidants, or combinations thereof.2025-12-29

[0258] Exemplary Vehicle 29: Commercial or proprietary topical base

[0267]

[0259] In another example, a topical delivery vehicle is a commercially available or proprietary topical base formulated for dermal or scalp application. In embodiments, the vehicle comprises a ready-to-use topical base (e.g., TrichoSol-type bases, dermatologically acceptable commercial scalp vehicles, compounding pharmacy bases, combinations thereof) configured to accept incorporation of an active agent without substantial modification.

[0268]

[0260] In embodiments, the commercial or proprietary topical base comprises one or more solvents, cosolvents, solubilizing agents, penetration enhancers, humectants, surfactants, rheology modifiers, preservatives, antioxidants, buffers, or combinations thereof, in proportions effective to provide a stable and cosmetically acceptable formulation. In embodiments, the base comprises an aqueous, hydroalcoholic, non-aqueous, or mixed solvent system.

[0269]

[0261] In embodiments, the active agent is incorporated into the commercial or proprietary topical base by mixing, stirring, shaking, or other low-shear processing, and the resulting composition substantially retains the physical stability, rheological properties, and application characteristics of the underlying base.

[0270]

[0262] Exemplary Vehicle 30: Niosomes

[0271]

[0263] In another example, a topical delivery vehicle is a niosomal vesicular dispersion comprising non-ionic surfactant vesicles. In embodiments, the vehicle comprises one or more non-ionic surfactants capable of forming bilayer vesicles (e.g., sorbitan esters, polysorbates, alkyl ethers, combinations thereof).

[0272]

[0264] In embodiments, the vehicle further comprises a sterol component (e.g., cholesterol, phytosterols, combinations thereof) in an amount effective to stabilize the niosomal bilayer structure. In embodiments, the niosomes encapsulate the active agent within an aqueous core and / or associate the active agent with the vesicular bilayer.

[0273]

[0265] In embodiments, the niosomes are dispersed in an aqueous phase with water q.s. to 100%, optionally comprising one or more cosolvents, humectants, buffers, chelating agents, antioxidants, or combinations thereof. In embodiments, the niosomes have a mean diameter of between about 50 nm and about 1000 nm.

[0274]

[0266] Exemplary Vehicle 31 : Ionic liquid or deep eutectic solvent carrier

[0275]

[0267] In another example, a topical delivery vehicle is an ionic liquid or deep eutectic solvent (IL / DES) carrier system configured to solubilize the active agent. In embodiments, the vehicle comprises an ionic liquid and / or deep eutectic solvent formed from a hydrogen bond donor and a hydrogen bond acceptor.

[0276]

[0268] In embodiments, the ionic liquid or deep eutectic solvent comprises organic salts, choline-based systems, amino acid-based systems, organic acid-based systems, or combinations thereof.2025-12-29 In embodiments, the IL / DES system solubilizes the active agent through ionic interactions, hydrogen bonding, or a combination thereof.

[0277]

[0269] In embodiments, the vehicle further comprises water in an amount of between about 0% and about 50% by weight of the composition, provided that the ionic liquid or deep eutectic solvent remains the primary solubilizing medium. In embodiments, the vehicle further comprises one or more cosolvents, penetration enhancers, viscosity modifiers, antioxidants, or combinations thereof.

[0278]

[0270] In embodiments, the IL / DES carrier system enhances solubility and / or dermal penetration of the active agent relative to conventional solvent systems.

[0279]

[0271] A topical delivery vehicle may comprise a combination of two or more vehicle systems described herein. In embodiments, the vehicle comprises a hybrid system combining, for example, a cyclodextrin inclusion system with an emulsion, a liposomal dispersion with a hydroalcoholic gel, or a nanosuspension incorporated into an emulsion or gel matrix.

[0280]

[0272] In embodiments, a combined vehicle system enhances solubility, stability, penetration, residence time, or user acceptability relative to a single vehicle system alone. In embodiments, a topical composition comprises olanzapine (e.g., free base and / or a pharmaceutically acceptable salt) in an amount of 0.000001-5% by weight and a vehicle selected from the scalp-compatible vehicle families described herein (including Exemplary Vehicles 1-31), such as comprising one or more of: (i) an anhydrous polar cosolvent system comprising a cyclic carbonate solvent and a polar penetration enhancer / solubilizer (e.g., propylene carbonate and dimethyl isosorbide, each independently 10-90% by weight, optionally with additional anhydrous cosolvents, oils, and / or structurants), (ii) an oil-dominant anhydrous vehicle comprising an oil phase (e.g., squalane and / or another saturated oil) and one or more polar solubilizers / cosolvents, optionally structured as an anhydrous organogel, (iii) aqueous and / or hydroalcoholic scalp carriers (including solutions, gels, foams, rinse-off shampoo / conditioner compositions, and / or pre-formed commercial bases), optionally buffered to pH 4.0-7.5, (iv) emulsion systems including O / W or W / O emulsions, microemulsions, and / or nanoemulsions, (v) vesicular lipid carriers including liposomes / lipid-vesicle dispersions, ethosomes / transethosomes and other deformable vesicles, and polymer-coated / layer-by-layer vesicles, (vi) particulate delivery systems including non-aqueous nanosuspensions, aqueous drug nanocrystals / nanosuspensions, lipid nanoparticles (e.g., SLN / NLC), polymeric nanoparticles and polymer-lipid hybrid nanoparticles, and microencapsulation / microsponges / porous bead reservoirs, and / or (vii) ionic-liquid and / or deep-eutectic-solvent carriers and depot / residence-time extender systems (including film-forming systems).2025-12-29 d. Additional Active Compounds

[0281]

[0273] In embodiments, the composition further comprises a therapeutically effective amount of an additional active compound. In embodiments, the additional active agent is selected to provide synergistic effects.

[0282]

[0274] In embodiments, “synergistic effects” will be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone, and / or are greater than the contribution of the isolated compounds on their own. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components when applied alone, thereby producing “1+1 > 2.” One such method is the isobologram analysis (or contour method) (Huang et al.

[0283] 2019).

[0284]

[0275] In embodiments, the additional active agent is selected to provide an additional therapeutic effect, such as antioxidant, anti-inflammatory, analgesic, antinociceptive, immunostimulant, immunosuppressive, anti-cancer, antiemetic, antiulcer, antihistamine, vasodilating, and vasoconstricting effects.

[0285]

[0276] In embodiments, the additional active agent is an amino acid, antioxidant, peptide, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, peptidase inhibitor, thyroid hormone, vitamin, vasodilator, or vasoconstrictor. These active agents may be in ion, freebase, or salt form, include polymorphs, and may be isomers.

[0286]

[0277] In embodiments, the additional active agent is triiodothyronine, finasteride, dutasteride, minoxidil, naltrexone, farnesol, thyrotropin-releasing hormone, or doxycycline. In embodiments, a composition comprises olanzapine and triiodothyronine. In embodiments, a composition comprises olanzapine and finasteride. In embodiments, a composition comprises olanzapine and dutasteride. In embodiments, a composition comprises olanzapine and minoxidil. In embodiments, a composition comprises olanzapine and naltrexone. In embodiments, a composition comprises olanzapine and doxycycline. In embodiments, a composition comprises olanzapine and farnesol. In embodiments, a composition comprises olanzapine and doxycycline. In embodiments, a composition comprises olanzapine and thyrotropin-releasing hormone.

[0287] e. Kits

[0288]

[0278] The present disclosure further provides kits, such as pharmaceutical kits, comprising the disclosed compositions. In embodiments, the kits provide disclosed compositions in unit dosage form.

[0289]

[0279] Kits generally comprise suitable packaging. Kits may comprise one or more containers comprising any composition described herein. Each component (if there is more than one component) can2025-12-29 be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. Kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.

[0290]

[0280] Disclosed kits, for example, may contain sufficient dosages of a disclosed composition for an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses and instructions for use and be packaged in quantities sufficient for storage at home or a retail location.

[0291]

[0281] Kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.

[0292] C. Methods of Use

[0293]

[0282] In one aspect, provided is a method of treating hair loss in a subject, comprising administering to the subject a therapeutically effective amount of a disclosed composition. In another aspect, provided is a method of preventing hair loss in a subject, comprising administering to the subject a therapeutically effective amount of a disclosed composition.

[0294]

[0283] In another aspect, provided is a method of treating hair graying in a subject, the method comprising administering to the subject a therapeutically effective amount of a disclosed composition. In another aspect, provided is a method of preventing hair graying in a subject, the method comprising administering to the subject a therapeutically effective amount of a disclosed composition.

[0295]

[0284] In another aspect, provided is a method of treating a dermatological condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a disclosed composition. In another aspect, provided is a method of preventing a dermatological condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a disclosed composition.

[0296]

[0285] In embodiments, a disclosed composition or method is particularly suitable for administration to a subject with certain qualities (e.g., biomarkers) indicative of high likelihood of treatment success, or low risk of treatment. For example, in some embodiments, only subjects above or below a specified biomarker level are subjected to a disclosed method or composition.

[0297]

[0286] In embodiments, a subject is subjected to bloodwork before treatment with a disclosed method or composition. In embodiments, a subject is selected for treatment with a disclosed composition or according to a disclosed method based on the results of a bloodwork test. In embodiments, a subject is2025-12-29 selected for treatment with a disclosed composition or according to a disclosed method if the subject has a biomarker level above or below a specified level.

[0298]

[0287] In embodiments, administration of a disclosed composition increases the level of a biomarker in the subject In embodiments, administration of a disclosed composition decreases the level of a biomarker in the subject. The “level” of a biomarker refers to a measurable quantity, quality, or characteristic of a biomarker, including concentration, amount, presence, frequency, activity, or expression. For example, the "level" of a biomarker may refer to its concentration in a biological sample (e.g., blood, plasma, serum, tissue), its rate of production or degradation, its expression in a cell or tissue (e.g., as determined by gene expression assays such as RT-PCR, RNA sequencing, or microarrays), its activity or functional state, or any other measurable parameter indicative of the biomarker's presence or effect. In embodiments, the biomarker is any of Ki-67, Cleaved Caspase-3, Versican, TGF|3-2, Androgen Receptor (AR), LEF1, a-SMA, AXIN2, Phospho-S6 (p-S6), CD34, CD31, MTCO1, Keratin-15 (K15 I CK15), p-Catenin, LGR5, ESR1 (ERa), ESR2 (ER ), TNFa, PPARa, PPARy, Phospho-PDPK1 (p-PDPK1), Collagen 17A1 (COL17A1), ACTH, NFATC1, YAP, VDAC, FRA-1 / F0SL1, c-Fos, CTGF, RARy (RARG), RARa (RARA), and LXR (pan-LXR). These and other biomarkers are known to those of skill in the art, as are the biological effects of increasing and decreasing a particular biomarker, and methods of measuring levels of biomarkers.

[0299]

[0288] In embodiments, administration of a disclosed composition inhibits (e.g., antagonizes) a dopamine receptor in a subject. In embodiments, administration of a disclosed composition inhibits any of dopamine 1 receptor (D1R), dopamine 2 receptor (D2R), dopamine 3 receptor (D3R), and dopamine 4 receptor (D4R) in a subject. In embodiments, administration of a disclosed composition inhibits D2R in a subject. In embodiments, administration of a disclosed composition downregulates or inhibits dopaminergic neurotransmission in a subject. In embodiments, “inhibits” refers to decreasing or blocking the activity of a target (e.g., receptor, protein, gene, enzyme, biological function), such as by directly binding to the target (e.g., receptor antagonism, enzyme inhibition), decreasing the expression of a target (e.g., downregulating a gene), and indirectly decreasing the activity of the target by inhibiting the activity of a signal transduction pathway of which the target is a member. “Downregulation” refers to a decrease in a biological activity and / or expression of a target. Measures of inhibition and downregulation are known to those of skill in the art.

[0300]

[0289] In embodiments, administration of a disclosed composition inhibits (e.g., antagonizes) a serotonin receptor in a subject, such as any of the 5-HT1A, 5-HT2A, and 5-HT2Creceptors. In embodiments, administration of a disclosed composition downregulates or inhibits serotonergic neurotransmission in a subject. In embodiments, administration of a disclosed composition results in upregulation of a serotonin receptor in a subject.2025-12-29 a. Methods of Administration

[0301]

[0290] In another aspect, provided are methods of administering disclosed compositions to subjects, such as for treating hair loss, preventing hair loss, treating hair graying, preventing hair graying, treating a dermatological condition, or preventing a dermatological condition.

[0302]

[0291] In embodiments, the composition is administered topically. In embodiments, the composition is administered transdermally. In embodiments, the composition is administered by a route of administration that results in systemic delivery of the active agent(s). In embodiments, the composition is administered by a route of administration that results in local delivery of the active agent(s).

[0303]

[0292] In embodiments, the substituted diazepine is administered at a concentration of between about 0.01 pM and 5 mM. In embodiments, the substituted diazepine is administered at a concentration of between about 0.01 pM and 1 mM. In embodiments, the substituted diazepine is administered at a concentration of between about 0.1 pM and 500 pM. In embodiments, the substituted diazepine is administered at a concentration of between about 1 pM and 50 pM. In embodiments, the substituted diazepine is administered at a concentration of between about 20 pM and 50 pM.

[0304]

[0293] In embodiments, the substituted diazepine is administered at a concentration of less than about 0.1 pM (including concentrations between about 1 nM and 0.1 pM, about 10 nM and about 0.1 pM, and about 50 nM and about 0.1 pM). In embodiments, the substituted diazepine is administered at a concentration of greater than about 500 pM (including concentrations between about 500 pM and about 1 mM, about 1 mM and about 100 mM, and about 100 mM and about 1 M). In embodiments, the substituted diazepine is administered at a concentration of about 1 pM. In embodiments, the substituted diazepine is administered at a concentration of about 20 pM. In embodiments, the substituted diazepine is administered at a concentration of about 50 pM.

[0305]

[0294] In embodiments, the total unit dose volume of a disclosed composition is between about 0.1 mL and 10 mL. In embodiments, the total unit dose volume is about 0.1 mL, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL. In embodiments, the total unit dose volume is about 0.1 mL. In embodiments, the total dose volume is about 0.5 mL. In embodiments, the total unit dose volume is about 1 mL. In embodiments, the total unit dose volume is about 2 mL. In embodiments, the total dose volume of a disclosed composition is about 3 mL. In embodiments, the total unit dose volume is about 4 mL. In embodiments, the total unit dose volume is about 5 mL. In embodiments, the total unit dose volume is about 6 mL. In embodiments, the total unit dose volume is about 7 mL. In embodiments, the total unit dose volume is about 8 mL. In embodiments, the total dose volume of a disclosed composition is about 9 mL. In embodiments, the total unit dose volume is about 10 mL.2025-12-29

[0295] Determination of appropriate dosing shall include not only the determination of single dose amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) preferable for administration.

[0306]

[0296] In embodiments, the composition is administered every day. In embodiments, the composition is administered every other day for a period of time, followed by a prolonged period without administration. For example, in some embodiments, the composition is administered every other day for 1 week followed by a prolonged period without administration. In embodiments, the composition is administered every other day for 2 weeks followed by a prolonged period without administration. In embodiments, the composition is administered every other day for 3 weeks followed by a prolonged period without administration. In embodiments, the composition is administered every other day for 4 weeks followed by a prolonged period without administration. In embodiments, the composition is administered every other day for 5 weeks followed by a prolonged period without administration. In embodiments, the composition is administered every other day for 6 weeks followed by a prolonged period without administration.

[0307]

[0297] In embodiments, the compositions may be administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Dosage levels thus may differ from patient to patient, for individual patients across time, and for different compositions and formulations, but shall be able to be determined with ordinary skill.

[0308]

[0298] In embodiments wherein a disclosed composition is used to create a desired effect, it will be readily appreciated that dose and dosage may vary depending upon the general health, age, gender, and race of the individual, bioavailability, potential adverse systemic, regional, or local side effects, the presence of any disorders or diseases in the individual, and other factors that will be appreciated by those in the art (e.g., medical or familial history).

[0309]

[0299] In general, dose amount, frequency of dosing, and / or duration of dosing, including as part of a dosing schedule or dosing regimen, may be modified, such as increased or reduced, as indicated by the therapeutic outcome(s) or effect(s) desired, the beneficial outcome(s) or effect(s) desired, and / or by the specific subjective outcome(s) or effect(s) desired.

[0310]

[0300] Those in the art will appreciate the factors that may influence the dose, frequency, and timing required to provide an amount sufficient or effective for providing a desired effect, and to do so depending on the type of desired effect and to avoid or minimize adverse effects.

[0311]

[0301] Dose and dosage may differ from patient to patient, for individuals across time, and for different compositions and formulations, but shall be able to be determined with ordinary skill.2025-12-29 Determination of appropriate dosing shall include not only the determination of single dose amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) preferable for administration.

[0312] b. Methods of Treating and Preventing Hair Loss or Hair Graying

[0313]

[0302] In embodiments, disclosed compositions and methods are for treating hair loss in a subject. In embodiments, disclosed compositions and methods are for preventing hair loss in a subject.

[0314]

[0303] In embodiments, the hair loss is caused by alopecia. In embodiments, the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia. In embodiments, the hair loss is caused by androgenetic alopecia. In embodiments, the hair loss is male pattern baldness. In embodiments, the hair loss is female pattern baldness.

[0315]

[0304] In embodiments, disclosed compositions and methods treat or prevent hair loss caused by alopecia. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by androgenetic alopecia. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by male pattern baldness. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by female pattern baldness.

[0316]

[0305] In embodiments, treating or preventing hair loss “caused by” a condition also refers to and includes treating or preventing hair loss associated with the condition. For example, embodiments where disclosed compositions and methods are used to treat or prevent hair loss caused by alopecia also refer to and include using disclosed compositions and methods to treat or prevent hair loss associated with alopecia, such as alopecia-associated hair loss.

[0317]

[0306] In embodiments, the hair loss is caused by telogen effluvium. In embodiments, the hair loss is caused by anagen effluvium. In embodiments, the hair loss is caused by a nutritional deficiency. In embodiments, the hair loss is caused by thyroid dysfunction. In embodiments, the hair loss is caused by chronic illness, such as diabetes or chronic kidney disease. In embodiments, the hair loss is caused by medication side effects, such as from beta blockers, retinoids, or anticonvulsants. In embodiments, the hair loss is caused by chemotherapy or radiation therapy. In embodiments, the hair loss is caused by environmental factors, such as UV damage or pollution. In embodiments, the hair loss is caused by an injury, such as burns or surgical scars. In embodiments, the hair loss is caused by aging.2025-12-29

[0307] In embodiments, disclosed compositions and methods treat or prevent hair loss caused by telogen effluvium. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by anagen effluvium. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by a nutritional deficiency. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by thyroid dysfunction. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by chronic illness, such as diabetes or chronic kidney disease. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by medication side effects, such as from beta blockers, retinoids, or anticonvulsants. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by chemotherapy or radiation therapy. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by environmental factors, such as UV damage or pollution. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by an injury, such as burns or surgical scars. In embodiments, disclosed compositions and methods treat or prevent hair loss caused by aging.

[0318]

[0308] Other causes of hair loss, treatable with disclosed compositions and methods, are known to those of skill in the art.

[0319]

[0309] In embodiments, administration of a disclosed composition alters hair cycle staging in a subject. In embodiments, administration of a disclosed composition alters the anagen (i.e., growth) phase. In embodiments, administration of a disclosed composition prolongs the anagen phase. In embodiments, administration of a disclosed composition delays the transition from the anagen to the catagen (i.e., transitional) phase. In embodiments, administration of a disclosed composition reduces the duration of the catagen phase. In embodiments, administration of a disclosed composition reduces the duration of the telogen (i.e., resting) phase.

[0320]

[0310] In embodiments, increases and decreases of a measure (e.g., duration of a hair style stage, hair shaft production, hair follicle length, rate of hair follicle growth, rate of decreasing hair follicle length, repigmentation, depigmentation) are determined by comparison with the measure in the subject prior to treatment with a disclosed composition or method. In embodiments, increases and decreases of a measure are determined by comparison with a different subject (i.e., a control subject) who has not been treated with a disclosed composition or method. In embodiments, increases and decreases of a measure are determined by comparison with an average of the measure in a population of subjects who have not been treated with a disclosed composition or method.

[0321] c. Methods of Treating and Preventing Dermatological Conditions

[0322]

[0311] In embodiments, disclosed compositions and methods are for treating a dermatological condition in a subject. In embodiments, disclosed compositions and methods are for preventing a dermatological condition in a subject.2025-12-29

[0312] Dermatological conditions treatable with disclosed compositions and methods and their causes, symptoms, and risk factors are known to those of skill in the art. In embodiments, the dermatological condition is a disease of the skin. The ICD-11, incorporated by reference herein in its entirety, defines “diseases of the skin” as conditions affecting the epidermis, its appendages (hair, hair follicle, sebaceous glands, apocrine sweat gland apparatus, eccrine sweat gland apparatus and nails) and associated mucous membranes (conjunctival, oral and genital), the dermis, the cutaneous vasculature and the subcutaneous tissue (subcutis). Diseases of the skin are also referred to as “skin conditions” herein, as shorthand.

[0323]

[0313] In embodiments, disclosed compositions and methods are for treating a skin condition. Skin conditions and the diagnosis thereof will be known to those in the art. Examples of a skin conditions, treatable using the disclosed compositions and methods, include diseases of the epidermis, dermis, epidermal appendages (e.g., hair, hair follicles, sebaceous glands, apocrine sweat gland apparatus, eccrine sweat gland apparatus, and nails), subcutaneous tissue, and cutaneous vasculature.

[0324]

[0314] In embodiments, the skin condition is an epidermal disease. Epidermal diseases and the diagnosis thereof will be known to those in the art. Examples of epidermal diseases, treatable using the disclosed compositions and methods, include psoriasis, dermatitis (e.g., atopic dermatitis, contact dermatitis, seborrheic dermatitis, nummular dermatitis), lichen planus, vitiligo, keratosis (e.g., actinic keratosis, keratosis pilaris, seborrheic keratosis), ichthyosis (e.g., ichthyosis vulgaris), melasma, pityriasis (e.g., pityriasis rosea, pityriasis alba), xerosis (i.e., dry skin).

[0325]

[0315] In embodiments, the skin condition is a dermal disease. Dermal diseases and the diagnosis thereof will be known to those in the art. Examples of dermal diseases, treatable using the disclosed compositions and methods, include scleroderma (e.g., localized scleroderma, systemic sclerosis), lupus erythematosus (e.g., discoid lupus erythematosus, systemic lupus erythematosus), rosacea (e.g., erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea), granuloma annulare (e.g., localized granuloma annulare, generalized granuloma annulare), and erythema multiforme.

[0326]

[0316] In embodiments, the skin condition is an epidermal appendage disease (which include diseases of, e.g., hair, nails, sweat glands, and sebaceous glands). Epidermal appendage diseases and the diagnosis thereof will be known to those in the art. Examples of epidermal appendage diseases, treatable using the disclosed compositions and methods, include acne (e.g., comedonal acne, inflammatory acne, nodulocystic acne), alopecia (e.g., alopecia areata, androgenic alopecia, telogen effluvium), follicular keratosis, hidradenitis suppurativa, brittle nails, onychodystrophy, hyperhidrosis (e.g., primary hyperhidrosis).

[0327]

[0317] In embodiments, the skin condition is a subcutaneous tissue disease. Subcutaneous tissue diseases and the diagnosis thereof will be known to those in the art. Examples of subcutaneous2025-12-29 tissue diseases, treatable using the disclosed compositions and methods, include lipomas, panniculitis (e.g., erythema nodosum), subcutaneous calcinosis, adiposis dolorosa.

[0328] D. Exemplary Aspects and Embodiments

[0329]

[0318] The following aspects and embodiments are included for illustrative purposes only and are not intended to limit the scope of the invention. These aspects and embodiments are not an extensive overview of the invention. They are not intended to identify key or critical elements of the invention or to delineate the scope thereof.

[0330]

[0319] In one aspect, provided is a composition formulated for treating or preventing hair loss, hair graying, or a dermatological condition, comprising:

[0331] i. a substituted diazepine, or a pharmaceutically acceptable salt thereof; and

[0332] ii. a solvent system.

[0333]

[0320] In embodiments, the composition comprises the substituted diazepine at a concentration of between about 0.1 pM and 500 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of between about 1 pM and about 100 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of between about 1 pM and about 10 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of about 1 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of between about 10 pM and about 80 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of about 20 pM. In embodiments, the composition comprises the substituted diazepine at a concentration of about 50 pM.

[0334]

[0321] In embodiments, the substituted diazepine is a thienobenzodiazepine. In embodiments, the thienobenzodiazepine is olanzapine

[0335]

[0322] In embodiments, the composition further comprises a pharmaceutically acceptable excipient. In embodiments, the pharmaceutically acceptable excipient is a penetration enhancer, carrier, diluent, emulsifier, stabilizer, viscosity modifying agent, adhesion modifying agent, preservative, antioxidant, adhesive polymer, solubilizing agent, colorant, binder, humectant, surfactant, or gelling agent.

[0336]

[0323] In embodiments, the composition further comprises an additional active agent. In embodiments, the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, peptidase inhibitor, hormone, vitamin, vasodilator, or vasoconstrictor.

[0337]

[0324] Also provided is a method of treating hair loss in a subject, comprising administering to the subject the composition of any of the disclosed embodiments.

[0338]

[0325] Also provided is a method of preventing hair loss in a subject, comprising administering to the subject the composition of any of the disclosed embodiments.2025-12-29

[0326] Also provided is a method of treating a dermatological condition in a subject, comprising administering to the subject the composition of any of the disclosed embodiments.

[0339]

[0327] In embodiments, a method comprises administering the composition daily. In embodiments, the composition is administered every other day. In embodiments, the composition is administered every other day for several consecutive weeks followed by a prolonged period without administration. In embodiments, the composition is administered every other day for two consecutive weeks followed by a prolonged period without administration. In embodiments, the prolonged period without administration is at least two weeks.

[0340]

[0328] In embodiments, the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia.

[0341]

[0329] In embodiments, administering the composition increases hair shaft production in the subject. In embodiments, administering the composition prolongs the anagen hair growth phase in the subject.

[0342]

[0330] In embodiments, the dermatological condition is a skin condition. In embodiments, the skin condition is an epidermal disease, dermal disease, epidermal appendage disease, or subcutaneous tissue disease.

[0343] E. Examples

[0344]

[0331] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0345] Example 1: Hair Follicle Organ Culture Model

[0346]

[0332] Methods:

[0347]

[0333] Hair Follicle Collection and Preparation: Human scalp hair follicles were obtained from a healthy male donor undergoing elective cosmetic surgery, with written informed consent and in compliance with the regulatory and ethical guidelines following a non-transplant anatomic tissue bank in the state of New York. 17 human scalp follicular units were sourced from the donor, with each follicular unit containing 1 or 2 hair follicles, totalling 32 measured human hair follicles.

[0348]

[0334] Organ Culture System: Human hair follicular unit biopsies containing terminal scalp hair follicles were placed in serum-free supplemented William’s E medium and incubated at 37 °C in a humidified atmosphere of 5% CO2. After 24 hours of culture for equilibration, follicular unit biopsies were treated with 1 mL serum-free supplemented William’s E medium (vehicle) or the same medium containing olanzapine (1 pM - 50 pM).

[0349]

[0335] From Day 1 - Day 7, medium change was performed every other day. At every medium change, each follicular unit was imaged to perform hair shaft length, width, and cycle staging analysis. At2025-12-29 the end of the seven days of culture, samples were embedded in OCT, snap-frozen in liquid nitrogen, and stored at -80 °C until further analyses.

[0350]

[0336] OCT-embedded follicular unit samples were cryosectioned (7 pm thickness) with a Leica CM3050S cryostat at -20 to -30 °C to maintain the follicles in a frozen state and prevent proteolysis.

[0351]

[0337] Dosage Titration and Experimental Design: Three dosages of topically applied olanzapine were selected for testing restoration of proper genetic function in human hair follicles without inducing local or systemic toxicity. Dissolution of the ingredients was tested; olanzapine was fully soluble at the highest concentration tested (50 pM).

[0352]

[0353]

[0354]

[0338] The experiments of this example were conducted according to the following timeline:

[0355]

[0356]

[0357] 2025-12-29

[0358]

[0359]

[0339] Experimental Treatments: All hair follicles were incubated in the supplemented medium only for 24 hours, to allow for post-distress resting and assessment of hair cycle staging. After the initial incubation period, olanzapine was prepared as a stock solution and diluted to the desired concentrations in the supplemented culture medium. Control follicles were treated with supplemented culture medium only. Each treatment was applied to a minimum of 5 hair follicles per experimental group.

[0360]

[0340] Assessment of Hair Follicle Viability and Growth: Hair follicle viability was assessed morphologically under an Echo Revolve 3 inverted microscope at 0, 1, 3, 5, and 7 days. Hair shaft elongation was measured daily using the Echo Revolve system’s digital scale and image-based analysis. Additionally, confirmation of shaft elongation may be performed using computer vision-based image analysis.

[0361]

[0341] For hair cycle staging analysis, macroscopic imaging and immunostains will be used to determine hair cycle stage ex vivo. Additionally, confirmation of hair cycle staging may be performed using computer vision-based image analysis.

[0362]

[0342] Statistical analysis: Data are reported as percent change vs. baseline, percent change vs. vehicle, or mean ± SEM, as indicated. Where statistical analysis is performed, significance may be evaluated, as appropriate, by two-tailed Student’s t-test or Mann-Whitney test when comparing two treatment groups (GraphPad Prism) or ANOVA when comparing three or more treatment groups, with p < 0.05 considered significant.

[0363]

[0343] Results:

[0364]

[0344] Hair Shaft Production: Table 1 shows measured lengths for each hair follicle in the study, where Short / Medium / Long = length in relation to other follicles in the well; Left / Right / Middle = position of the follicle in relation to the other follicles in the well; and Only = only follicle in the well. ALength = change in hair follicle length on day 7 vs. day 0.

[0365]

[0345] Olanzapine increased hair follicle length during seven days of ex vivo organ culture. Individual follicle length measurements from Days 0, 1 , 3, 5 and 7 are provided in Table 1 , including well plate identifiers for traceability. In controls, the average change in length was modest (+0.05 mm, +1.31% vs. Day 0; Table 2). In contrast, follicles treated with 1 pM olanzapine increased by +0.23 mm (+5.33% vs. Day 0), while 20 pM olanzapine produced the largest average increase (+0.50 mm, +15.96% vs. Day 0). Treatment with 50 pM olanzapine also increased length on average (+0.26 mm, +10.41% vs. Day 0; Table2025-12-29 2). When normalized to Day 1 , 20 pM olanzapine again showed the greatest average increase (+0.20 mm, +5.27% vs. Day 1), whereas controls increased by +0.03 mm (+0.82% vs. Day 1; Table 2).

[0366]

[0346] Inter-follicle Variability: Growth responses varied across individual follicles (Table 1), consistent with expected heterogeneity in baseline hair cycle state and dissection-related stress. In some wells, olanzapine-treated follicles showed substantial elongation, for example a 20 pM-treated follicle in well 11-B1 increased by 1.768 mm (60.92%), and a 50 pM-treated follicle in well 22-A3 increased by 1.506 mm (69.66%) over the culture period (Table 1). A minority of follicles exhibited little growth or net shortening; for example, a 1 pM follicle in well 22-C4 decreased by 0.424 mm (-9.64%), and a 50 pM follicle in well 11-B2 decreased by 0.212 mm (-4.05%) (Table 1).

[0367]

[0347] Hair Cycle Morphology: Hair cycle staging at Day 7 is summarized in Table 3. In the control group, 62.5% of follicles remained in anagen, with 12.5% classified as early-catagen and 25.0% classified as catagen. Olanzapine-treated groups showed dose-dependent shifts in morphology. The 1 pM group exhibited 75.0% anagen follicles, whereas the 50 pM group exhibited the highest proportion of anagen follicles (87.5%) and no follicles in full catagen (Table 3). When early-catagen and catagen were combined as a single non-anagen category, the proportion of non-anagen follicles was 37.5% in controls, 25.0% in the 1 pM group, 50.0% in the 20 pM group, and 12.5% in the 50 pM group..

[0368] Table 1. Hair Follicle Length

[0369]

[0370] 2025-12-29

[0371]

[0372] Table 1A. Hair Cycle Morphology (Per Follicle)

[0373]

[0374] 2025-12-29

[0375]

[0376] Table 2. Summary of length changes in the control and drug test groups.

[0377]

[0378] 2025-12-29

[0379]

[0380] Table 3. Hair Cycle Morphology at Day 7.

[0381]

[0382] ‘Classification based on macroscopic morphological assessment; histomorphometric confirmation is ongoing.

[0383]

[0348] Discussion:

[0384]

[0349] Summary of Findings: Across the endpoints measured in Example 1, olanzapine increased hair shaft production in human hair follicle organ culture relative to untreated controls, with the greatest average effect observed at 20 pM (Table 2). These data support the concept that olanzapine, when delivered to intact human hair follicles ex vivo, can promote measurable increases in hair follicle length over a one-week culture interval.

[0385]

[0350] Dose-Response Considerations: The magnitude of length increase was not strictly monotonic across the tested concentrations. While 20 pM provided the largest average increase (+0.50 mm vs. Day 0), the 50 pM group showed a smaller average increase (+0.26 mm) despite having the highest fraction of anagen follicles at Day 7 (87.5%; Table 3). This pattern is consistent with multiple, non-mutually exclusive explanations, including (i) biological heterogeneity in starting follicle state, (ii) sensitivity of elongation measurements to initial hair shaft exposure and positioning, and (iii) concentration-dependent tradeoffs between elongation rate and maintenance of anagen morphology under ex vivo conditions. In embodiments, the optimal concentration for stimulating shaft production may differ from the optimal concentration for preserving anagen morphology, and both parameters may be tuned by vehicle selection, dosing frequency, and the local dose delivered to the follicle bulb.

[0386]

[0351] Relationship to Anagen Maintenance: Hair cycle morphology data suggest that higher-dose olanzapine may support maintenance of anagen-like features during culture. Notably, the 50 pM group showed 0% catagen follicles at Day 7 compared to 25% in controls (Table 3). Although the 20 pM group contained a higher fraction of eariy-catagen follicles (37.5%), this may reflect the limited sample size and well-to-well variability rather than a consistent catagen-promoting effect. Future studies increasing the number of follicles per condition and incorporating multiple donors can clarify whether olanzapine reproducibly delays catagen entry and / or accelerates anagen-associated shaft production.2025-12-29

[0352] Planned Mechanistic Readouts: Immunohistochemistry (IHC) and quantitative (immuno-)histomorphometry are expected to provide mechanistic context for the observed macroscopic elongation. The above mentioned antibodies have been incubated with one or more of the sections, and both imaging on the microscope and analysis of the fluorescence still remains in the experiment. Additional follow-up experiments may evaluate markers of proliferation (e.g., Ki-67), apoptosis (e.g., cleaved caspase-3), and additional pathway or compartment markers relevant to hair cycling and follicle health (see Example 2).

[0387]

[0353] Translation to Topical Use: Because the present data were generated in an ex vivo organ culture system with controlled drug exposure, future work may assess delivery in the context of topical formulations designed to concentrate olanzapine within the follicular unit while minimizing systemic exposure. In embodiments, the concentration ranges tested here (1-50 pM) inform topical dose selection and formulation screening for maximizing follicular delivery and biological response. Additional studies may include human scalp skin organ culture with topical application, diffusion and retention measurements, and in vivo evaluation where appropriate.

[0388] Example 2: Hair Follicle Organ Culture Model: Immunohistochemistry & Immunohistomorphometry

[0354] Purpose: The purpose of this experiment is to determine whether olanzapine increases length primarily by enhancing matrix keratinocyte proliferation, reducing apoptosis, modulating dermal papilla signaling, and / or altering the timing of anagen-to-catagen transition.

[0389]

[0355] Methods: Human hair follicular unit biopsies are prepared, cultured, and treated (i.e., subjected to treatment with either topical olanzapine or control according to the described experimental design) as described in Example 1. Statistical analysis is also conducted as described in Example 1.

[0390]

[0356] Immunohistochemistry: Immunostaining was performed for one or more markers described herein, and microscope imaging and quantitative analysis are ongoing. For immunofluorescence staining, sections were air-dried for 10-20 min, fixed for 10 min in the fixative indicated below, washed for 15 min, and incubated in a combined blocking / permeabilization buffer (5% normal goat serum (NGS), 1% bovine serum albumin (BSA), and 0.3% Triton X-100 in PBS), followed by incubation with a primary antibody overnight at 4 °C where indicated below. After three 5-min washes in PBS, sections were incubated with a fluorescently tagged secondary antibody (Alexa Fluor 488 and / or Alexa Fluor 555; ~1 h, RT) and mounted in an antifade mounting medium containing DAPI (Sigma-Aldrich or Thermo Fisher Scientific). Primary-negative controls were performed by omitting the primary antibody.

[0391]

[0357] Ki-67. Fix: 4% paraformaldehyde (PFA) in PBS (RT, 10 min). Primary: mouse anti-Ki-67 (1 :50-1 :800; Cell Signaling Technology) or rabbit anti-Ki-67 (1 :50; Abeam). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1 :200-1 :500); goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :200).2025-12-29

[0358] Cleaved Caspase-3. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-cleaved caspase-3 (1:50-1:400; Cell Signaling Technology) or (1:75-1:300; R&D Systems). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400-1 :500).

[0392]

[0359] Versican. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-Versican (1:6.25; DSHB) or (1:100; Bio-Techne). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:500).

[0393]

[0360] TGF -2. Fix: cold methanol (-20 °C, 10 min) or 4% PFA in PBS (RT, 10 min). Primary: mouse anti-TGFfJ-2 (1:40-1:65; Bio-Techne) or rabbit anti-TGF0-2 (1:50-1:100; Abeam) or (1:100-1:200; ProteinTech). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1 :200) (mouse primaries); goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400) (rabbit primaries).

[0394]

[0361] Androgen Receptor (AR). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-AR (1:75-1:100; Abeam) or mouse anti-AR (1:50-1:500; Thermo Fisher Scientific). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :200-1 :500) (rabbit primaries); donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:1000) (mouse primaries).

[0395]

[0362] LEF1. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-LEF1 (1:100-1:200; Cell Signaling Technology) or (1:75-1:100; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 (1:400; Cell Signaling Technology) or (1 :200-1 :500; Abeam), or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400; Cell Signaling Technology) or (1 :200-1 :500; Abeam).

[0396]

[0363] a-SMA. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-a-SMA (1:50-1:200; Thermo Fisher Scientific). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 (1:400) or donkey anti-mouse IgG-Alexa Fluor 555 (1 :400-1 :500).

[0397]

[0364] AXIN2. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-AXIN2 (1:100; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400-1 :500).

[0398]

[0365] Phospho-S6 (p-S6). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-phospho-S6 (Ser235 / 236) (1 :200; Cell Signaling Technology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :200).

[0399]

[0366] CD34. Fix: cold acetone (-20 °C, 10 min) or 4% PFA in PBS (RT, 10 min). Primary: mouse anti-CD34 (1:50-1:100; Abeam) or (1:50-1:200; Thermo Fisher Scientific). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1 :400-1 :500).

[0400]

[0367] CD31. Fix: cold acetone (-20 °C, 10 min) or 4% PFA in PBS (RT, 10 min). Primary: mouse anti-CD31 (1 :50-1 : 100; Abeam). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:500).2025-12-29

[0368] MTC01. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-MTCO1 (1:100; Abeam). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:500).

[0401]

[0369] Keratin-15 (K15 I CK15). Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-CK15 (1 :200; Abeam). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:500).

[0402]

[0370] P-Catenin. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-0-Catenin (1:200; Thermo Fisher Scientific). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:500).

[0403]

[0371] LGR5. Fix: cold acetone (-20 °C, 10 min) or 4% PFA in PBS (RT, 10 min). Primary: mouse anti-LGR5 (1:100; Thermo Fisher Scientific). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1 :200).

[0404]

[0372] ESR1 (ERa). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-ERa (1:50-1:100; Thermo Fisher Scientific). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:400).

[0405]

[0373] ESR2 (ERp). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-ERp (1:50-1:100; Thermo Fisher Scientific). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:400).

[0406]

[0374] TNFa. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-TNFa (1:50-1:200; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400).

[0407]

[0375] PPARa. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-PPARa (1:100-1:200; Proteintech). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:1000).

[0408]

[0376] PPARy. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-PPARy (1 :50-1 :100; Santa Cruz Biotechnology). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:1000).

[0409]

[0377] Phospho-PDPK1 (p-PDPK1). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-p-PDPK1 (1:100-1:200; Bioss). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :200).

[0410]

[0378] Collagen 17A1 (COL17A1). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-COL17A1 (1:100-1:200; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:1000).

[0411]

[0379] ACTH. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-ACTH (1:50-1:100; Santa Cruz Biotechnology). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:1000).2025-12-29

[0380] NFATC1. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-NFATC1 (1:50-1:100; Santa Cruz Biotechnology). Secondary: donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400-1:1000).

[0412]

[0381] YAP. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-YAP (1:50-1:100; Cell Signaling Technology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:400).

[0413]

[0382] VDAC. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-VDAC (1 :50-1 :100; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400).

[0414]

[0383] FRA-1 I FOSL1. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-FRA-1 / FOSL1 (1:50-1:100; Thermo Fisher Scientific). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400).

[0415]

[0384] c-Fos. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-c-Fos (1:200-1:1600; Cell Signaling Technology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:1000).

[0416]

[0385] CTGF. Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-CTGF (1 :100-1 :200; Abeam). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400).

[0417]

[0386] RARy (RARG). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-RARy (1 : 100-1 :200; Cell Signaling Technology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400).

[0418]

[0387] RARa (RARA). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-RARa (1 : 100-1 :200; Cell Signaling Technology) or mouse anti-RARa (1:100-1:200; Santa Cruz Biotechnology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1 :400) (rabbit primaries); donkey anti-mouse IgG-Alexa Fluor 488 or donkey anti-mouse IgG-Alexa Fluor 555 (1:400) (mouse primaries).

[0419]

[0388] LXR (pan-LXR). Fix: 4% PFA in PBS (RT, 10 min). Primary: rabbit anti-pan-LXR (1:50-1:100; Santa Cruz Biotechnology). Secondary: goat anti-rabbit IgG-Alexa Fluor 488 or donkey anti-rabbit IgG-Alexa Fluor 555 (1:400-1:1000).

[0420]

[0389] Quantitative (Immuno-)Histomorphometrv and Microscopy: Images are being acquired using a BZ-X1000 all-in-one fluorescence microscope (Keyence Corporation) and its native imaging software at 10* and 20* magnification. Images will be analyzed using NIH Imaged (National Institutes of Health) within defined reference areas (indicated by dotted outlines in control images). Mean fluorescence intensity (MFI) will be measured per reference area. Imaged Cell Counter will be used to count single- and double-positive cells.

[0421] Example 3: Transcriptomic Profiling (RNA-Sequencing) in Human Hair Follicle Organ Culture2025-12-29

[0390] Purpose: To evaluate transcriptomic changes induced by topical olanzapine treatment in ex vivo human hair follicle organ culture, and to identify molecular pathways associated with increased hair shaft elongation and / or prolonged anagen.

[0422]

[0391] Methods: Hair follicular units are isolated from human scalp biopsies containing terminal follicles and acclimated in serum-free, supplemented William’s E medium. Follicles are randomly assigned to vehicle control or olanzapine treatment groups. In embodiments, olanzapine is administered at one or more concentrations selected from 0.1 pM, 1 piM, 5 pM, 10 pM, 20 pM, 50 pM, and 100 pM. In embodiments, olanzapine is formulated for topical delivery at one or more concentrations selected from 0.00001% to 5% (w / w) in a dermatologically acceptable vehicle. Medium is changed every other day, and follicles are imaged longitudinally to measure hair shaft elongation and to stage follicles by morphology (e.g., anagen, early-catagen, catagen).

[0423]

[0392] RNA-Sequencing: At a defined endpoint (e.g., Day 7), follicles are staged by morphology and snap-frozen for nucleic acid extraction. In embodiments, samples are processed as individual follicles, pooled follicles per condition, and / or microdissected compartments (e.g., follicular epithelium and dermal papilla) to obtain sufficient RNA yield. Total RNA is extracted and quality-controlled (e.g., RNA integrity metrics). Sequencing libraries are generated using poly(A) selection or rRNA depletion, and sequenced using paired-end reads to a depth sufficient for differential expression analysis.

[0424]

[0393] Bioinformatics and Analysis: Sequencing reads are quality-filtered and aligned to a human reference genome, and gene-level counts are generated using standard RNA-seq pipelines. Differential expression is evaluated between olanzapine-treated and vehicle-treated follicles. In embodiments, analyses are stratified by morphological stage (e.g., anagen versus early-catagen / catagen) and / or by growth response (e.g., high-elongation versus low-elongation follicles). Pathway and gene-set enrichment analyses are performed, including Gene Ontology, KEGG and / or Reactome, to identify pathways modulated by olanzapine treatment. In embodiments, selected transcripts are validated by qPCR or other orthogonal methods.

[0425]

[0394] Results: Based on the organ-culture length and staging phenotypes described herein, olanzapine-treated follicles are expected to demonstrate a transcriptomic signature consistent with a pro-growth state. In embodiments, olanzapine treatment is expected to increase expression of genes and / or pathways associated with keratinocyte proliferation, hair shaft formation and differentiation, follicular stem / progenitor activity, and extracellular matrix remodeling consistent with maintenance of anagen. In embodiments, olanzapine treatment is expected to decrease expression of genes and / or pathways associated with catagen initiation, apoptosis, and inflammatory signaling. In embodiments, transcriptomic signatures are expected to correlate with quantitative endpoints, including increased hair shaft elongation and increased probability of remaining in anagen during the culture period.2025-12-29

[0395] Example 4: Clinical Study Design for Assessing Efficacy of Disclosed Topical Olanzapine Compositions

[0426]

[0396] Purpose: To evaluate the efficacy and safety of topical olanzapine compositions for treating hair loss in human subjects, and to determine one or more dose levels and / or regimens that provide a clinically meaningful improvement in hair growth.

[0427]

[0397] Eligibility: Subjects undergo collection of medical history, concomitant medication review, and baseline scalp assessment In embodiments, eligible subjects include adults with androgenetic alopecia (e.g., Hamilton-Norwood II— V for men and / or Ludwig l-ll for women). In embodiments, subjects with known hypersensitivity to olanzapine or formulation components, or conditions that confound hair growth assessment, are excluded. In embodiments, subjects with clinically significant uncontrolled metabolic disease or other contraindications are excluded or monitored according to good clinical practice.

[0428]

[0398] Study design overview: In embodiments, the study is randomized, double-blind, and vehicle-controlled, with parallel arms. Subjects are assigned to vehicle control or to one or more olanzapine dose arms (e.g., 0.001%, 0.01%, 0.1%, 0.5%, or 1% w / w, or other concentrations described herein). Subjects self-administer the topical composition to affected scalp regions once daily or twice daily for a treatment period of 12 to 24 weeks. Standardized global photography, dermoscopy / trichoscopy, and / or phototrichogram measurements are performed at baseline and at predetermined follow-up visits (e.g., weeks 4, 8, 12, and 24).

[0429]

[0399] Endpoints: Primary endpoints include change from baseline in terminal hair density (hairs / cm2) and / or non-vellus hair density in target scalp regions. Secondary endpoints include change in hair shaft thickness, change in anagen / telogen ratio, investigator-rated improvement scores, subject self-assessment scores, and / or change in shedding metrics.

[0430]

[0400] Biomarkers and optional tissue assessments: In embodiments, a subset of subjects undergoes collection of tape strips, plucked hairs, and / or scalp punch biopsies at baseline and follow-up for molecular and histological analyses. Biomarkers may include proliferation and apoptosis markers, markers of follicular differentiation and stem / progenitor activity, extracellular matrix markers, angiogenic markers, inflammation markers, and pigmentation markers. These assessments may be used to corroborate mechanism of action and to identify responder subgroups.

[0431]

[0401] Safety monitoring: Safety assessments include adverse-event monitoring, local tolerability scoring (e.g., erythema, scaling, pruritus), and laboratory testing as appropriate. In embodiments, systemic exposure is evaluated by measuring plasma olanzapine concentrations at one or more visits. In embodiments, metabolic parameters (e.g., fasting glucose, HbA1c, and lipids) are monitored where clinically appropriate.

[0432]

[0402] Results: Based on ex vivo organ-culture data described herein, subjects receiving topical olanzapine are expected to exhibit increased hair density and / or increased hair shaft thickness relative to2025-12-29 vehicle control, with minimal systemic exposure. In embodiments, efficacy is expected to be dose-dependent, enabling selection of an optimal concentration and regimen that balances clinical benefit with local tolerability. In embodiments, the study may be expanded to additional cohorts, longer treatment durations, and / or combination regimens to determine the efficacy and safety of each dose of olanzapine.

[0433] Example 5: Individual Administration of Disclosed Topical Olanzapine Compositions for Treating Hair Loss

[0434]

[0403] Described herein are exemplary treatment protocols for treating hair loss by topical administration of olanzapine compositions. These protocols are provided for illustrative purposes and may be modified according to patient characteristics, scalp region affected, and clinical response.

[0435]

[0404] Patient 1: Androgenetic alopecia (male). Patient 1 is diagnosed with androgenetic alopecia and exhibits decreased hair density in the frontal scalp and vertex. Patient 1 self-administers a topical olanzapine composition (e.g., 0.01% to 0.5% w / w) once daily to the affected scalp for 24 weeks. Hair density and hair shaft diameter are measured at baseline and at weeks 8, 12, and 24. Patient 1 is expected to show increased terminal hair density and / or increased shaft thickness relative to baseline and relative to a vehicle-treated control population.

[0436]

[0405] Patient 2: Female pattern hair loss. Patient 2 is diagnosed with female pattern hair loss with diffuse crown thinning. Patient 2 self-administers a topical olanzapine composition (e.g., 0.001% to 0.1% w / w) once daily for 24 weeks. Patient 2 is monitored for scalp tolerability. Patient 2 is expected to show reduced shedding and improved hair density over the treatment period.

[0437]

[0406] Patient 3: Alopecia areata. Patient 3 is diagnosed with patchy alopecia areata. Patient 3 self-administers a topical olanzapine composition to affected patches once daily or twice daily for 12 to 24 weeks. In embodiments, the composition is used alone or in combination with standard-of-care therapies. Patient 3 is expected to show partial or complete regrowth within treated patches and improved follicular activity by trichoscopy.

[0438]

[0407] Patient 4: Telogen effluvium. Patient 4 presents with increased hair shedding following a physiological stressor. Patient 4 self-administers a topical olanzapine composition (e.g., 0.001% to 0.1% w / w) once daily for 12 to 16 weeks. Patient 4 is expected to show decreased shedding and a return toward baseline anagen / telogen balance.

[0439]

[0408] In embodiments, responders are identified based on early changes in hair density, shaft thickness, and / or biomarker readouts, and treatment may be continued, tapered to a maintenance regimen, or adjusted in concentration. In embodiments, systemic exposure is monitored in patients at higher risk for adverse effects, and dosing is modified accordingly to maintain a favorable safety profile for topical administration.

[0440] Example 6: Follicular Deposition of Olanzapine from Lipid Particle Compositions2025-12-29

[0409] Purpose: To quantify follicular deposition and retention of olanzapine delivered from lipid particle formulations, including solid lipid nanoparticles and nanostructured lipid carriers, under finite dose topical application conditions.

[0441]

[0410] Methods: A follicular deposition study is performed using human scalp skin or porcine ear skin mounted in diffusion cells. A finite topical dose of each formulation is applied to the stratum corneum surface, and receptor fluid is sampled over time to assess permeation. After a predetermined exposure period, skin is processed to quantify compartmental distribution of olanzapine.

[0442]

[0411] Lipid particle formulations: In embodiments, olanzapine is formulated as a solid lipid nanoparticle (SLN) or nanostructured lipid carrier (NLC) dispersion. In embodiments, the lipid phase is 0.1% to 20% w / w and comprises one or more saturated lipids and / or a blend of solid and liquid lipids, and a surfactant is included at 0.1% to 10% w / w. In embodiments, the particle size is 50 nm to 500 nm. In embodiments, the formulation further comprises a lipid phase antioxidant and is prepared and stored with oxygen and light minimization.

[0443]

[0412] Non-limiting exemplary formulation: An NLC formulation comprises olanzapine at 0.001% to 1% w / w, a solid lipid and liquid lipid blend at 1% to 10% w / w, a surfactant system at 0.5% to 5% w / w, and water q.s. In embodiments, the formulation is prepared by hot homogenization and / or sonication to yield submicron particles, followed by cooling to form a stable dispersion.

[0444]

[0413] Comparators and alternative embodiments: In embodiments, additional formulations are assessed as comparators or alternative embodiments, including nanoemulsions and liposomal formulations. In embodiments, a nanoemulsion comprises an oil phase at 1% to 30% w / w and a surfactant and / or co surfactant system at 5% to 60% w / w, and has a droplet size of 20 nm to 300 nm. In embodiments, a liposomal formulation comprises a phospholipid at 0.1% to 10% w / w and optional cholesterol at 0% to 5% w / w, and has a vesicle size of 50 nm to 300 nm.

[0445]

[0414] Tissue processing and analysis: In embodiments, the stratum corneum is removed by tape stripping, follicular contents are recovered by follicular casting and / or cyanoacrylate stripping, and remaining tissue is separated into epidermis and dermis. Olanzapine levels are quantified in each compartment by LC MS or LC MS MS. In embodiments, lipid particle formulations are assessed for increased follicular deposition relative to a non particulate formulation, as measured by increased olanzapine content in the follicular fraction.

[0446]

[0415] Results: Lipid particle formulations are expected to provide increased deposition of olanzapine in the follicular fraction and / or sustained local retention relative to non particulate formulations, supporting use for topical treatment of hair loss.

[0447]

[0416] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific2025-12-29 embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise compositions, formulations, methods, or the like disclosed; many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

2025-12-29CLAIMSThe invention claimed is:

1. A topical composition for treating or preventing hair loss, comprising olanzapine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle.

2. The topical composition of claim 1 , comprising the olanzapine at a concentration of between about 0.1 piM and about 5 mM.

3. The topical composition of claim 2, comprising the olanzapine at a concentration of between about 0.1 pM and about 500 pM.

4. The topical composition of claim 3, comprising the olanzapine at a concentration of between about 1 pM and about 100 pM.

5. The topical composition of claim 4, comprising the olanzapine at a concentration of between about 1 pM and about 50 pM.

6. The topical composition of claim 5, comprising the olanzapine at a concentration of between about 20 pM and about 50 pM.

7. The topical composition of claim 1 , wherein the topical delivery vehicle comprises a solvent system.

8. The topical composition of claim 7, wherein the solvent system comprises any one or more solvents selected from the group consisting of polar aprotic solvents, water, alcohols, oils, and silicones.

9. The topical composition of claim 8, comprising a polar aprotic solvent.

10. The topical composition of claim 8, comprising one or more alcohols.

11. The topical composition of claim 10, wherein the one or more alcohols are selected from the group consisting of ethanol, isopropanol, glycerin, butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, and diglycerin.

12. The topical composition of claim 8, comprising one or more oils.

13. The topical composition of claim 12, wherein the one or more oils are selected from the group consisting of fatty alcohols, fatty acids, waxes, triglycerides, hydrogenated oils, vegetable oils, mineral oil, squalane, isopropyl myristate, and esters thereof.

14. The topical composition of claim 8, comprising one or more silicones.

15. The topical composition of claim 14, wherein the one or more silicones are selected from the group consisting of cyclomethicone, cyclopentasiloxane, cyclohexasiloxane, dimethicone, dimethiconol, and phenyltrimethicone.

16. The topical composition of claim 1 , wherein the topical delivery vehicle comprises one or more pharmaceutically acceptable excipients.2025-12-29 17. The topical composition of claim 16, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, viscosity modifying agents, adhesion modifying agents, preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, or gelling agents.

18. The topical composition of claim 1 , wherein the topical delivery vehicle is a hydroalcoholic solution or gel, an aqueous gel, an aqueous solution, an anhydrous solution or gel, an emulsion, a microemulsion, a nanoemulsion, a solid lipid nanoparticle, a nanostructured lipid carrier, an ethosome, a transethosome, a silicone composition, a foam, a film-forming composition, an aqueous cyclodextrin inclusion system, or a depot vehicle.

19. The topical composition of claim 18, wherein the topical delivery vehicle is selected from the group consisting of:i. an anhydrous solution or gel comprising: one or more polar aprotic solvents; and optionally, one or more pharmaceutically acceptable excipients.ii. a hydroalcoholic solution or gel comprising: water; one or more alcohols; and optionally, one or more pharmaceutically acceptable excipients;ill. an aqueous gel comprising: water; a humectant; a gelling agent; optionally, a buffering agent; and optionally, a solubilizing agent;iv. an emulsion comprising: water; one or more oils; and one or more emulsifiers;v. a microemulsion or nanoemulsion comprising: water; one or more additional solvents; one or more oils; and one or more surfactants;vi. a solid lipid nanoparticle or nanostructured lipid carrier comprising: one or more lipids; one or more surfactants; and optionally one or more antioxidants;vii. an ethosome or transethosome comprising lipid vesicles;viii. an aqueous solution comprising one or more mineral salts or phytocomplexes;ix. an aqueous cyclodextrin inclusion system comprising water and one or more cyclodextrins; orx. a silicone composition comprising a silicone and one or more solvents.

20. The topical composition of claim 19, wherein the anhydrous solution or gel comprises propylene carbonate and dimethyl isosorbide.

21. The topical composition of claim 1 , wherein the topical delivery vehicle is selected from the group consisting of an anhydrous polar cosolvent liquid, an oil-dominant anhydrous liquid, a non-aqueous soft nanosuspension, an aqueous cyclodextrin inclusion system, a liposomal or lipid-vesicle dispersion, a hydroalcoholic solution or gel, an aqueous gel, an emulsion, a microemulsion or nanoemulsion, solid lipid nanoparticles or nanostructured lipid carriers, ethosomes or2025-12-29 transethosomes, niosomes, a commercial or proprietary topical base, a foam or foamable scalp vehicle, an anhydrous organogel or structured oil, a micellar solution, deformable liposomes, liquid-crystalline lipid nanoparticles, a wash-off scalp vehicle, biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, an aqueous drug nanocrystal or nanosuspension, an ointment or pomade scalp vehicle, a solid stick or wax-stick applicator, a patch, laminate, or strip sustained-release scalp system, a microneedle-enabled scalp delivery system, microencapsulation systems, polymer-coated or layer-by-layer vesicles, an ionic-liquid or deep-eutectic-solvent carrier system, silicone-based topical compositions, film-forming topical compositions, depot or sustained-release topical vehicles, foam or mousse formulations, and combination or hybrid vehicle systems.

22. The topical composition of claim 1 , further comprising an additional active agent.

23. The topical composition of claim 22, wherein the additional active agent is an amino acid, antioxidant, peptide, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, peptidase inhibitor, hormone, vitamin, vasodilator, or vasoconstrictor.

24. The topical composition of claim 22, wherein the additional active agent is triiodothyronine, finasteride, dutasteride, minoxidil, naltrexone, farnesol, thyrotropin-releasing hormone, or doxycycline.

25. The topical composition of claim 1 , formulated as a spray, ointment, salve, gel, paste, lotion, liniment, or cream.

26. The topical composition of claim 1 , in unit dosage form.

27. The topical composition of claim 1 , for treating hair loss.

28. The topical composition of claim 1 , for preventing hair loss.

29. The topical composition of claim 1 , for administering daily.

30. The topical composition of claim 1 , wherein administration of the composition to a subject increases hair shaft production in the subject.

31. The topical composition of claim 1 , wherein administration of the composition to a subject prolongs the anagen hair growth phase in the subject.

32. The topical composition of any of claims 1-31 , wherein the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia, traction alopecia, alopecia barbae, or postpartum alopecia.2025-12-29 33. A composition comprising a substituted diazepine, or a pharmaceutically acceptable salt thereof;wherein the composition is formulated for topical administration, or wherein the composition is formulated according to any of claims 1-32.

34. The composition of claim 33, for treating or preventing hair graying.

35. The composition of claim 33, for treating or preventing a dermatological condition.

36. The composition of claim 35, wherein the dermatological condition is a skin condition.

37. The composition of claim 36, wherein the skin condition is an epidermal disease, dermal disease, epidermal appendage disease, or subcutaneous tissue disease.

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