Topical compositions of tetracyclines 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 tetracycline, for example doxycycline. 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 TETRACYCLINES 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 / 739,598, filed December 29, 2024, and incorporated by reference for all purposes as if fully set forth herein.

[0007] FIELD OF THE INVENTION

[0008]

[0002] The present disclosure relates in some aspects to pharmaceutical compositions useful for treating or preventing hair loss, hair graying, and dermatological conditions in a subject, such as comprising a tetracycline. Also disclosed are kits comprising the compositions, and methods of their use for treating or preventing hair loss, hair graying, 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 admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art.2025-12-29

[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 doxycycline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, the composition comprises the doxycycline 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: i. an anhydrous solution or gel comprising: one or more polar aprotic solvents; and optionally, one or more pharmaceutically acceptable excipients.2025-12-29 ii. a hydroalcoholic solution or gel comprising: water; one or more alcohols; and optionally, one or more pharmaceutically acceptable excipients;

[0021] iii. an aqueous gel comprising: water; a humectant; a gelling agent; optionally, a buffering agent; and optionally, a solubilizing agent;

[0022] iv. an emulsion comprising: water; one or more oils; and one or more emulsifiers;

[0023] v. a microemulsion or nanoemulsion comprising: water; one or more additional solvents; one or more oils; and one or more surfactants;

[0024] vi. a solid lipid nanoparticle or nanostructured lipid carrier comprising: one or more lipids; one or more surfactants; and optionally one or more antioxidants;

[0025] vii. an ethosome or transethosome comprising liposomes;

[0026] viii. an aqueous solution comprising one or more mineral salts or phytocomplexes;

[0027] ix. an aqueous cyclodextrin inclusion system comprising water and one or more cyclodextrins; or

[0028] x. a silicone composition comprising a silicone and one or more solvents.

[0029]

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

[0030]

[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.

[0031]

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

[0032]

[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 be2025-12-29 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] BRIEF DESCRIPTION OF THE FIGURES

[0035]

[0017] To further clarify various aspects of the invention, a more particular description is rendered by reference to certain exemplary embodiments illustrated in the figures. It will be appreciated that these figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[0036]

[0018] FIG. 1 shows library size per sample for the RNA-seq dataset;

[0037]

[0019] FIG. 2 shows a principal component analysis (PCA) of RNA-seq samples to assess sample clustering and identify outliers;

[0038]

[0020] FIG. 3 shows a volcano plot of differentially expressed genes for doxycycline compared with control;

[0039]

[0021] FIG. 4 shows KEGG pathway enrichment for doxycycline compared with control;

[0040]

[0022] FIG. 5 shows a volcano plot of differentially expressed genes for the Farnesol + Doxycycline combination compared with control; and

[0041]

[0023] FIG. 6 shows KEGG pathway enrichment for the Farnesol + Doxycycline combination compared with control.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043]

[0024] 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.

[0044]

[0025] 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 as2025-12-29 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.

[0045]

[0026] 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 otherwise 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.

[0046]

[0027] 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.

[0047]

[0028] 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.

[0048]

[0029] 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.2025-12-29 A. General Definitions and Terms

[0049]

[0030] 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.

[0050]

[0031] 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.

[0051]

[0032] 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 referred to simply as a “composition," and other such shorthand terms will be readily appreciated in view of the disclosure.

[0052]

[0033] Unless context indicates a distinction relevant to a described or claimed embodiment, “composition” and “formulation” are used interchangeably and equivalently herein.

[0053]

[0034] “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.”

[0054]

[0035] 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."

[0055]

[0036] 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 some embodiments, “about” refers to plus or minus one percent (±1%) of the recited unit of measure. In some embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In some embodiments, “about" refers to plus or minus ten percent (±10%) of the recited unit of measure.

[0056]

[0037] 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%.2025-12-29

[0038] 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.”

[0057]

[0039] In some 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.

[0058]

[0040] 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.”

[0059]

[0041] 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.

[0060]

[0042] 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.

[0061]

[0043] Further definitions follow, to assist a reader in understanding the embodiments.

[0062]

[0044] “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.

[0063]

[0045] “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 with2025-12-29 a condition from occurring in a subject; or (c) delays the onset of one or more symptoms or pathologies associated with a condition.

[0064]

[0046] 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.

[0065]

[0047] 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, the 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.

[0066]

[0048] “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 in the art.

[0067]

[0049] 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 some 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.

[0068]

[0050] Still additional definitions and abbreviations are provided elsewhere herein.

[0069] B. Pharmaceutical Compositions

[0070]

[0051] The present disclosure relates in some aspects to compositions, such as pharmaceutical compositions, useful for treating hair loss and dermatological conditions.

[0071]

[0052] “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.”

[0072]

[0053] 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 tetracycline, for administration to an animal, such as a2025-12-29 human. In some embodiments, a composition comprises a disclosed compound, such as a tetracycline, together with a, preferably pharmaceutically acceptable, carrier, diluent, or excipient.

[0073]

[0054] 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 some 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.”

[0074]

[0055] In some 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, or 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 some embodiments, a disclosed compound, such as a tetracycline, may be administered without an excipient, or without a specific disclosed excipient, such as without hydroxypropyl cellulose or without another hydroxyalkylcellulose.

[0075]

[0056] 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).

[0076]

[0057] 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.

[0077]

[0058] In one aspect, provided is a composition comprising a therapeutically effective amount of tetracycline.

[0078]

[0059] In another aspect, provided is a topical composition comprising: a tetracycline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, a composition comprises: (i) a tetracycline; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In embodiments, a composition comprises doxycycline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle. In embodiments, a composition comprises: (i) doxycycline, or a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable excipients and / or one or more solvents.

[0079]

[0060] In some embodiments, the composition comprises (i) a tetracycline, (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the composition contains tetracycline as the only active ingredient. Hence, also provided is a composition comprising: (i) a tetracycline as the only active ingredient; and (ii) a pharmaceutically acceptable excipient. In some embodiments, the composition comprises: (i) a tetracycline as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the composition2025-12-29 consists essentially of: (I) a tetracycline; and (ii) a pharmaceutically acceptable excipient. In some embodiments, the composition consists essentially of: (I) a tetracycline; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0080]

[0061] In some embodiments, the composition comprises (i) doxycycline, (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the composition contains doxycycline as the only active ingredient. Hence, also provided is a composition comprising: (i) doxycycline as the only active ingredient; and (ii) a pharmaceutically acceptable excipient. In some embodiments, the composition comprises: (i) doxycycline as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the composition consists essentially of: (i) doxycycline; and (ii) a pharmaceutically acceptable excipient. In some embodiments, the composition consists essentially of: (i) doxycycline; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0081]

[0062] In some embodiments, a disclosed composition is for treating hair loss. In some embodiments, a disclosed composition is for preventing hair loss.

[0082]

[0063] In some embodiments, a disclosed composition is for treating hair graying. In some embodiments, a disclosed composition is for preventing hair graying.

[0083]

[0064] In some embodiments, a disclosed composition is for treating a dermatological condition. In some embodiments, a disclosed composition is for preventing a dermatological condition.

[0084] a. Tetracyclines

[0085]

[0065] In some embodiments, a disclosed composition comprises a tetracycline. A “tetracycline” is a compound comprising the following fused tetracyclic (naphthacene) core structure:

[0086]

[0087] wherein each ring of the naphthacene core may be fully unsaturated, partially unsaturated, or fully saturated; and wherein each available carbon vertex may be optionally substituted.

[0088]

[0066] “Optionally substituted” means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and2025-12-29 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group. These and other substituents are known to those of skill in the art.

[0089]

[0067] A comprehensive list of abbreviations utilized by organic chemists of ordinary skill is in the first issue of each volume of the Journal of Organic Chemistry, typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is incorporated by reference as if fully set forth herein.

[0090]

[0068] Tetracyclines include first-generation “classic” tetracyclines (i.e., naturally occurring tetracyclines produced by certain Streptomyces species, such as tetracycline, oxytetracycline, and chlortetracycline), second-generation tetracyclines (i.e., semi-synthetic derivatives of the first-generation tetracyclines, such as doxycycline and minocycline), and third-generation tetracyclines (e.g., tigecycline, omadacycline, eravacycline), each of which is known to those of skill in the art. As will be known to those of skill in the art, these “generations” are generally defined by structural modifications to the tetracyclic scaffold, such as the addition, removal, or rearrangement of functional groups.

[0091]

[0069] Tetracyclines also include synthesized and semi-synthesized derivatives of each of the foregoing. Such derivatives include compounds derived (e.g., synthesized) from a tetracycline as the starting material, such as by the modification, addition, or subtraction of one or more functional groups, atoms, or moieties. For example, derivatives may involve substitutions at the C4, C5, C6, C7, C9, C10, C11 , or C12 positions, such as dehydroxylation at C6 (e.g., doxycycline), dimethylamino substitutions at C4 (e.g., minocycline), or glycylamido substitutions at C9 (e.g., tigecycline). Other modifications may include the replacement of functional groups with other substituents (e.g., alkyl, alkoxy, halogen, amino).

[0092]

[0070] Tetracyclines also include compounds not synthesized from a tetracycline as the starting material but whose structures include an optionally substituted naphthacene.

[0093]

[0071] In some embodiments, the tetracycline is doxycycline, tetracycline, minocycline, tigecycline, lymecycline, demeclocycline, sarecycline, omadacycline, eravacycline, 4-dedimethylaminosancycline, chlortetracycline, oxytetracycline, methacycline, or rolitetracycline.

[0094]

[0072] In some embodiments, the tetracycline is doxycycline. Doxycycline (also marketed and sold using the tradenames DOXY®, DORYX®, VIBRAMYCIN®, and others) is a semisynthetic tetracycline that has broad-spectrum antibacterial activity. Doxycycline is primarily used in infectious disease treatment, but also demonstrates anti-inflammatory and immunomodulatory effects, including inhibiting MMPs that break down extracellular matrix components. Doxycycline has the IUPAC name2025-12-29 (4S,4aR,5S,5aR,6R,12aR)-4-(dimethylamino)-1 ,5,10,11 ,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-t etrahydro-4H-tetracene-2-carboxamide, and the chemical structure:

[0095]

[0096]

[0073] Tetracyclines may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The invention includes all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)-and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art. Examples of methods that can be used to obtain optical isomers of tetracyclines include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography). Likewise, tautomeric forms are included.

[0097]

[0074] When the tetracycline contains olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the tetracyclines include both E and Z geometric isomers.

[0098]

[0075] The disclosure therefore includes all possible isomers (e.g., geometric isomers, structural isomers) of doxycycline, including all possible combinations of the 4R, 4S, 4aR, 4aS, 5R, 5S, 5aR, 5aS, 6R, 6S, 12aR, and 12aS isomers, including mixtures thereof. In some embodiments, a composition comprises only a single isomer of doxycycline. In some embodiments, a composition comprises two or more isomers of doxycycline.

[0099]

[0076] In some embodiments, the tetracycline is provided as a salt. Herein, unless context clearly demands otherwise, a “tetracycline” or reference to any particular tetracycline, such as doxycycline, will be understood to include its salts.

[0100]

[0077] A tetracycline salt includes any salt prepared from a non-toxic acid or base, such as synthesized by conventional chemical methods. Generally, a tetracycline salt can be prepared by reacting the free acid or base forms of the tetracycline 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 available2025-12-29 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.

[0101]

[0078] 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, hydroxybenzoate, 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, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, 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).

[0102]

[0079] A tetracycline can exist in solid or liquid form. In a solid form, a tetracycline may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates. For example, where a composition comprises doxycycline, the doxycycline may be a solvate or hydrate, including a salt of a solvate or hydrate. In some embodiments, the doxycycline is doxycycline hyclate (e.g., doxycycline2025-12-29 hydrochloride hemiethanolate hemihydrate). In some embodiments, the doxycycline is doxycycline monohydrate, or a salt thereof.

[0103]

[0080] The skilled artisan will further appreciate that certain tetracyclines described herein that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The subject matter disclosed herein includes such polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0104] b. Formulations and Excipients

[0105]

[0081] In some embodiments, the composition is suitable for topical or transdermal administration. In some embodiments, the composition is formulated for topical administration. In some embodiments, the composition is formulated for transdermal administration. In some embodiments, the composition suitable for topical or transdermal administration comprises a pharmaceutically acceptable excipient.

[0106]

[0082] In some 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.

[0107]

[0083] 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.2025-12-29

[0084] 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.

[0108]

[0085] In another aspect, provided is a topical composition comprising: (i) a tetracycline; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0109]

[0086] In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.01 pM and 40 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 40 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.01 pM and 30 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 30 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.01 pM and 20 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 20 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.01 pM and 10 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 10 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.01 pM and 2 mM. In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 1 mM.

[0110]

[0087] In some embodiments, the composition comprises a tetracycline at a concentration of between about 0.1 pM and 400 pM. In some embodiments, the composition comprises the tetracycline at a concentration between about 0.1 pM and 400 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, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, 200 pM, 210 pM, 220 pM, 230 pM, 240 pM, 250 pM, 260 pM, 270 pM, 280 pM, 290 pM, 300 pM, 310 pM, 320 pM, 330 pM, 340 pM, 350 pM, 360 pM, 370 pM, 380 pM,2025-12-29 390 pM, and 400 pM, including amounts and open- and closed-ended ranges between these concentrations.

[0111]

[0088] In some embodiments, the composition comprises a tetracycline at a concentration of less than about 0.1 pM (including concentrations between about 1 nM and 0.1 pM, about 20 nM and about 0.1 iM, and about 50 nM and about 0.1 pM). In some embodiments, the composition comprises a tetracycline at a concentration of greater than about 400 pM (including concentrations between about 400 pM and about 1 mM, about 400 pM and about 10 mM, and about 400 pM and about 100 mM). In some embodiments, the composition comprises a tetracycline at a concentration of about 1 pM. In some embodiments, the composition comprises a tetracycline at a concentration of about 10 pM. In some embodiments, the composition comprises a tetracycline at a concentration of about 40 pM.

[0112]

[0089] In embodiments, wherein a composition comprises doxycycline or a pharmaceutically acceptable salt thereof (e.g., doxycycline hyclate), the concentration of doxycycline in the composition is between about 0.00004 mg / mL and about 2.6 mg / mL. In embodiments, the concentration of doxycycline is between about 0.00005 mg / mL and about 2.5 mg / mL. In embodiments, the concentration of doxycycline is between about 0.0001 mg / mL and about 2.0 mg / mL. In embodiments, the concentration of doxycycline is between about 0.001 mg / mL and about 1.0 mg / mL. In embodiments, the concentration of doxycycline is between about 0.01 mg / mL and about 0.5 mg / mL. In embodiments, the concentration of doxycycline is between about 0.05 mg / mL and about 0.3 mg / mL. In embodiments, the concentration of doxycycline is about 0.1 mg / mL. In embodiments, the concentration of doxycycline is about 0.2 mg / mL. In embodiments, the concentration of doxycycline is about 0.25 mg / mL.

[0113]

[0090] In embodiments, the concentration of doxycycline is expressed as a weight / volume percentage and is between about 0.000004% (w / v) and about 0.26% (w / v), between about 0.000005% (w / v) and about 0.25% (w / v), or between about 0.001% (w / v) and about 0.05% (w / v). In embodiments, the doxycycline is doxycycline hyclate, and the concentration corresponding to about 100 nM to about 5 mM is between about 0.051 pg / mL and about 2.565 mg / mL. In embodiments, the doxycycline is doxycycline free base, and the concentration corresponding to about 100 nM to about 5 mM is between about 0.044 pg / mL and about 2.22 mg / mL. In embodiments, the composition comprises doxycycline at any individual concentration recited herein, as well as any open-ended or closed-ended subrange formed therefrom.

[0114]

[0091] In some 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, solubilizing agents, colorants,2025-12-29 binders, humectants, surfactants, gelling agents, and other such ingredients generally known to one of skill.

[0115]

[0092] “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.

[0116]

[0093] 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.

[0117]

[0094] In some 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.

[0118]

[0095] In some 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 some embodiments, including a penetration enhancer in the composition increases the bioavailability of the active agent(s) by improving the ability of the active 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 (MOT), 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.

[0119]

[0096] 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, sodium2025-12-29 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).

[0120]

[0097] In some 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 some 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 some 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.

[0121]

[0098] 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, 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).

[0122]

[0099] 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, magnesium2025-12-29 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).

[0123]

[0100] In some 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).

[0124]

[0101] In some 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;

[0125]

[0102] In some 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., p-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,2025-12-29 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). 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).

[0126]

[0103] 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).

[0127]

[0104] In some 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).2025-12-29

[0105] In some embodiments, the composition comprises a cosmetically and / or dermo-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).

[0128]

[0106] 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 from 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).

[0129]

[0107] In some 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 some embodiments, the composition comprises hydroxymethylcellulose. In some2025-12-29 embodiments, the composition comprises hydroxyethylcellulose. In some embodiments, the composition comprises hydroxypropylcellulose.

[0130]

[0108] In some 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 some 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 some 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 some 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).

[0131]

[0109] 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.

[0132]

[0110] 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).

[0133]

[0111] 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.

[0134]

[0112] In some embodiments, the composition comprises a viscosity modifying agent. In some embodiments, the viscosity modifying agent is a thickener. Common thickeners include acrylates,2025-12-29 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 some 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 some 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).

[0135]

[0113] 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 some embodiments, a disclosed composition comprises between about 1% (w / v) and about 10% (w / v) of hydroxypropylcellulose. In some embodiments, a disclosed composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (w / v) of hydroxypropylcellulose. In some embodiments, a disclosed composition comprises about 2% (w / v) of hydroxypropylcellulose. In some 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 some 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.2025-12-29

[0114] In some embodiments, the composition comprises an adhesion modifying agent. In some embodiments, the composition comprises an adhesive polymer. Adhesive polymers have physicochemical properties that allow prolonged binding to tissue surfaces. In some 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, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In some 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).

[0136]

[0115] In some 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).

[0137]

[0116] In some 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 some 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).

[0138]

[0117] 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 solubilizing2025-12-29 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).

[0139]

[0118] In some 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).

[0140]

[0119] In some embodiments, the composition comprises a binder. Binders include polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starches, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, 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).

[0141]

[0120] In some 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 more 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).

[0142]

[0121] In some embodiments, the composition comprises a surfactant. Surfactants include anionic, nonionic, and amphoteric compounds. Anionic surfactants include, for example, higher alkyl2025-12-29 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 some 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).

[0143]

[0122] In some 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 some embodiments, a pectin is a amidated pectin, non-amidated pectin, high methoxyl pectin, low methoxyl pectin, or a combination thereof. In some 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).

[0144]

[0123] 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.

[0145]

[0124] In some 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.

[0146]

[0125] 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 the2025-12-29 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.

[0147]

[0126] In some embodiments, the composition comprises liposomes. In some embodiments, the composition comprises liposomes, wherein the active agent(s) (e.g., a tetracycline 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.

[0148]

[0127] 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.

[0149]

[0128] 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).

[0150]

[0129] In some 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., distearoylphosphatidylethanolamine-PEG, dipalmitoylphosphatidylethanolamine-PEG) and functionalized polymers (e.g., PEG-amine, PEG-maleimide).

[0151]

[0130] 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,

[0152]

[0131] 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 (Pick2025-12-29 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.

[0153] 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.

[0154] c. Topical Delivery Vehicles

[0155]

[0132] In embodiments, a composition comprises doxycycline and a topical delivery vehicle.

[0156]

[0133] In embodiments, a topical composition comprises doxycycline or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., doxycycline hyclate) in an amount of between about 0.000001% and about 10% by weight of the composition. In embodiments, the composition further comprises water in an amount of between about 0% and about 90% by weight, depending on the vehicle family, wherein anhydrous or low-water vehicles comprise no more than about 10%, 5%, or 1% water by weight. In embodiments where water is present, the composition has a pH of between about 4.0 and about 7.5, including between about 5.0 and about 6.5.

[0157]

[0134] In embodiments, the composition further comprises one or more chelating agents (e.g., EDTA) in an amount of between about 0% and about 0.1% by weight, particularly in aqueous or hydroalcoholic systems. In embodiments, the composition further comprises one or more antioxidants (e.g., a-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate) in an amount of between about 0% and about 1% by weight, particularly in anhydrous or lipid-containing systems. In embodiments, the composition further comprises one or more preservatives, particularly in aqueous systems, in an amount of between about 0% and about 2% by weight. In embodiments, the composition is formulated to minimize water activity and / or oxidative degradation pathways while maintaining scalp compatibility and follicular delivery.

[0158]

[0135] In embodiments, the topical delivery vehicle is selected from one or more scalp-compatible vehicle families described herein, including an anhydrous structured oil oroleogel, a silicone-based carrier or silicone elastomer matrix, an in-situ gelling liquid-crystal precursor system, a solid lipid nanoparticle or nanostructured lipid carrier system, an anhydrous polar cosolvent serum, a deep eutectic solvent system, an aqueous cyclodextrin inclusion system, a proniosomal gel, an ethosomal or transethosomal vesicular dispersion, a liposomal dispersion, a self-emulsifying drug delivery system, a reverse lecithin organogel, a film-forming spray, an anhydrous foam or thermolabile melting balm, a bigel or emulgel hybrid system, a nanoemulsion or microemulsion, a polymeric nanogel, biodegradable microspheres, a hydroalcoholic solution or gel, an aqueous gel, an emulsion, a non-aqueous nanosuspension, a commercial or proprietary topical base, a foam or foamable scalp vehicle, a micellar solution, deformable liposomes including transfersomes or invasomes, a wash-off scalp vehicle, biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, an aqueous drug nanocrystal or nanosuspension, a solid stick or2025-12-29 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, or combinations or hybrid systems thereof.

[0159]

[0136] Exemplary Vehicle 1 : Anhydrous structured oil or oleogel

[0160]

[0137] In one example, a topical delivery vehicle is an anhydrous structured oil or oleogel comprising a hydrophobic liquid phase structured into a semi-solid or gel-like form. In embodiments, the vehicle is substantially anhydrous and comprises an oil phase (e.g., squalane, medium-chain triglycerides, caprylic / capric triglycerides, hydrogenated polyisobutene, isopropyl myristate, silicone oils, combinations thereof) in an amount of between about 60% and about 99% by weight of the composition.

[0161]

[0138] In embodiments, the vehicle further comprises one or more structurants or oleogelators (e.g., fumed silica, waxes, hydrogenated castor oil, fatty alcohols, glyceryl behenate, combinations thereof) in an amount of between about 0.5% and about 20% by weight of the composition, sufficient to impart a non-flowing or shear-thinning gel consistency while maintaining an anhydrous continuous phase.

[0162]

[0139] In embodiments, the vehicle further comprises one or more polar solubilizing agents or cosolvents (e.g., dimethyl isosorbide, triacetin, triethyl citrate, propylene carbonate, diethylene glycol monoethyl ether, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the polar solubilizing agent facilitates incorporation of doxycycline and / or a pharmaceutically acceptable salt thereof into the anhydrous matrix.

[0163]

[0140] In embodiments, the vehicle further comprises one or more lipophilic antioxidants in an amount of between about 0% and about 1% by weight of the composition. In embodiments, doxycycline is dissolved, dispersed, or molecularly distributed within the structured oil or oleogel, and the vehicle is formulated to provide prolonged residence time on the scalp and controlled release of doxycycline to follicular structures following topical application.

[0164]

[0141] Exemplary Vehicle 2: Silicone-based carrier or silicone elastomer matrix

[0165]

[0142] In another example, a topical delivery vehicle is a silicone-based carrier or silicone elastomer matrix comprising one or more volatile and / or non-volatile silicones. In embodiments, the vehicle comprises one or more volatile silicones (e.g., cyclomethicone, isododecane, combinations thereof) in an amount of between about 0% and about 80% by weight of the composition and one or more non-volatile silicones (e.g., dimethicone, phenyltrimethicone, combinations thereof) in an amount of between about 0% and about 70% by weight of the composition.

[0166]

[0143] In embodiments, the vehicle further comprises a silicone elastomer or crosslinked silicone network (e.g., dimethicone crosspolymer) in an amount of between about 0% and about 30% by weight of the composition, providing a gel-like, dry-touch, or semi-solid consistency suitable for scalp application.

[0167]

[0144] In embodiments, the vehicle further comprises one or more polar solubilizing agents and / or cosolvents compatible with silicone systems (e.g., dimethyl isosorbide, triacetin, triethyl citrate,2025-12-29 diethylene glycol monoethyl ether, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the polar solubilizing agent facilitates incorporation of doxycycline and / or a pharmaceutically acceptable salt thereof into the silicone matrix.

[0168]

[0145] In embodiments, the vehicle further comprises one or more antioxidants in amounts suitable for silicone-based formulations. In embodiments, doxycycline is dissolved or dispersed within the silicone-based carrier or elastomer matrix, and the vehicle is formulated to provide rapid spreading, reduced greasiness, and controlled release of doxycycline to the scalp and follicular structures.

[0169]

[0146] Exemplary Vehicle 3: Anhydrous polar cosolvent serum

[0170]

[0147] In another example, a topical delivery vehicle is an anhydrous polar cosolvent serum comprising one or more polar solubilizing agents and, optionally, a cyclic carbonate solvent. In embodiments, the vehicle is substantially anhydrous and comprises a polar solubilizing agent (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, triacetin, triethyl citrate, propylene carbonate, combinations thereof) in an amount of between about 40% and about 99% by weight of the composition.

[0171]

[0148] 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 80% by weight of the composition. In embodiments, the combined polar cosolvent fraction is at least about 50% by weight of the composition.

[0172]

[0149] In embodiments, the vehicle further comprises one or more optional anhydrous cosolvents (e.g., ethanol, ethyl lactate, diethyl phthalate, dermatologically acceptable glycol ethers, combinations thereof) in an amount of between about 0% and about 40% by weight, with the polar solubilizing agent and / or cyclic carbonate solvent reduced q.s.

[0173]

[0150] In embodiments, the vehicle further comprises one or more antioxidants in an amount of between about 0% and about 1% by weight of the composition. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved in the anhydrous polar cosolvent serum, and the vehicle is formulated to maintain doxycycline in a solubilized state while promoting rapid spreading and follicular penetration following topical application.

[0174]

[0151] Exemplary Vehicle 4: Deep eutectic solvent system

[0175]

[0152] In another example, a topical delivery vehicle is a deep eutectic solvent system comprising two or more components that, when combined, form a liquid carrier with a melting point lower than that of the individual components. In embodiments, the vehicle comprises one or more hydrogen bond donors and one or more hydrogen bond acceptors selected to form a hydrophobic or amphiphilic eutectic mixture.

[0176]

[0153] In embodiments, the deep eutectic solvent system comprises components such as organic acids, alcohols, amides, esters, terpenes, polyols, or combinations thereof, present in molar ratios sufficient to form a liquid phase at room temperature. In embodiments, the deep eutectic solvent system is substantially anhydrous.2025-12-29

[0154] In embodiments, the vehicle further comprises one or more polar solubilizing agents and / or cosolvents (e.g., dimethyl isosorbide, triacetin, diethylene glycol monoethyl ether, propylene carbonate, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition, where such components are compatible with the eutectic mixture.

[0177]

[0155] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or molecularly dispersed within the deep eutectic solvent system. In embodiments, the vehicle is formulated to increase the apparent solubility and stability of doxycycline while promoting partitioning of doxycycline from the vehicle into the stratum corneum and follicular structures following topical application.

[0178]

[0156] Exemplary Vehicle 5: In situ gelling liquid-crystal precursor system

[0179]

[0157] In another example, a topical delivery vehicle is an in situ gelling liquid-crystal precursor system formulated to undergo a phase transition upon contact with skin moisture, ions, and / or temperature. In embodiments, the vehicle comprises one or more amphiphilic lipids capable of forming liquid-crystalline phases (e.g., monoacylglycerols, glycerol monooleate, phytantriol, combinations thereof) in an amount of between about 5% and about 60% by weight of the composition.

[0180]

[0158] In embodiments, the vehicle further comprises one or more solvents or cosolvents (e.g., ethanol, propylene glycol, dimethyl isosorbide, water, combinations thereof) in an amount of between about 10% and about 90% by weight of the composition, such that the formulation is initially flowable and transitions to a more viscous or gel-like liquid-crystalline phase after topical application.

[0181]

[0159] In embodiments, the vehicle further comprises one or more stabilizers, antioxidants, and / or chelating agents in amounts suitable to maintain chemical stability prior to phase transition. In embodiments, the system is substantially anhydrous prior to application or comprises a limited amount of water sufficient to initiate phase formation upon application.

[0182]

[0160] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within the precursor formulation, and the vehicle is formulated to form a structured liquid-crystalline matrix on the scalp that increases residence time and provides sustained release of doxycycline to follicular structures following topical application.

[0183]

[0161] Exemplary Vehicle 6: Solid lipid nanoparticles or nanostructured lipid carriers

[0184]

[0162] In another example, a topical delivery vehicle comprises solid lipid nanoparticles or nanostructured lipid carriers dispersed in an aqueous or mixed solvent medium. In embodiments, the vehicle comprises one or more solid lipids (e.g., glyceryl behenate, cetyl palmitate, stearic acid, hydrogenated triglycerides, combinations thereof) in an amount of between about 1% and about 30% by weight of the composition.

[0185]

[0163] In embodiments, the vehicle further comprises one or more liquid lipids (for nanostructured lipid carriers) (e.g., medium-chain triglycerides, squalane, fatty acid esters, combinations thereof) in an2025-12-29 amount of between about 0% and about 30% by weight of the composition, wherein the ratio of solid lipid to liquid lipid is selected to modulate crystallinity, loading capacity, and release kinetics.

[0186]

[0164] In embodiments, the vehicle further comprises a surfactant and / or stabilizer system (e.g., nonionic surfactants, poloxamers, polymeric stabilizers, combinations thereof) in an amount of between about 0.1% and about 10% by weight of the composition, with water and / or buffer q.s. to 100%. In embodiments, the vehicle further comprises one or more chelating agents and / or antioxidants in amounts suitable for lipid nanoparticle dispersions.

[0187]

[0165] In embodiments, the lipid nanoparticles have a mean particle diameter of between about 20 nm and about 1000 nm, including between about 50 nm and about 500 nm. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is encapsulated within and / or associated with the lipid matrix, and the vehicle is formulated to provide sustained release and enhanced follicular delivery of doxycycline following topical application.

[0188]

[0166] Exemplary Vehicle 7: Aqueous cyclodextrin inclusion system

[0189]

[0167] In another example, a topical delivery vehicle is an aqueous cyclodextrin inclusion system comprising doxycycline and / or a pharmaceutically acceptable salt thereof complexed with a cyclodextrin. In embodiments, the vehicle comprises one or more cyclodextrins (e.g., hydroxypropyl-p-cyclodextrin, sulfobutyl ether-p-cyclodextrin, methyl-p-cyclodextrin, combinations thereof) in an amount of between about 0.5% and about 30% by weight of the composition.

[0190]

[0168] In embodiments, doxycycline and the cyclodextrin are present at a molar ratio sufficient to form an inclusion complex that increases the apparent aqueous solubility and chemical stability of doxycycline. In embodiments, the doxycycline-to-cyclodextrin molar ratio is between about 1 :0.5 and about 1:10, including between about 1:1 and about 1:5.

[0191]

[0169] In embodiments, the vehicle further comprises water q.s. to 100% by weight of the composition and optionally one or more buffers, chelating agents, antioxidants, and / or preservatives in amounts suitable for aqueous inclusion systems. In embodiments, the composition is buffered to a pH of between about 4.0 and about 7.5.

[0192]

[0170] In embodiments, doxycycline is present predominantly as a cyclodextrin inclusion complex in the aqueous phase, and the vehicle is formulated to provide a clear or translucent topical solution or gel while enabling release of doxycycline upon contact with skin and follicular structures.

[0193]

[0171] Exemplary Vehicle 8: Proniosomal gel

[0194]

[0172] In another example, a topical delivery vehicle is a proniosomal gel comprising a dry or semi-solid precursor formulation that forms niosomes upon hydration. In embodiments, the vehicle comprises one or more non-ionic surfactants capable of forming vesicular structures upon contact with water (e.g., sorbitan esters, alkyl polyglucosides, polyglyceryl esters, combinations thereof) in an amount of between about 1 % and about 40% by weight of the composition.2025-12-29

[0173] In embodiments, the vehicle further comprises one or more lipid components or membrane stabilizers (e.g., cholesterol, fatty alcohols, phospholipids, combinations thereof) in an amount of between about 0% and about 30% by weight of the composition. In embodiments, the proniosomal gel is substantially anhydrous or contains a limited amount of water insufficient to fully hydrate the surfactant system prior to application.

[0195]

[0174] In embodiments, the vehicle further comprises one or more polar solubilizing agents and / or cosolvents (e.g., dimethyl isosorbide, propylene glycol, diethylene glycol monoethyl ether, triacetin, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the vehicle further comprises one or more antioxidants and / or chelating agents in amounts suitable to maintain chemical stability during storage.

[0196]

[0175] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within the proniosomal gel, and the vehicle is formulated to convert to a niosomal vesicular dispersion upon contact with skin moisture, thereby enhancing residence time and follicular delivery of doxycycline following topical application.

[0197]

[0176] Exemplary Vehicle 9: Ethosomal or transethosomal vesicular dispersion

[0198]

[0177] In another example, a topical delivery vehicle is an ethosomal or transethosomal vesicular dispersion comprising phospholipid vesicles in an ethanol-rich medium. In embodiments, the vehicle comprises ethanol in an amount of between about 20% and about 45% by weight of the composition.

[0199]

[0178] In embodiments, the vehicle further comprises one or more phospholipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, saturated phospholipids, combinations thereof) in an amount of between about 0.1% and about 10% by weight of the composition. In embodiments, the ethanol-rich environment increases vesicle deformability and permeability relative to conventional liposomes.

[0200]

[0179] In embodiments, the vehicle further comprises one or more optional cosolvents and / or polyols (e.g., propylene glycol, glycerin, dimethyl isosorbide, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition, with water q.s. to 100%. In embodiments, the aqueous phase is optionally buffered to a pH of between about 4.0 and about 7.5.

[0201]

[0180] In embodiments, the ethosomes or transethosomes have a mean vesicle diameter of between about 30 nm and about 2000 nm, including between about 50 nm and about 500 nm. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is incorporated within the vesicles, and the vehicle is formulated to enhance penetration of doxycycline into the stratum corneum and follicular structures relative to non-ethanol vesicular systems.

[0202]

[0181] Exemplary Vehicle 10: Liposomal dispersion

[0203]

[0182] In another example, a topical delivery vehicle is a liposomal dispersion comprising phospholipid vesicles dispersed in an aqueous or mixed solvent medium. In embodiments, the vehicle2025-12-29 comprises one or more phospholipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, saturated phospholipids, combinations thereof) in an amount of between about 0.05% and about 20% by weight of the composition.

[0204]

[0183] In embodiments, the vehicle further comprises one or more sterols (e.g., cholesterol, phytosterols, combinations thereof) in an amount of between about 0% and about 50 mol% of the total lipid content, wherein the lipid composition is selected to modulate vesicle rigidity, permeability, and stability.

[0205]

[0184] In embodiments, the vehicle further comprises an aqueous phase with water q.s. to 100% by weight of the composition and optionally one or more buffers, chelating agents, antioxidants, and / or preservatives in amounts suitable for liposomal dispersions. In embodiments, the dispersion is buffered to a pH of between about 4.0 and about 7.5.

[0206]

[0185] In embodiments, the liposomes have a mean vesicle diameter of between about 30 nm and about 2000 nm, including between about 50 nm and about 500 nm. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is encapsulated within the aqueous core and / or associated with the lipid bilayer, and the vehicle is formulated to enhance stability and follicular delivery of doxycycline relative to non-vesicular aqueous systems.

[0207]

[0186] Exemplary Vehicle 11: Self-emulsifying drug delivery system (SEDDS)

[0208]

[0187] In another example, a topical delivery vehicle is a self-emulsifying drug delivery system comprising an oil phase, a surfactant system, and, optionally, one or more cosurfactants, wherein the system forms a fine emulsion upon contact with water. In embodiments, the vehicle is an anhydrous or low-water system prior to application.

[0209]

[0188] In embodiments, the vehicle comprises an oil phase (e.g., medium-chain triglycerides, caprylic / capric triglycerides, isopropyl myristate, squalane, fatty acid esters, combinations thereof) in an amount of between about 10% and about 70% by weight of the composition. In embodiments, the vehicle further comprises one or more surfactants and / or cosurfactants (e.g., nonionic surfactants, amphiphilic esters, combinations thereof) in an amount of between about 20% and about 80% by weight of the composition.

[0210]

[0189] In embodiments, the relative proportions of the oil phase and surfactant system are selected such that the composition spontaneously forms an oil-in-water emulsion with droplet sizes in the nano- or micro-range upon dilution with water present on the skin or scalp. In embodiments, the system forms droplets having a mean diameter of less than about 500 nm, including less than about 200 nm.

[0211]

[0190] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within the self-emulsifying system, and the vehicle is formulated to enhance apparent solubility, improve physical stability, and promote uniform distribution and follicular delivery of doxycycline following topical application.

[0212]

[0191] Exemplary Vehicle 12: Reverse lecithin organogel2025-12-29

[0192] In another example, a topical delivery vehicle is a reverse lecithin organogel comprising a phospholipid-based gel network formed in a non-aqueous or low-water continuous phase. In embodiments, the vehicle comprises one or more phospholipids (e.g., lecithin, phosphatidylcholine, hydrogenated lecithin, combinations thereof) in an amount of between about 5% and about 40% by weight of the composition.

[0213]

[0193] In embodiments, the vehicle further comprises a non-aqueous continuous phase (e.g., isopropyl myristate, medium-chain triglycerides, squalane, fatty acid esters, combinations thereof) in an amount of between about 40% and about 95% by weight of the composition. In embodiments, a limited amount of water or polar solvent is present (e.g., <10% by weight) to induce formation of the organogel network.

[0214]

[0194] In embodiments, the reverse lecithin organogel forms a three-dimensional phospholipid network that immobilizes the continuous phase and creates internal polar domains capable of associating with doxycycline and / or a pharmaceutically acceptable salt thereof. In embodiments, the gel structure provides shear-thinning behavior suitable for topical application.

[0215]

[0195] In embodiments, doxycycline is dissolved or dispersed within the reverse lecithin organogel, and the vehicle is formulated to increase residence time on the scalp and provide sustained release of doxycycline to follicular structures following topical application.

[0216]

[0196] Exemplary Vehicle 13: Film-forming topical composition

[0217]

[0197] In another example, a topical delivery vehicle is a film-forming topical composition formulated to form a continuous or semi-continuous film on the scalp following application and solvent evaporation. In embodiments, the vehicle comprises one or more film-forming polymers (e.g., acrylate copolymers, polyurethane dispersions, cellulose derivatives, vinyl polymers, combinations thereof) in an amount of between about 0.1 % and about 20% by weight of the composition.

[0218]

[0198] In embodiments, the vehicle further comprises one or more volatile carriers or solvents (e.g., water, ethanol, isopropanol, combinations thereof) in an amount sufficient to permit spreading and application, wherein the volatile carrier evaporates after application to leave a polymeric film on the scalp. In embodiments, the vehicle further comprises one or more plasticizers (e.g., triethyl citrate, propylene glycol, glycerin, combinations thereof) in an amount of between about 0% and about 20% by weight of the composition to modulate film flexibility and adhesion.

[0219]

[0199] In embodiments, the vehicle further comprises one or more antioxidants, chelating agents, and / or preservatives in amounts suitable for film-forming systems. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is incorporated within the film-forming matrix.

[0220]

[0200] In embodiments, the film-forming topical composition is formulated to provide prolonged residence time on the scalp, resistance to wash-off, and sustained release of doxycycline to follicular structures following topical application.

[0221]

[0201] Exemplary Vehicle 14: Anhydrous foam or thermolabile melting balm2025-12-29

[0202] In another example, a topical delivery vehicle is an anhydrous foam or a thermolabile melting balm formulated to transition from a solid or semi-solid state to a liquid upon contact with skin temperature. In embodiments, the vehicle is substantially anhydrous and comprises one or more lipophilic carriers (e.g., oils, esters, hydrocarbons, silicones, combinations thereof) in an amount of between about 40% and about 95% by weight of the composition.

[0222]

[0203] In embodiments, the vehicle further comprises one or more structuring agents or phase-change materials (e.g., waxes, fatty alcohols, fatty acids, combinations thereof) in an amount of between about 5% and about 40% by weight of the composition, selected to provide a melting point at or near skin temperature. In embodiments, the vehicle transitions to a low-viscosity liquid upon application, enabling rapid spreading across the scalp.

[0223]

[0204] In embodiments, the vehicle further comprises one or more propellants (for foam formulations), gas-generating agents, or foaming aids in amounts suitable to generate a foam upon dispensing. In embodiments, the vehicle further comprises one or more solubilizing agents, antioxidants, and / or chelating agents in amounts suitable for anhydrous systems.

[0224]

[0205] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within the anhydrous foam or melting balm, and the vehicle is formulated to provide uniform scalp coverage, improved sensory properties, and controlled delivery of doxycycline to follicular structures following topical application.

[0225]

[0206] Exemplary Vehicle 15: Bigel or emulgel hybrid system

[0226]

[0207] In another example, a topical delivery vehicle is a bigel or emulgel hybrid system comprising an oil-based phase and a gelled aqueous phase combined into a biphasic or interpenetrating network. In embodiments, the vehicle comprises an oleaginous phase (e.g., oils, esters, silicones, combinations thereof) in an amount of between about 10% and about 70% by weight of the composition and an aqueous gel phase comprising water q.s. to 100% by weight of the composition.

[0227]

[0208] In embodiments, the aqueous gel phase comprises one or more gelling agents (e.g., carbomers, cellulose derivatives, polyacrylates, poloxamers, combinations thereof) in an amount of between about 0.1% and about 5% by weight of the composition. In embodiments, the oil phase is structured or emulsified within the gel matrix using one or more emulsifiers or stabilizers in an amount of between about 0.1% and about 10% by weight of the composition.

[0228]

[0209] In embodiments, the vehicle further comprises one or more solubilizing agents, penetration enhancers, antioxidants, chelating agents, and / or preservatives in amounts suitable for hybrid gel systems. In embodiments, the relative proportions of the oil phase and gel phase are selected to balance spreadability, residence time, and drug release characteristics.

[0229]

[0210] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within one or both phases of the bigel or emulgel hybrid system, and the vehicle is2025-12-29 formulated to provide improved stability and sustained delivery of doxycycline to the scalp and follicular structures relative to single-phase systems.

[0230]

[0211] Exemplary Vehicle 16: Nanoemulsion or microemulsion

[0231]

[0212] In another example, a topical delivery vehicle is a nanoemulsion or microemulsion comprising an oil phase, an aqueous phase, and a surfactant system. In embodiments, the oil phase is present in an amount of between about 1% and about 30% by weight of the composition, the aqueous phase comprises water q.s. to 100% by weight of the composition, and the surfactant system is present in an amount of between about 5% and about 60% by weight of the composition.

[0232]

[0213] In embodiments, the surfactant system comprises one or more nonionic surfactants, co-surfactants, or amphiphilic components (e.g., polyglyceryl esters, sorbitan esters, alkyl polyglucosides, combinations thereof) selected to form a thermodynamically stable microemulsion or a kinetically stable nanoemulsion. In embodiments, the dispersed oil droplets have a mean diameter of between about 10 nm and about 300 nm, including between about 20 nm and about 200 nm.

[0233]

[0214] In embodiments, the vehicle further comprises one or more polar solubilizing agents and / or cosolvents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, propylene glycol, butylene glycol, triacetin, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the vehicle further comprises one or more antioxidants and, where water is present, one or more chelating agents in amounts suitable for emulsion systems.

[0234]

[0215] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is solubilized within the oil phase and / or interfacial region of the nanoemulsion or microemulsion, and the vehicle is formulated to enhance apparent solubility, physical stability, and follicular delivery of doxycycline relative to conventional emulsions.

[0235]

[0216] Exemplary Vehicle 17: Hydroalcoholic solution or gel

[0236]

[0217] In another example, a topical delivery vehicle is a hydroalcoholic solution or gel comprising one or more alcohols, one or more polyols, and water. In embodiments, the vehicle comprises ethanol and / or isopropanol in an amount of between about 10% and about 80% by weight of the composition.

[0237]

[0218] In embodiments, the vehicle further comprises one or more polyols or humectants (e.g., propylene glycol, butylene glycol, glycerin, 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 gelling agent or viscosity modifier (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, combinations thereof) in an amount of between about 0% and about 5% by weight of the composition, such that the vehicle is formulated as a low-viscosity solution or as a gel.

[0238]

[0219] In embodiments, the vehicle further comprises one or more solubilizing agents and / or penetration enhancers (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, triacetin, propylene2025-12-29 carbonate, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the vehicle further comprises one or more antioxidants, chelating agents, and / or preservatives in amounts suitable for hydroalcoholic systems.

[0239]

[0220] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved or dispersed within the hydroalcoholic solution or gel, and the vehicle is formulated to provide rapid spreading, fast drying, and effective delivery of doxycycline to scalp and follicular structures following topical application.

[0240]

[0221] Exemplary Vehicle 18: Aqueous gel

[0241]

[0222] In another example, a topical delivery vehicle is an aqueous gel comprising water as the primary continuous phase and one or more polymeric gelling agents. In embodiments, the vehicle comprises water q.s. to 100% by weight of the composition.

[0242]

[0223] In embodiments, the vehicle further comprises one or more gellants or rheology modifiers (e.g., carbomers, hydroxypropyl methylcellulose, hydroxyethyl cellulose, poloxamers, combinations thereof) in an amount of between about 0.1% and about 5% by weight of the composition, sufficient to provide a gel consistency suitable for scalp application.

[0243]

[0224] In embodiments, the vehicle further comprises one or more polyols or humectants (e.g., glycerin, propylene glycol, butylene glycol, combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the vehicle further comprises one or more chelating agents, preservatives, and / or antioxidants in amounts suitable for aqueous systems, and is optionally buffered to a pH of between about 4.0 and about 7.5.

[0244]

[0225] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved, complexed, or dispersed within the aqueous gel, and the vehicle is formulated to provide alcohol-free topical delivery with increased residence time on the scalp and controlled diffusion of doxycycline to follicular structures.

[0245]

[0226] Exemplary Vehicle 19: Micellar solution

[0246]

[0227] In another example, a topical delivery vehicle is a micellar solution comprising doxycycline and / or a pharmaceutically acceptable salt thereof solubilized within micelles formed by one or more surfactants in an aqueous continuous phase. In embodiments, the vehicle comprises water q.s. to 100% by weight of the composition.

[0247]

[0228] In embodiments, the vehicle further comprises a micelle-forming surfactant system (e.g., nonionic surfactants, amphoteric surfactants, zwitterionic surfactants, alkyl polyglucosides, combinations thereof) in an amount of between about 0.1% and about 10% by weight of the composition, sufficient to form micelles that associate with doxycycline.

[0248]

[0229] In embodiments, the vehicle further comprises one or more solubilizing agents and / or cosolvents (e.g., dimethyl isosorbide, diethylene glycol monoethyl ether, propylene glycol, butylene glycol,2025-12-29 combinations thereof) in an amount of between about 0% and about 40% by weight of the composition. In embodiments, the vehicle comprises no more than about 5% oil by weight, including no more than about 2%, 1 %, or 0.5%, and in embodiments is substantially free of added oils.

[0249]

[0230] In embodiments, the micellar solution is optionally buffered to a pH of between about 4.0 and about 7.5 and further comprises one or more chelating agents, antioxidants, and / or preservatives in amounts suitable for aqueous systems. In embodiments, doxycycline is present predominantly in a micelle-associated state, and the vehicle is formulated to provide a clear or translucent scalp tonic that spreads easily and leaves minimal residue after application.

[0250]

[0231] Exemplary Vehicle 20: Foam or foamable scalp vehicle

[0251]

[0232] In another example, a topical delivery vehicle is a foam or foamable scalp vehicle formulated to generate a foam upon dispensing. In embodiments, the vehicle is provided as a pump-foam formulation or a pressurized foam formulation.

[0252]

[0233] In embodiments, the vehicle comprises a liquid carrier system selected from an aqueous system, a hydroalcoholic system, or a mixed solvent system, with the liquid carrier system present q.s. to 100% by weight of the composition. 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.

[0253]

[0234] In embodiments, the vehicle further comprises one or more solubilizing agents, penetration enhancers, humectants, viscosity modifiers, chelating agents, antioxidants, preservatives, or combinations thereof, in amounts suitable for foamable scalp formulations. In embodiments, the vehicle further comprises a propellant system (e.g., hydrocarbons, compressed gases, combinations thereof) where formulated as a pressurized foam.

[0254]

[0235] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved, solubilized, or dispersed within the foamable scalp vehicle, and the vehicle is formulated to spread readily across hair-bearing skin, provide uniform coverage of the scalp and follicular openings, and collapse after application to leave minimal residue.

[0255]

[0236] Exemplary Vehicle 21 : Wash-off scalp vehicle

[0256]

[0237] In another example, a topical delivery vehicle is a wash-off scalp vehicle formulated 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.

[0257]

[0238] 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, and / or conditioning performance. In embodiments, the surfactant system is selected to provide mild cleansing suitable for repeated application to the scalp.2025-12-29

[0239] In embodiments, the vehicle further comprises one or more conditioning agents, humectants, thickeners, opacifiers, pearlizing agents, chelating agents, antioxidants, preservatives, fragrances, or combinations thereof, in amounts suitable for wash-off scalp formulations. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is incorporated in a form that deposits onto the scalp and / or hair follicle structures during washing and rinsing.

[0258]

[0240] In embodiments, the wash-off scalp vehicle is formulated to be applied to wet hair and scalp, massaged, and rinsed after a contact time sufficient to deliver doxycycline to the scalp and follicular structures.

[0259]

[0241] Exemplary Vehicle 22: Non-aqueous nanosuspension

[0260]

[0242] In another example, a topical delivery vehicle is a non-aqueous nanosuspension comprising doxycycline and / or a pharmaceutically acceptable salt thereof present as suspended solid particles dispersed in an anhydrous continuous phase. In embodiments, the continuous phase comprises one or more oils, esters, silicones, or combinations thereof.

[0261]

[0243] In embodiments, the nanosuspension further comprises one or more stabilizers and / or dispersants (e.g., polymeric stabilizers, nonionic surfactants, amphiphilic compounds, combinations thereof) in an amount of between about 0.01% and about 10% by weight of the composition, sufficient to inhibit particle aggregation and sedimentation.

[0262]

[0244] In embodiments, the doxycycline particles have a particle size distribution characterized by a mean particle diameter of between about 50 nm and about 2000 nm, including between about 100 nm and about 500 nm. In embodiments, doxycycline remains predominantly in the solid state within the vehicle.

[0263]

[0245] In embodiments, the non-aqueous nanosuspension is formulated to provide high thermodynamic activity of doxycycline at the skin surface and to enhance dissolution and partitioning of doxycycline into the stratum corneum and hair follicle structures following topical application.

[0264]

[0246] Exemplary Vehicle 23: Aqueous drug nanocrystal or nanosuspension

[0265]

[0247] In another example, a topical delivery vehicle is an aqueous drug nanocrystal or nanosuspension comprising doxycycline and / or a pharmaceutically acceptable salt thereof present as suspended solid particles dispersed in an aqueous continuous phase. In embodiments, the continuous phase comprises water q.s. to 100% by weight of the composition.

[0266]

[0248] In embodiments, the nanosuspension further comprises one or more stabilizers and / or dispersants (e.g., polymeric stabilizers, nonionic surfactants, amphoteric surfactants, combinations thereof) in an amount of between about 0.01% and about 10% by weight of the composition, sufficient to inhibit particle growth, aggregation, and sedimentation. In embodiments, the stabilizer system is selected to be compatible with doxycycline and to maintain chemical stability in aqueous media.2025-12-29

[0249] In embodiments, the doxycycline nanocrystals have a particle size distribution characterized by a mean particle diameter of between about 50 nm and about 2000 nm, including between about 100 nm and about 500 nm. In embodiments, doxycycline remains predominantly in the solid crystalline or amorphous particulate state.

[0267]

[0250] In embodiments, the aqueous drug nanocrystal or nanosuspension is formulated to provide a high surface-area reservoir of doxycycline at the skin surface, thereby enhancing dissolution, concentration gradients, and partitioning of doxycycline into the stratum corneum and hair follicle structures following topical application.

[0268]

[0251] Exemplary Vehicle 24: Biodegradable polymeric nanoparticles

[0269]

[0252] In another example, a topical delivery vehicle comprises biodegradable polymeric nanoparticles dispersed in an aqueous or mixed solvent medium. In embodiments, the vehicle comprises one or more biodegradable polymers (e.g., poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), polycaprolactone (PCL), poly(lactic-co-caprolactone), combinations thereof) in an amount of between about 0.1 % and about 20% by weight of the composition.

[0270]

[0253] In embodiments, the polymeric nanoparticles encapsulate doxycycline and / or a pharmaceutically acceptable salt thereof within a polymer matrix and / or associate doxycycline within hydrophilic or hydrophobic domains of the polymer. In embodiments, the nanoparticles have a mean particle diameter of between about 50 nm and about 2000 nm, including between about 100 nm and about 500 nm.

[0271]

[0254] In embodiments, the vehicle further comprises one or more stabilizers and / or surfactants (e.g., polymeric stabilizers, nonionic surfactants, amphoteric surfactants, combinations thereof) in an amount of between about 0.01% and about 5% by weight of the composition, with water and / or buffer q.s. to 100%. In embodiments, the vehicle further comprises one or more antioxidants and / or chelating agents in amounts suitable for polymeric nanoparticle dispersions.

[0272]

[0255] In embodiments, doxycycline is encapsulated within the biodegradable polymeric nanoparticles, and the vehicle is formulated to provide controlled or sustained release of doxycycline and enhanced follicular targeting relative to non-particulate topical formulations.

[0273]

[0256] Exemplary Vehicle 25: Polymer-lipid hybrid nanoparticles

[0274]

[0257] In another example, a topical delivery vehicle comprises polymer-lipid hybrid nanoparticles having a polymeric core and a lipid shell dispersed in an aqueous or mixed solvent medium. In embodiments, the vehicle comprises one or more biodegradable polymers forming a nanoparticle core (e.g., poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, combinations thereof) and one or more lipid components forming an outer shell (e.g., phospholipids, fatty acids, fatty alcohols, cholesterol, combinations thereof).2025-12-29

[0258] In embodiments, the polymer-lipid hybrid nanoparticles have a mean particle diameter of between about 50 nm and about 2000 nm, including between about 100 nm and about 500 nm. In embodiments, the lipid shell partially or fully surrounds the polymeric core, thereby modulating surface properties, stability, and interaction with skin lipids.

[0275]

[0259] In embodiments, the vehicle further comprises one or more stabilizers and / or surfactants (e.g., nonionic surfactants, polymeric stabilizers, combinations thereof) in an amount of between about 0.01% and about 5% by weight of the composition, with water and / or buffer q.s. to 100%. In embodiments, the vehicle further comprises one or more antioxidants and / or chelating agents in amounts suitable for hybrid nanoparticle dispersions.

[0276]

[0260] In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is encapsulated within the polymeric core, associated with the lipid shell, or both, and the vehicle is formulated to combine the sustained-release characteristics of polymeric nanoparticles with the skin-interactive properties of lipid-based carriers to enhance follicular delivery of doxycycline.

[0277]

[0261] Exemplary Vehicle 26: Commercial or proprietary topical base

[0278]

[0262] In another example, a topical delivery vehicle is a commercial or proprietary topical base formulated for dermal or scalp application. In embodiments, the vehicle comprises a ready-to-use topical base (e.g., dermatologically acceptable commercial scalp vehicles, compounding pharmacy bases, TrichoSol-type bases, combinations thereof) present q.s. to 100% by weight of the composition.

[0279]

[0263] In embodiments, the topical base is selected to provide predefined rheological, sensory, and stability characteristics suitable for scalp application. In embodiments, the base is aqueous, hydroalcoholic, anhydrous, silicone-based, or a hybrid system. In embodiments where water is present, the base is buffered to a pH of between about 4.0 and about 7.5.

[0280]

[0264] In embodiments, the vehicle further comprises one or more added solubilizing agents, penetration enhancers, humectants, antioxidants, chelating agents, preservatives, or combinations thereof, in amounts compatible with the underlying base and sufficient to accommodate incorporation of doxycycline and / or a pharmaceutically acceptable salt thereof without destabilizing the formulation.

[0281]

[0265] In embodiments, doxycycline is incorporated into the commercial or proprietary topical base with minimal modification to the base composition, and the vehicle is formulated to retain the physical stability, application properties, and user acceptability of the base while delivering doxycycline to the scalp and follicular structures.

[0282]

[0266] Exemplary Vehicle 27: Solid stick or wax-stick applicator

[0283]

[0267] In another example, a topical delivery vehicle is a solid stick or wax-stick applicator formulated as a doseable solid or semi-solid composition for direct application to the scalp or skin. In embodiments, the vehicle is an anhydrous or substantially anhydrous composition.2025-12-29

[0268] 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 sufficient to form a solid or semi-solid stick that retains its shape at room temperature. In embodiments, the vehicle further comprises one or more liquid carriers (e.g., oils, esters, silicones, combinations thereof) in amounts sufficient to modulate hardness, glide, and spreadability during application.

[0284]

[0269] In embodiments, the vehicle further comprises one or more solubilizing agents and / or penetration enhancers suitable for anhydrous systems, as well as one or more antioxidants in amounts suitable for solid formulations. In embodiments, doxycycline and / or a pharmaceutically acceptable salt thereof is dissolved, dispersed, or suspended within the solid matrix.

[0285]

[0270] In embodiments, the solid stick or wax-stick applicator is formulated to allow controlled, localized delivery of doxycycline to the scalp or skin with minimal run-off and improved dosing precision relative to liquid topical formulations.

[0286]

[0271] Exemplary Vehicle 28: Patch, laminate, or strip sustained-release scalp system

[0287]

[0272] In another example, a topical delivery vehicle is a patch, laminate, or strip formulated as an occlusive sustained-release scalp delivery system. In embodiments, the vehicle comprises a matrix layer containing doxycycline and / or a pharmaceutically acceptable salt thereof, wherein the matrix layer is formulated to maintain prolonged contact with the scalp or hair-bearing skin.

[0288]

[0273] In embodiments, the matrix layer comprises one or more polymers (e.g., pressure-sensitive adhesives, polyacrylates, silicones, polyisobutylenes, hydrogels, elastomers, combinations thereof) in which doxycycline is dissolved, dispersed, or both. In embodiments, the matrix layer is an anhydrous matrix or a hydrated matrix.

[0289]

[0274] In embodiments, the vehicle further comprises an adhesive layer formulated to secure the patch, laminate, or strip to the scalp for a defined wear period and optionally a backing layer formulated to provide mechanical support and occlusion. In embodiments, the backing layer is occlusive or semi-occlusive.

[0290]

[0275] In embodiments, the patch, laminate, or strip sustained-release scalp system is formulated to deliver doxycycline over a period of hours to days while minimizing loss due to evaporation, abrasion, or wash-off and maintaining close contact with follicular openings.

[0291]

[0276] Exemplary Vehicle 29: Microneedle-enabled scalp delivery system

[0292]

[0277] In another example, a topical delivery vehicle is a microneedle-enabled scalp delivery system formulated to enhance penetration of doxycycline and / or a pharmaceutically acceptable salt thereof through the stratum corneum and into follicular and perifollicular structures. In embodiments, the vehicle comprises a microneedle array suitable for application to the scalp.2025-12-29

[0278] In embodiments, the microneedles are dissolving microneedles, swellable microneedles, solid microneedles, or coated microneedles (e.g., microneedles formed from water-soluble polymers, biodegradable polymers, sugars, combinations thereof). In embodiments, doxycycline is incorporated within the microneedle matrix, coated onto the microneedles, or delivered via a topical formulation applied before, during, or after microneedle application.

[0293]

[0279] In embodiments, the microneedles have a needle length of between about 100 pm and about 1000 pm, including between about 200 pm and about 700 pm, sufficient to create microchannels in the stratum comeum without causing significant bleeding. In embodiments, the microneedle array is used alone or in combination with a topical formulation comprising doxycycline, including any vehicle described herein.

[0294]

[0280] In embodiments, the microneedle-enabled scalp delivery system is formulated to increase local bioavailability of doxycycline at follicular targets and to reduce reliance on passive diffusion from the topical vehicle alone.

[0295]

[0281] 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 or lipid-vesicle dispersion with a hydroalcoholic gel, or a nanosuspension incorporated into an emulsion, gel, or film-forming matrix. In embodiments, a combined vehicle system enhances solubility, stability, penetration, residence time, and / or user acceptability relative to a single vehicle system alone.

[0296]

[0282] In embodiments, a topical composition comprises doxycycline (e.g., free base and / or a pharmaceutically acceptable salt thereof) in an amount of 0.000001-5% by weight and a vehicle selected from the scalp-compatible vehicle families described herein (including Exemplary Vehicles 1-29), such as comprising one or more of: (I) an anhydrous polar cosolvent system comprising a cyclic carbonate solvent and a polar penetration enhancer and / or solubilizing agent (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 solubilizing agents and / or cosolvents, optionally structured as an anhydrous organogel or structured oil, (ill) aqueous and / or hydroalcoholic scalp carriers (including solutions, gels, foams, wash-off shampoo or conditioner compositions, and / or pre-formed commercial or proprietary bases), optionally buffered to pH 4.0-7.5, (iv) emulsion systems including oil-in-water or water-in-oil emulsions, microemulsions, and / or nanoemulsions, (v) vesicular lipid carriers including liposomes or lipid-vesicle dispersions, ethosomes or transethosomes and other deformable vesicles, niosomes, proniosomal systems, reverse lecithin organogels, and polymer-coated or layer-by-layer vesicles, (vi) particulate delivery systems including non-aqueous nanosuspensions, aqueous drug nanocrystals or nanosuspensions, lipid nanoparticles (e.g., solid lipid nanoparticles and / or nanostructured2025-12-29 lipid carriers), biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, and self-emulsifying systems, and / or (vii) deep-eutectic-solvent carriers, film-forming systems, depot or residence-time extender systems, microneedle-enabled delivery systems, and solid or semi-solid applicators.

[0297] d. Additional Active Compounds

[0298]

[0283] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound. In some embodiments, the additional active agent is selected to provide synergistic effects.

[0299]

[0284] 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.

[0300] 2019).

[0301]

[0285] 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.

[0302]

[0286] In embodiments, the additional active agent is triiodothyronine, finasteride, dutasteride, minoxidil, olanzapine, farnesol, or thyrotropin-releasing hormone. In embodiments, a composition comprises doxycycline and triiodothyronine. In embodiments, a composition comprises doxycycline and finasteride. In embodiments, a composition comprises doxycycline and dutasteride. In embodiments, a composition comprises doxycycline and minoxidil. In embodiments, a composition comprises doxycycline and olanzapine. In embodiments, a composition comprises doxycycline and farnesol. In embodiments, a composition comprises doxycycline and thyrotropin-releasing hormone

[0303] e. Kits

[0304]

[0287] The present disclosure further provides kits, such as pharmaceutical kits, comprising the disclosed compositions. In some embodiments, the kits provide disclosed compositions in unit dosage form.

[0305]

[0288] 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) can be packaged in separate containers or some components can be combined in one container where2025-12-29 cross-reactivity and shelf life permit. Kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.

[0306]

[0289] 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.

[0307]

[0290] 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.

[0308] C. Methods of Use

[0309]

[0291] 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.

[0310]

[0292] 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.

[0311]

[0293] 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.

[0312]

[0294] In some 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.

[0313]

[0295] In some embodiments, a subject is subjected to bloodwork before treatment with a disclosed method or composition. In some 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 some embodiments, a subject is 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.2025-12-29

[0296] 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, TGF0-2, Androgen Receptor (AR), LEF1, a-SMA, AXIN2, Phospho-S6 (p-S6), CD34, CD31, MTCO1, Keratin-15 (K15 / CK15), P-Catenin, LGR5, ESR1 (ERa), ESR2 (ERP), 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.

[0314] a. Methods of Administration

[0315]

[0297] 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.

[0316]

[0298] In some embodiments, the composition is administered topically. In some embodiments, the composition is administered transdermally. In some embodiments, the composition is administered by a route of administration that results in systemic delivery of the active agent(s). In some embodiments, the composition is administered by a route of administration that results in local delivery of the active agent(s).

[0317]

[0299] In some embodiments, the tetracycline is administered at a concentration of between about 0.1 pM and 400 pM. In some embodiments, the tetracycline is administered at a concentration between about 0.1 pM and 400 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, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, 200 pM, 210 pM, 220 pM, 230 pM, 240 pM, 250 pM, 260 pM, 270 pM, 280 pM, 290 pM, 300 pM, 310 pM, 320 pM, 330 pM, 340 pM, 350 pM, 360 pM, 370 pM, 380 pM, 390 pM, and 400 pM, including amounts and open- and closed-ended ranges between these concentrations.

[0318]

[0300] In some embodiments, the tetracycline is administered at a concentration of less than about 0.1 pM (including concentrations between about 1 nM and 0.1 pM, about 20 nM and about 0.1 pM, and about 50 nM and about 0.1 pM). In some embodiments, the tetracycline is administered at a2025-12-29 concentration of greater than about 400 M (including concentrations between about 400 M and about 1 mM, about 400 pM and about 10 mM, and about 400 pM and about 100 mM). In some embodiments, the tetracycline is administered at a concentration of about 1 pM. In some embodiments, the tetracycline is administered at a concentration of about 10 pM. In some embodiments, the tetracycline is administered at a concentration of about 40 pM.

[0319]

[0301] In some embodiments, the total unit dose volume of a disclosed composition is between about 0.1 mL and 10 mL. In some 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 some embodiments, the total unit dose volume is about 0.1 mL. In some embodiments, the total dose volume is about 0.5 mL. In some embodiments, the total unit dose volume is about 1 mL. In some embodiments, the total unit dose volume is about 2 mL. In some embodiments, the total dose volume of a disclosed composition is about 3 mL. In some embodiments, the total unit dose volume is about 4 mL. In some embodiments, the total unit dose volume is about 5 mL. In some embodiments, the total unit dose volume is about 6 mL. In some embodiments, the total unit dose volume is about 7 mL. In some embodiments, the total unit dose volume is about 8 mL. In some embodiments, the total dose volume of a disclosed composition is about 9 mL. In some embodiments, the total unit dose volume is about 10 mL.

[0320]

[0302] 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.

[0321]

[0303] In some embodiments, the composition is administered every day. In some 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 some embodiments, the composition is administered every other day for 2 weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for 3 weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for 4 weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for 5 weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for 6 weeks followed by a prolonged period without administration.

[0322]

[0304] In some 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 to2025-12-29 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.

[0323]

[0305] 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).

[0324]

[0306] 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.

[0325]

[0307] 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.

[0326]

[0308] Dose and dosage levels 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. 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.

[0327] b. Methods of Treating and Preventing Hair Loss or Hair Graying

[0328]

[0309] In some embodiments, disclosed compositions and methods are for treating hair loss in a subject. In some embodiments, disclosed compositions and methods are for preventing hair loss in a subject.

[0329]

[0310] In some embodiments, the hair loss is caused by alopecia. In some 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 some embodiments, the hair loss is caused by androgenetic alopecia. In some embodiments, the hair loss is male pattern baldness. In some embodiments, the hair loss is female pattern baldness.

[0330]

[0311] In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by alopecia. In some 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,2025-12-29 frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by androgenetic alopecia. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by male pattern baldness. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by female pattern baldness.

[0331]

[0312] In some 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.

[0332]

[0313] In some embodiments, the hair loss is caused by telogen effluvium. In some embodiments, the hair loss is caused by anagen effluvium. In some embodiments, the hair loss is caused by a nutritional deficiency. In some embodiments, the hair loss is caused by thyroid dysfunction. In some embodiments, the hair loss is caused by chronic illness, such as diabetes or chronic kidney disease. In some embodiments, the hair loss is caused by medication side effects, such as from beta blockers, retinoids, or anticonvulsants. In some embodiments, the hair loss is caused by chemotherapy or radiation therapy. In some embodiments, the hair loss is caused by environmental factors, such as UV damage or pollution. In some embodiments, the hair loss is caused by an injury, such as burns or surgical scars. In some embodiments, the hair loss is caused by aging.

[0333]

[0314] In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by telogen effluvium. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by anagen effluvium. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by a nutritional deficiency. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by thyroid dysfunction. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by chronic illness, such as diabetes or chronic kidney disease. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by medication side effects, such as from beta blockers, retinoids, or anticonvulsants. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by chemotherapy or radiation therapy. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by environmental factors, such as UV damage or pollution. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by an injury, such as burns or surgical scars. In some embodiments, disclosed compositions and methods treat or prevent hair loss caused by aging.

[0334]

[0315] Other causes of hair loss, treatable with disclosed compositions and methods, are known to those of skill in the art.2025-12-29

[0316] In embodiments, administration of a disclosed composition alters hair cycle staging in a subject. In some embodiments, administration of a disclosed composition alters the anagen (i.e., growth) phase. In some embodiments, administration of a disclosed composition prolongs the anagen phase. In some embodiments, administration of a disclosed composition delays the transition from the anagen to the catagen (i.e., transitional) phase. In some embodiments, administration of a disclosed composition reduces the duration of the catagen phase. In some embodiments, administration of a disclosed composition reduces the duration of the telogen (i.e., resting) phase.

[0335]

[0317] In some 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 some 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 some 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.

[0336] c. Methods of Treating and Preventing Dermatological Conditions

[0337]

[0318] In some embodiments, disclosed compositions and methods are for treating a dermatological condition in a subject. In some embodiments, disclosed compositions and methods are for preventing a dermatological condition in a subject.

[0338]

[0319] 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 some 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.

[0339]

[0320] In some 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.

[0340]

[0321] In some 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,2025-12-29 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).

[0341]

[0322] In some 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.

[0342]

[0323] In some 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).

[0343]

[0324] In some 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 subcutaneous tissue diseases, treatable using the disclosed compositions and methods, include lipomas, panniculitis (e.g., erythema nodosum), subcutaneous calcinosis, adiposis dolorosa.

[0344] D. Exemplary Aspects and Embodiments

[0345]

[0325] 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.

[0346]

[0326] In one aspect, provided is a composition formulated for treating hair loss, hair graying, or a dermatological condition, comprising:

[0347] i. a tetracycline, or a pharmaceutically acceptable salt thereof; and

[0348] ii. a solvent system.

[0349]

[0327] In some embodiments, the composition comprises the tetracycline at a concentration of between about 0.1 pM and about 400 pM. In some embodiments, the composition comprises the tetracycline at a concentration of between about 1 pM and about 100 pM. In some embodiments, the composition comprises the tetracycline at a concentration of between about 1 pM and about 50 pM. In some embodiments, the composition comprises the tetracycline at a concentration of about 1 pM. In some2025-12-29 embodiments, the composition comprises the tetracycline at a concentration of about 10 M. In some embodiments, the composition comprises the tetracycline at a concentration of about 40 piM.

[0350]

[0328] In some embodiments, the tetracycline is doxycycline, tetracycline, minocycline, tigecycline, lymecycline, demecycline, sarecycline, omadacycline, eravacycline, 4-dedimethylaminosancycline, demeclocycline, methacycline, chlortetracycline, oxytetracycline, or rolitetracycline.

[0351]

[0329] In some embodiments, the tetracycline is doxycycline.

[0352]

[0330] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some 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.

[0353]

[0331] In some embodiments, the composition further comprises an additional active agent. In some 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.

[0354]

[0332] 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.

[0355]

[0333] 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.

[0356]

[0334] 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.

[0357]

[0335] In some embodiments, a method comprises administering the composition daily. In some embodiments, the composition is administered every other day. In some embodiments, the composition is administered every other day for several consecutive weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for two consecutive weeks followed by a prolonged period without administration. In some embodiments, the prolonged period without administration is at least two weeks.

[0358]

[0336] In some 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.

[0359]

[0337] In some embodiments, administering the composition increases hair shaft production in the subject. In some embodiments, administering the composition prolongs the anagen hair growth phase in the subject.2025-12-29

[0338] In some embodiments, the dermatological condition is a skin condition. In some embodiments, the skin condition is an epidermal disease, dermal disease, epidermal appendage disease, or subcutaneous tissue disease.

[0360] E. Examples

[0361]

[0339] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0362] EXAMPLE 1: Hair Follicle Organ Culture Model

[0363]

[0340] 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 doxycycline hyclate (“doxycycline”) at 1 pM - 40 pM.

[0364]

[0341] 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. At 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.

[0365]

[0342] 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.

[0366]

[0343] Immunofluorescence. 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.

[0367]

[0344] 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).

[0368]

[0345] 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).2025-12-29

[0346] 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).

[0369]

[0347] TGFp-2. Fix: cold methanol (-20 °C, 10 min) or 4% PFA in PBS (RT, 10 min). Primary: mouse anti-TGFp-2 (1:40-1:65; Bio-Techne) or rabbit anti-TGFfl-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).

[0370]

[0348] 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).

[0371]

[0349] 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).

[0372]

[0350] 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).

[0373]

[0351] 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).

[0374]

[0352] 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).

[0375]

[0353] 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).

[0376]

[0354] 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).

[0377]

[0355] MTCO1. 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).2025-12-29

[0356] 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).

[0378]

[0357] 0-Catenin. Fix: 4% PFA in PBS (RT, 10 min). Primary: mouse anti-£-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).

[0379]

[0358] 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).

[0380]

[0359] 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).

[0381]

[0360] 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).

[0382]

[0361] 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).

[0383]

[0362] 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).

[0384]

[0363] 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).

[0385]

[0364] 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).

[0386]

[0365] 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).

[0387]

[0366] 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).

[0388]

[0367] 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).2025-12-29

[0368] 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).

[0389]

[0369] 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).

[0390]

[0370] 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).

[0391]

[0371] 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).

[0392]

[0372] 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).

[0393]

[0373] 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).

[0394]

[0374] 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).

[0395]

[0375] 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).

[0396]

[0376] Quantitative (Immuno-)Histomorphometry 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 vehicle images). Mean fluorescence intensity (MFI) will be measured per reference area. Imaged Cell Counter will be used to count single- and double-positive cells.

[0397]

[0377] 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.2025-12-29

[0378] 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.

[0398]

[0379] 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 f-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.

[0399]

[0380] Dosage Titration and Experimental Design: Three doxycycline concentrations (1 pM, 10 pM, and 40 pM) were evaluated in human hair follicle organ culture. Dissolution was confirmed; doxycycline was fully soluble at the highest concentration tested (40 pM).

[0400]

[0401]

[0402]

[0381] The experiments of this example were conducted according to the following timeline:

[0403]

[0404] 2025-12-29

[0405]

[0406]

[0407]

[0382] 16 human scalp follicular units were sourced from the scalp skin of one male donor, with each follicular unit containing 1-3 hair follicles, totalling 29 measured human hair follicles (28 follicles with Day 7 length measurements):

[0408]

[0383] Results:

[0409]

[0384] Hair Shaft Production. Relative to vehicle controls, the 10 pM doxycycline group showed the greatest average length increase over Day 0-7 (+0.52 mm; +11.24%; Table 2), compared to vehicle (+0.37 mm; +7.97%). The 1 pM and 40 pM groups showed smaller average Day 0-7 changes (+0.26 mm; +5.15% and +0.13 mm; +3.15%, respectively; Table 2).

[0410]

[0385] Inter-follicle Variability. Growth responses varied across individual follicles. The largest increase was observed in 10 pM doxycycline (well 44-A6), which increased by 1.197 mm (+25.25%). In contrast, the largest decrease was observed in 1 pM doxycycline (well 44-D4), which changed by -0.425 mm (-12.46%) (Table 1).

[0411]

[0386] Hair Cycle Morphology. Hair cycle staging at Day 7 is summarized in Table 3. Day 7 anagen proportions were 2 (22.2%) for vehicle controls, 2 (33.3%) for 1 pM doxycycline, 1 (14.3%) for 10 pM doxycycline, and 3 (50.0%) for 40 pM doxycycline.

[0412]

[0387] Discussion:

[0413]

[0388] Summary of Findings. Over the 7-day culture interval, doxycycline produced concentration-associated differences in hair shaft elongation relative to vehicle controls. The 10 pM group showed the greatest mean length increase versus Day 0 (+0.52 mm; +11.24%) compared with vehicle (+0.37 mm; +7.97%) (Table 2).2025-12-29

[0389] Dose-Response Considerations. Hair shaft elongation changes were non-monotonic across the tested concentrations, with the greatest mean increase at 10 pM and smaller mean changes at 1 pM and 40 pM (Table 2). Variability may reflect baseline follicle state, inter-follicle variability, and effective exposure during media exchange (Table 1).

[0414]

[0390] Relationship to Anagen Maintenance. Preliminary Day 7 morphology suggests group-specific differences in staging (Table 3). The 40 pM group retained a higher anagen fraction (50.0%) and a lower catagen fraction (33.3%) than the 10 pM group (14.3% anagen; 57.1% catagen). Morphology-based staging is preliminary and will be confirmed by histomorphometry and immunostains.

[0415]

[0391] Planned Mechanistic Readouts. Ongoing microscopy will be quantified in Imaged by mean fluorescence intensity (MFI) and single- and double-positive cell counts, with optional computer vision-based confirmation. These readouts may be used to interpret treated versus vehicle follicles across markers described herein.

[0416]

[0392] Translation to Topical Use. Because these data were generated in ex vivo organ culture, translation to topical application may depend on follicular delivery, retention, and local concentration at the follicle bulb, and may be optimized by formulation and dosing adjustments.

[0417] TABLE 1. Hair Follicle Length

[0418]

[0419] 2025-12-29

[0420]

[0421] 2025-12-29

[0422]

[0423]

[0393] TABLE 1 A. Hair Cycle Morphology (Per Follicle)

[0424]

[0425] 2025-12-29

[0426]

[0427] 2025-12-29

[0428]

[0429] ‘Classification based on macroscopic morphological assessment; histomorphometric confirmation is ongoing.

[0430] TABLE 2. Summary Hair Follicle Length Change

[0431]

[0432] TABLE 3. Hair Cycle Morphology (Day 7 Summary)2025-12-29

[0433]

[0434] EXAMPLE 2: Human Hair Follicle Organ Culture

[0435]

[0394] Purpose: The study described herein was designed to test the effects of administration of disclosed topical compositions on human scalp hair follicular units, with surrounding scalp skin, in organ culture. In this work, novel doxycycline and farnesol individual dosages and combinations altered transcriptional programs in human hair follicles consistent with a pro-growth, anabolic state, including pathways related to protein synthesis, mitochondrial energy production, and one-carbon metabolism.

[0436]

[0395] Methods:

[0437]

[0396] Follicular Unit Biopsy: Hair follicular unit biopsies containing terminal hair follicles were prepared and 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 of serum-free supplemented William’s E medium prepared in our laboratory, either containing William’s E medium alone (untreated control) or containing doxycycline (20 pM), farnesol (2 pM), or a combination of doxycycline (20 pM) and farnesol (2 pM).

[0438]

[0397] From Day 1 to Day 7, media changes were performed every other day. At each media change, each follicular unit was imaged to perform hair shaft length and width analysis. At the end of the seven days of culture, samples were snap-frozen in liquid nitrogen, stored at -80°C, and delivered to a third-party laboratory for RNA-sequencing.

[0439]

[0398] RNA-Seauencing: Total RNA was extracted from hair follicles treated with farnesol, doxycycline, the combination or an untreated control. RNA extraction, sample quality control, rRNA-depleted library preparation, and sequencing were performed by Azenta NGS Laboratory (Azenta Life Sciences) under quotation number 30-1134872315. Sixteen fresh frozen tissue samples (17-19 pL each) were submitted for processing. The service bundle included UMI control, ERCC spike-in controls, and sFTP data delivery, with a target depth of approximately 50 million reads per sample. As part of vendor QC, nucleic acid purity was assessed by NanoDrop (A260 / A280 and A260 / A230), RNA concentration by Qubit, and RNA integrity / fragment distribution by Agilent TapeStation, including DV200 (42.72-90.34) and, where available, RNA integrity numbers (RIN; e.g., 7.9-9.7). Several samples were flagged by the vendor for limited starting material and / or DV200<70. Raw sequences were aligned to the human reference genome (GRCh38) using the STAR algorithm. Gene-level read counts were quantified using2025-12-29 featureCounts, with counts assigned based on GENCODE annotation. Quality control metrics were assessed for all samples, including library size, number of genes detected, and mitochondrial read fraction. Sample C1 was removed because its library size was <10% of the other samples and too few reads were available to align the sample. D1 (untreated control) was identified as an outlier based on multiple quality control metrics, including separation from other samples in PCA space, substantially higher library size (approximately 45 million reads, about 40% above the group median), and a maximum Cook’s distance >50, indicating disproportionate influence on differential expression analyses.

[0440]

[0399] Statistical Analysis: Gene-level raw count matrices were analysed using DESeq2. For each pairwise comparison, raw counts were filtered to retain genes with >10 reads in at least 2 samples within the comparison subset to define a per-comparison gene universe. DESeq2 was used to normalise counts via size-factor estimation, model gene-wise dispersion using a negative-binomial generalised linear model, and test differential expression using the Wald test. Independent filtering was applied to optimise detection power by removing genes with consistently low counts. P values were adjusted for multiple testing using the Benjamini-Hochberg false discovery rate method. To improve effect-size estimates, adaptive shrinkage was applied to Iog2 fold changes. Genes were considered differentially expressed at adjusted p < 0.05. Gene ontology analysis and KEGG pathway enrichment were performed for functional interpretation.

[0441]

[0400] Formulation and Experimental Design: The doxycycline and farnesol formulations were designed based on their ability to shift hair follicle RNA expression to a pro-growth state.

[0442]

[0401] The formulations of doxycycline and farnesol were as follows:

[0443]

[0444]

[0402] The experiments of this example were conducted according to the following timeline:

[0445]

[0446] 2025-12-29

[0447]

[0448]

[0449]

[0450] 2025-12-29

[0451]

[0452]

[0403] After QC filtering, the final sample size was control n=3, farnesol n=4, doxycycline n=3, and the combination of doxycycline + farnesol n=4.

[0453]

[0404] Results:

[0454]

[0405] Global transcriptional changes: FIG. 2 depicts a principal-component analysis (PCA) assessing sample clustering and outliers. PCA revealed some level of clustering by treatment but high within-group variability for control samples, with limited separation between groups, which reduces statistical power for differential expression analyses.

[0455]

[0406] Differential expression analysis quantified treatment-associated changes: Compared with untreated control, doxycycline treatment yielded 155 significantly differentially expressed genes (adjusted p < 0.05) (FIG. 3). The combination of doxycycline + farnesol yielded 232 significantly differentially expressed genes (adjusted p < 0.05) (FIG. 5).

[0456]

[0407] Functional enrichment: KEGG pathway analysis highlighted several biological themes consistent with increased follicular growth demand. In the doxycycline-treated follicles, enrichment was observed in protein-synthesis pathways, including ribosome, translation initiation and aminoacyl-tRNA biosynthesis, driven by increased expression of ribosomal protein genes (e.g., RPS6, RPLP2, RPL2, RPL13, RPS24, and RPL3) and aminoacyl-tRNA synthetases (e.g., IARS1, AARS1, and YARS1) (FIG. 4).

[0457]

[0408] Mitochondrial energy pathways were also enriched, including electron transfer in complex I and oxidative phosphorylation. Doxycycline treatment increased expression of genes encoding complex I subunits ND1, ND2 and ND3, which are critical for ATP production (FIG. 4). In addition, one-carbon pool by folate was enriched, including up-regulation of mitochondrial folate enzymes MTHFD2 and MTHFD1L, consistent with increased nucleotide synthesis and methylation capacity in a proliferative follicular system.

[0458]

[0409] Farnesol + doxycycline combination: Combination treatment altered additional genes with hair-relevant functions. For example, CD36 was up-regulated, and EDN3 was up-regulated, consistent with pathways involved in lipid uptake and melanocyte stem-cell regenerative responses. ALX4 was up-regulated, and LCN2 was down-regulated. KEGG analysis of the combination treatment also revealed enrichment of aminoacyl-tRNA biosynthesis, driven by coordinated up-regulation of multiple aminoacyl-tRNA synthetases (including IARS1 , YARS1 , AARS1 , CARS1, and EPRS1) (FIG. 6).

[0459]

[0410] Discussion: RNA-sequencing of human hair follicular units treated with doxycycline, farnesol, and their combination identified transcriptional programs consistent with a growth-permissive2025-12-29 follicular state. Doxycycline treatment increased expression of ribosomal and aminoacyl-tRNA biosynthesis genes, consistent with elevated translational capacity required for hair-shaft production during anagen.

[0460]

[0411] Mitochondrial and metabolic pathways were also enriched. Up-regulation of complex I and oxidative phosphorylation genes suggests enhanced ATP production capacity, which is mechanistically plausible because hair follicles are energy-intensive mini-organs. Enrichment of one-carbon / folate metabolism further supports increased biosynthetic and proliferative capacity, as folate-dependent one-carbon metabolism supplies nucleotide synthesis and methylation processes.

[0461]

[0412] Despite these findings, the transcriptomic dataset showed high within-group variability and limited separation of treatment groups in PCA space, indicating that larger cohorts and additional donors may be needed to increase statistical power and validate these pathways. Nonetheless, the identified enrichment of translational, mitochondrial and one-carbon metabolism pathways provides mechanistic support for doxycycline- and doxycycline+farnesol-based topical compositions in promoting hair growth. EXAMPLE 3: Clinical Study Design for Assessing Efficacy of Disclosed Topical Doxycycline Compositions

[0462]

[0413] Purpose: To evaluate the efficacy and safety of topical doxycycline 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.

[0463]

[0414] 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 doxycycline / tetracyclines or formulation components, those receiving systemic tetracyclines, and / or conditions that confound hair growth assessment, are excluded. In embodiments, subjects who are pregnant or breastfeeding are excluded, and appropriate contraception requirements are applied where clinically appropriate.

[0464]

[0415] 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 doxycycline dose arms (e.g., 0.00001%, 0.0001%, 0.0005%, 0.01%, 0.1%, or 0.2% w / v, or other concentrations described herein).

[0465]

[0416] 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.

[0466]

[0417] 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, markers2025-12-29 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.

[0467]

[0418] 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 doxycycline concentrations at one or more visits. In embodiments, subjects are monitored for photosensitivity and gastrointestinal adverse effects, and dosing is modified according to tolerability to maintain a favorable safety profile for topical administration.

[0468]

[0419] Results: Based on ex vivo organ-culture data described herein, subjects receiving topical doxycycline are expected to exhibit increased hair density and / or increased hair shaft thickness relative to 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 doxycycline.

[0469] EXAMPLE 4: Individual Administration of Disclosed Topical Doxycycline Compositions for Treating Hair Loss

[0470]

[0420] Described herein are exemplary treatment protocols for treating hair loss by topical administration of doxycycline compositions. These protocols are provided for illustrative purposes and may be modified according to patient characteristics, scalp region affected, and clinical response.

[0471]

[0421] 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 doxycycline composition (e.g., 0.01% to 0.1% w / v) once daily or twice daily to the affected scalp for 12 to 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.

[0472]

[0422] 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 doxycycline composition (e.g., 0.00001% to 0.2% w / v) once daily for 12 to 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.

[0473]

[0423] Patient 3: Alopecia areata. Patient 3 is diagnosed with patchy alopecia areata. Patient 3 self-administers a topical doxycycline 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.2025-12-29

[0424] Patient 4: Telogen effluvium. Patient 4 presents with increased hair shedding following a physiological stressor. Patient 4 self-administers a topical doxycycline composition (e.g., 0.0001% to 0.001% w / v) once daily for 12 to 16 weeks. Patient 4 is expected to show decreased shedding and a return toward baseline anagen / telogen balance.

[0474]

[0425] 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 subjects at higher risk for adverse effects, and dosing is modified accordingly to maintain a favorable safety profile for topical administration.

[0475] EXAMPLE 5: Representative Topical Doxycycline Formulations Across Scalp-Compatible Vehicle Families

[0476]

[0426] Purpose: To provide exemplary, non-limiting topical doxycycline formulations spanning multiple vehicle families described herein, suitable for scalp application and follicular delivery.

[0477]

[0427] Dosage range: In embodiments, because topical delivery efficiency to the hair follicle bulb may vary by vehicle, doxycycline is formulated and / or administered over a broad applied concentration range, for example from 0.0513 g / mL (100 nM; 0.00000513% w / v) to 2.565 mg / mL (5 mM; 0.257% w / v) as doxycycline hyclate, or from 0.0444 g / mL (100 nM; 0.00000444% w / v) to 2.22 mg / mL (5 mM; 0.222% w / v) as doxycycline (free base). In embodiments, an algorithmic dosing model is used to estimate the applied dose needed to achieve a target bulb exposure (e.g., 1—40 pM), and the above applied range is disclosed to account for uncertainty and to provide coverage for multiple vehicles. An exemplary mid-range concentration is about 200 pg / mL (-0.02% w / v), recognizing that the preferred dose may depend on the delivery vehicle.

[0478]

[0428] Formulation set: In embodiments, doxycycline is provided as doxycycline (free base) and / or a pharmaceutically acceptable salt (e.g., hyclate), and may be present in dissolved form, complexed / ion-paired form, or as a dispersed solid depending on vehicle family.

[0479]

[0429] Formulation A (hydroalcoholic solution / gel): Doxycycline (0.0001-2% w / w); ethanol (10-70%); propylene glycol and / or butylene glycol (5-40%); water q.s.; optional thickener (e.g., HPC / HPMC, 0.1-2%); optional pH adjuster / buffer to pH 4.0-7.5; optional chelator (e.g., EDTA, 0.001-0.1%).

[0480]

[0430] Formulation B (aqueous gel): Doxycycline (0.0001-2% w / w); water q.s.; gelling agent (e.g., carbomer 0.1-2% and neutralizer, and / or HPMC 0.1-3%); humectant (e.g., glycerol 1-20%); optional buffer to pH 4.0-7.5; optional preservative and / or chelator (e.g., EDTA, 0.001-0.1%).

[0481]

[0431] Formulation C (O / W emulsion lotion / cream): Doxycycline (0.0001-2% w / w) in an aqueous phase; oil phase (5-40%) comprising one or more saturated oils / emollients; emulsifier system (0.5-10%); water q.s.; optional polymeric thickener (0.1-2%); optional pH control (pH 4.0-7.5).2025-12-29

[0432] Formulation D (microemulsion / nanoemulsion or SEDDS concentrate): Doxycycline (0.0001-2% w / w); oil (e.g., MCT, 5-40%); surfactant (5-40%); co-surfactant / solubilizer (e.g., DMI, Transcutol, or similar, 0-30%); water q.s. (for emulsion) or anhydrous concentrate (for SEDDS) that self-emulsifies upon contact with aqueous media.

[0482]

[0433] Formulation E (liposomal dispersion): Doxycycline (0.0001-1% w / w) entrapped and / or dissolved; phospholipid (0.1-10%); optional sterol (0-50 mol% of total lipid); aqueous buffer q.s. (pH 4.0-7.5); optional chelator / antioxidant (e.g., EDTA 0.001-0.1% and / or antioxidant 0.01-1%).

[0483]

[0434] Formulation F (ethosome / transethosome or deformable vesicles): Doxycycline (0.0001-1% w / w); phospholipid (0.1-5%); ethanol (10-45%); water q.s.; optional edge activator and / or additional penetration enhancers (0-10%); optional buffer / chelators.

[0484]

[0435] Formulation G (SLN / NLC lipid nanoparticles): Doxycycline (0.0001-1% w / w) in a lipid nanoparticle system; solid lipid (0.5-20%); optional liquid lipid (0-20%); surfactant (0.5-10%); aqueous phase q.s.; optional chelator / antioxidant.

[0485]

[0436] Formulation H (film-forming depot spray): Doxycycline (0.0001-2% w / w); volatile solvent system (e.g., ethanol 10-80% plus water / PG); film-forming polymer (0.1-10%); optional plasticizer (0-10%); optional pH control and stabilizers. In embodiments, the composition forms a thin, flexible film on the scalp to increase residence time and follicular delivery.

[0486]

[0437] In embodiments, one or more of the above formulations is prepared by combining components under mixing, optionally heating to dissolve excipients, adjusting pH where applicable, and filtering and / or homogenizing to achieve a desired clarity or particle / vesicle size distribution. In embodiments, compositions are packaged in light-protective containers and stored at 2-8 °C or at controlled room temperature.

[0487] EXAMPLE 6: Ex Vivo Topical Doxycycline Dosing in Human Scalp Skin Organ Culture (Air-Liquid Interface)

[0488]

[0438] Purpose: To assess follicular responses to topical doxycycline formulations applied to human scalp skin in organ culture and to compare representative vehicle families for follicular delivery and biological activity.

[0489]

[0439] Dosage range: In embodiments, because topical delivery efficiency to the hair follicle bulb may vary by vehicle, doxycycline is formulated and / or administered over a broad applied concentration range, for example from 0.0513 ig / mL (100 nM; 0.00000513% w / v) to 2.565 mg / mL (5 mM; 0.257% w / v) as doxycycline hyclate, or from 0.0444 g / mL (100 nM; 0.00000444% w / v) to 2.22 mg / mL (5 mM; 0.222% w / v) as doxycycline (free base). In embodiments, an algorithmic dosing model is used to estimate the applied dose needed to achieve a target bulb exposure (e.g., 1-40 M), and the above applied range is disclosed to account for uncertainty and to provide coverage for multiple vehicles. An exemplary mid-range2025-12-29 concentration is about 200 pg / mL (-0.02% w / v), recognizing that the preferred dose may depend on the delivery vehicle.

[0490]

[0440] Methods: Human scalp skin containing terminal hair follicles is obtained as full-thickness biopsies and cultured at an air-liquid interface in supplemented William’s E medium at 37 °C in 5% C02. After equilibration (e.g., 24 h), formulations from Example 5 (or subsets thereof) are topically applied to the epidermal surface (e.g., 1-5 pL per follicular unit or per defined scalp area) once daily or once every other day for a treatment period (e.g., 7-14 days). Vehicle controls are included for each vehicle family.

[0491]

[0441] Endpoints: Hair shaft elongation, hair cycle staging (anagen / early catagen / catagen), and morphological scoring are assessed longitudinally by imaging. At study end, tissue is embedded, cryosectioned, and analyzed by immunofluorescence and / or histochemistry for markers of proliferation, apoptosis, follicular differentiation, stem / progenitor activity, extracellular matrix remodeling, and inflammation. In embodiments, drug levels are quantified in epidermis / dermis and / or follicular compartments by LC-MS / MS.

[0492]

[0442] Results: In embodiments, topical doxycycline formulations increase hair shaft elongation and / or favor an anagen-associated follicular state relative to matched vehicle controls. In embodiments, differences between vehicle families are observed in follicular delivery (e.g., follicular drug deposition) and in biomarker readouts, enabling selection of a preferred topical formulation for further development.

[0493] EXAMPLE 7: Skin Permeation and Follicular Deposition of Topical Doxycycline Formulations

[0443] Purpose: To quantify delivery of doxycycline to follicular and skin compartments following topical administration and to compare representative vehicle families for follicular targeting and low systemic flux.

[0494]

[0444] Dosage range: In embodiments, because topical delivery efficiency to the hair follicle bulb may vary by vehicle, doxycycline is formulated and / or administered over a broad applied concentration range, for example from 0.0513 pg / mL (100 nM; 0.00000513% w / v) to 2.565 mg / mL (5 mM; 0.257% w / v) as doxycycline hyclate, or from 0.0444 pg / mL (100 nM; 0.00000444% w / v) to 2.22 mg / mL (5 mM; 0.222% w / v) as doxycycline (free base). In embodiments, an algorithmic dosing model is used to estimate the applied dose needed to achieve a target bulb exposure (e.g., 1-40 pM), and the above applied range is disclosed to account for uncertainty and to provide coverage for multiple vehicles. An exemplary mid-range concentration is about 200 pg / mL (-0.02% w / v), recognizing that the preferred dose may depend on the delivery vehicle.

[0495]

[0445] Methods: Representative formulations (e.g., 2-6 formulations from Example 5) are applied as finite doses to excised human scalp skin or porcine ear skin mounted on Franz diffusion cells. The receptor chamber contains a physiologically compatible receptor solution maintained at 32 °C with continuous stirring. At predetermined time points (e.g., 1, 4, 8, 24 h), receptor samples are collected to quantify transdermal permeation. At study end, the donor formulation is removed, and the skin is2025-12-29 processed to quantify doxycycline in stratum corneum (e.g., tape stripping), epidermis, dermis, and hair follicle-rich fractions (e.g., follicle isolation or cyanoacrylate follicular biopsy). Doxycycline is quantified by LC-MS / MS using appropriate internal standards.

[0496]

[0446] Endpoints: Primary endpoints include follicular drug deposition (e.g., ng / follicle or ng / cm2in follicular fraction) and transdermal flux (e.g., cumulative amount in receptor). Secondary endpoints include skin layer distribution and a follicular targeting index (follicular deposition relative to non-follicular skin deposition and / or receptor permeation).

[0497]

[0447] Results: In embodiments, one or more vehicle families provide enhanced follicular deposition of doxycycline with low transdermal flux relative to comparator formulations, supporting selection of a scalp-compatible, follicle-targeted topical formulation with reduced systemic exposure potential.

[0498] EXAMPLE 8: Stability and Compatibility Testing of Topical Doxycycline Formulations

[0499]

[0448] Purpose: To evaluate chemical and physical stability of doxycycline in representative topical vehicles and to identify stabilizing conditions (e.g., pH control, chelators, antioxidants, and low-peroxide excipients) suitable for commercial development.

[0500] Dosage range: In embodiments, because topical delivery efficiency to the hair follicle bulb may vary by vehicle, doxycycline is formulated and / or administered over a broad applied concentration range, for example from 0.0513 g / mL (100 nM; 0.00000513% w / v) to 2.565 mg / mL (5 mM; 0.257% w / v) as doxycycline hyclate, or from 0.0444 g / mL (100 nM; 0.00000444% w / v) to 2.22 mg / mL (5 mM; 0.222% w / v) as doxycycline (free base). In embodiments, an algorithmic dosing model is used to estimate the applied dose needed to achieve a target bulb exposure (e.g., 1—40 M), and the above applied range is disclosed to account for uncertainty and to provide coverage for multiple vehicles. An exemplary mid-range concentration is about 200 g / mL (-0.02% w / v), recognizing that the preferred dose may depend on the delivery vehicle.

[0501]

[0449] Methods: Representative formulations spanning multiple vehicle families (e.g., hydroalcoholic gel, aqueous gel, emulsion, nanoemulsion / SEDDS, vesicular carrier, and SLN / NLC; Example 5) are prepared and packaged in light-protective containers. Samples are stored under conditions including refrigerated (2-8 °C), controlled room temperature, and accelerated aging (e.g., 40 °C). In embodiments, photostability is assessed under controlled light exposure. At predetermined intervals, samples are evaluated for appearance, phase separation, viscosity / rheology, pH (where applicable), and doxycycline assay / related substances by a stability-indicating analytical method (e.g., LC-UV or LC-MS / MS).

[0502]

[0450] Acceptance criteria: In embodiments, formulations meet one or more criteria including: maintenance of physical integrity (no unacceptable phase separation), acceptable pH drift, and retention of doxycycline potency (e.g., >90% of initial assay) with controlled levels of degradation products.2025-12-29

[0451] Results: In embodiments, stability is improved by selecting an appropriate pM window, incorporating chelators (e.g., EDTA) and antioxidants where compatible, limiting peroxide content of excipients, and optimizing packaging to reduce light and oxygen exposure. Formulations meeting stability criteria are advanced for further development and scale-up.

[0503]

[0452] 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 specific 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 doxycycline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable topical delivery vehicle.

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

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

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

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

6. The topical composition of claim 5, comprising the doxycycline at a concentration of between about 1 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 oil-dominant anhydrous liquid 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 micellar solution, a silicone composition, a foam, a film-forming composition, 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 liposomes;viii. an aqueous solution comprising one or more mineral salts or phytocomplexes;lx. 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, an anhydrous oleogel or structured oil, a hydrophobic deep-eutectic or terpene-rich solvent system, an anhydrous foaming oil, a silicone-based carrier, a hydrophilic anhydrous polyol gel, a hydroalcoholic solution or gel, an aqueous gel, an emulsion, a microemulsion or nanoemulsion, a2025-12-29 Pickering emulsion, a self-microemulsifying drug delivery system, a bigel or emulgel hybrid, a liposomal or lipid-vesicle dispersion, transfersomes, ethosomes or transethosomes, invasomes, glycerosomes, niosomes or proniosomes, polymer-coated or layer-by-layer vesicles, nanostructured lipid carriers, solid lipid nanoparticles, cubosomes or hexosomes, polymeric micelles, biodegradable polymeric nanoparticles, polymer-lipid hybrid nanoparticles, chitosan nanoparticles, mesoporous silica nanoparticles, microencapsulation systems, an aqueous cyclodextrin inclusion system, a non-aqueous or aqueous nanosuspension, a foam or foamable microemulsion, a wash-off scalp vehicle, a commercial or proprietary topical base, a film-forming topical composition, an adhesive patch or transdermal reservoir, a dissolving microneedle array matrix, a solid stick or wax-stick applicator, an ointment or pomade scalp vehicle, an ionic-liquid or deep-eutectic-solvent carrier system, a depot or residence-time-extender topical vehicle, or a combination or hybrid vehicle system.

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, olanzapine, 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 tetracycline, 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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