Composition

Abstract

Disclosed herein is a composition formulated for topical use. The composition can include microparticles, at least one bioactive compound, and optionally a permeation enhancer. Also disclosed herein is the use of the composition for a method of treatment, the use comprising administering the composition to at least a portion of the skin of a subject in need thereof. The composition can be formulated for cosmeceutical purposes, excluding skin malignancies.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority from Australian Provisional Patent Application No. 2022 / 901602, filed on June 10, 2022, and Australian Provisional Patent Application No. 2023 / 900867, filed on March 28, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to compositions and methods for the topical delivery of bioactive compounds. More specifically, the present invention relates to compositions comprising a bioactive compound formulated for topical administration, methods of its application and / or administration, and its use. The composition may comprise microparticles, at least one bioactive compound, and optionally a permeability enhancer. The composition may comprise a bioactive compound such as a hormonal regulator, and the composition may be formulated for cosmetic or pharmaceutical purposes, excluding cutaneous malignancies.

Background Art

[0003] The skin is a structurally complex and relatively thick membrane that provides an effective barrier against the entry of any substance into the body. For a drug molecule to be delivered to or through the skin, it first needs to penetrate the stratum corneum and any substances on its surface. The molecule then needs to penetrate at least the epidermis, but to reach the bloodstream or lymphatic vessels, it is required to pass through the dermis and / or the capillary wall. To be absorbed in this way, the molecule needs to overcome different resistances to permeability to each type of tissue. Thus, transport through the skin membrane is a complex phenomenon. However, the first barrier to the absorption of topical compositions is presented by the cells of the stratum corneum. The stratum corneum is a thin layer of highly keratinized cells, approximately 10 - 15 microns thick, that covers most of the body.

[0004] One technique for delivering bioactive compounds through the skin is transdermal delivery. The term "transdermal delivery" is used to diffuse solutes through different layers of the skin in order to reach the systemic circulation and elicit a therapeutic effect. Active and passive approaches are used to optimize transdermal delivery. In the active approach, drug delivery is enhanced using physical methods. In the passive approach, the drug or formulation is optimized to improve skin permeability. However, drugs delivered through the skin by passive transport need to be lipophilic and have a molecular weight of less than 500 Da, which can limit passive transdermal delivery for smaller drugs. Transdermal delivery of drugs offers certain advantages, including eliminating the need for intravenous, subcutaneous, or intramuscular injections, avoiding drug degradation in the gastrointestinal tract, maintaining the drug at therapeutic concentrations for a long time, minimizing the frequency of administration, improving patient compliance, and the potential ability to terminate drug delivery by removing the transdermal patch.

[0005] Commonly used transdermal delivery systems include topical creams and subcutaneous injection needles (which can be used to deliver drugs directly to the dermis). However, topical creams have limited permeability, and subcutaneous injection needles generally cause pain and may cause damage or bleeding to the skin at the insertion site, and are thus less acceptable to patients.

[0006] Recent techniques for transdermal delivery include transdermal patches and microneedle arrays. However, transdermal patches can be limited in delivering small molecules as the small molecules have to diffuse through several layers before reaching the systemic circulation, while microneedle drug delivery systems require a support structure such as an array, increasing the complexity and cost of manufacturing and using such devices. Another drawback of transdermal patches and microneedle arrays is that their size and shape limit the delivery of bioactive compounds to the accessible area of the skin with a given surface area and reduce patient comfort due to the attachment of the patch or microneedle array.

[0007] In particular, in patients with sensitive or very thin skin, or in the case of administration to sensitive skin areas such as the genitalia, the microneedle array may present discomfort and poor patient acceptance of this delivery mode.

[0008] Furthermore, delivery via a transdermal patch is not particularly suitable for avoiding systemic administration of bioactive compounds, and the slow diffusion of small molecules that can be delivered causes these drugs to preferentially saturate receptors localized in the intradermal region of drug permeation and reach the systemic circulation instead of depositing at the application site, which can result in undesirable systemic side effects.

[0009] Accordingly, there is a need for means of local delivery of bioactive compounds through the stratum corneum that deliver the compounds primarily locally rather than systemically.

[0010] Any consideration of the documents, acts, materials, devices, articles, etc. included in this specification shall not be construed as admitting that any or all of these matters form part of the prior art base or are common general knowledge in the field related to this disclosure if any of them existed prior to the priority date of each of the appended patent claims.

Summary of the Invention

[0011] The present invention relates to a composition capable of providing advantageous topical delivery of certain bioactive compounds. The compositions described herein comprise one or more bioactive compounds and microparticles, which are engineered to preferentially penetrate the outer portion of a biological barrier such as the skin, e.g., the stratum corneum of the skin, to enable topical administration of the one or more bioactive compounds for a local effect and minimize or avoid a systemic effect. The compositions described herein can be administered, for example, by applying force to the composition on the skin surface such that at least a portion of the composition penetrates the stratum corneum of the skin to facilitate topical delivery of the one or more bioactive compounds. The compositions of the present invention can enable improved topical delivery of one or more bioactive compounds while limiting or reducing systemic entry.

[0012] Accordingly, in one aspect of the present invention, there is provided a composition comprising a plurality of microparticles, at least one bioactive compound, wherein the at least one bioactive compound is optionally a coating on at least a portion of the plurality of microparticles, and an optional permeability enhancer, wherein the composition is formulated for topical application. In one embodiment, the plurality of microparticles, the at least one bioactive compound, and the optional permeability enhancer can be applied in situ locally individually or in combination thereof, e.g., to a subject.

[0013] Also provided is a composition comprising a plurality of microparticles, at least one bioactive compound, wherein the at least one bioactive compound is a coating on at least a portion of the plurality of microparticles, and an optional permeability enhancer, wherein the composition is formulated for topical application.

[0014] Also provided is a composition comprising a plurality of microparticles, at least one bioactive compound, wherein the at least one bioactive compound is optionally a coating on at least a portion of the plurality of microparticles, and optionally a permeability enhancer, wherein the composition is formulated for topical application and provided that after application of the composition to a portion of the subject's skin, the bioactive compound is not delivered, or is substantially not delivered, to the bloodstream at all.

[0015] Also provided is a composition comprising a plurality of microparticles, at least one bioactive compound, wherein the at least one bioactive compound is optionally a coating on at least a portion of the plurality of microparticles, and a permeability enhancer, wherein the composition is formulated for topical application and provided that after application of the composition to a portion of the subject's skin, the bioactive compound is not delivered, or is substantially not delivered, to the bloodstream at all.

[0016] Also provided is a composition for topical application comprising a plurality of microparticles, optionally a permeability enhancer, and at least one bioactive compound that is a ligand of the nuclear receptor superfamily. In some embodiments, the composition further comprises a permeability enhancer.

[0017] In some embodiments, the composition is formulated for application to the skin, optionally the stratum corneum of the skin.

[0018] In some embodiments, the at least one bioactive compound is selected from the group consisting of therapeutic compounds, cosmeceuticals, pharmaceuticals, nutraceuticals, diagnostic agents, and mixtures thereof.

[0019] In some embodiments, at least one bioactive compound is optionally selected from the group consisting of estradiol, estrone, estriol, 5α-dihydrotestosterone, finasteride, cortisone, spironolactone, or mixtures thereof, a steroid or corticosteroid; minoxidil, minoxidil sulfate, or derivatives or mixtures thereof; a vitamin optionally selected from vitamins A, B, C, D3, and / or E; or a retinoid optionally selected from the group consisting of retinoic acid, tretinoin, and mixtures thereof. Other bioactive compounds can include 5-aminolevulinic acid hydrochloride, diclofenac sodium, fluorescein sodium, or mixtures thereof.

[0020] In some embodiments, the composition includes a permeability enhancer selected from the group consisting of a nonpolar solvent, a polar protic solvent, an aprotic polar solvent, an alcohol (optionally a polyol), an ionic surfactant, a nonionic surfactant solvent, an aliphatic hydrocarbon, a fatty acid, and mixtures thereof, the permeability enhancer being optionally selected from the group consisting of ethanol, dimethyl sulfoxide, propylene glycol, isopropanol, polyoxyethylene (20) sorbitan monooleate, urea, sodium dodecyl sulfate, menthol, limonene, oleic acid, isopropyl myristate, undecanoic acid, and mixtures thereof.

[0021] In some embodiments, the microparticles comprise or consist of silicon, silica, and mixtures thereof. In one embodiment, the microparticles do not contain or consist of titanium. In one embodiment, the microparticles do not contain or consist of a silicon-titanium composite.

[0022] In some embodiments, the microparticles are coated with a material, the material optionally being a dry coating and optionally selected from the group consisting of alginate, crosslinked alginate, carboxymethyl cellulose, and mixtures thereof.

[0023] In some embodiments, the microparticles have the following characteristics: - The microparticles are cylindrical or substantially cylindrical, and / or - The microparticles are elongated and optionally have an aspect ratio of about 2:1 to about 50:1, or about 5:1 to about 50:1, optionally about 10:1 to about 20:1, and / or - The microparticles are etched, and / or - The microparticles are hollow, solid, or a mixture thereof, and / or - At least a portion of the microparticles has one or more substantially flat ends, and / or - At least a portion of the microparticles has one or more substantially convex ends, and / or - The strength of the microparticles is such that it can withstand an applied force of at least 0.1 Newton, and / or - The microparticles have at least one of being substantially uniform in size.

[0024] In some embodiments, the composition is in the form of a liquid, gel, ointment, cream, lotion, paste, plaster, spray, or any mixture thereof.

[0025] In some embodiments, the composition - At least one solvent optionally selected from the group consisting of water, ethanol, and mixtures thereof, and / or - A gelling agent and / or crosslinking agent optionally selected from the group consisting of carboxymethyl cellulose, salts, and mixtures thereof, wherein the salt is optionally selected from the group consisting of calcium chloride and mixtures thereof, further comprising a gelling agent and / or crosslinking agent.

[0026] In some embodiments, the compositions defined herein are provided on the condition that, after application of the composition to a portion of the subject's skin, little or substantially no bioactive compound is delivered to the bloodstream.

[0027] In some embodiments, when formulated for topical delivery, there are provided the compositions, pharmaceutical compositions, and / or cosmeceutical compositions described herein.

[0028] Also provided is a pharmaceutical composition comprising the composition defined herein and at least one pharmaceutically acceptable excipient.

[0029] Also provided is a cosmeceutical composition comprising the composition defined herein and at least one excipient, optionally at least one pharmaceutically acceptable excipient.

[0030] Also provided is an applicator adapted to administer the composition defined herein, the pharmaceutical composition defined herein, or the cosmeceutical composition defined herein. In some embodiments, the applicator comprises a microtextured surface. In some embodiments, the microtextured surface comprises angled surfaces that define spaces for receiving microparticles during use of the applicator.

[0031] Also provided is a method of treating and / or preventing at least one menopausal symptom in a subject, the method comprising administering to the subject the composition defined herein, the pharmaceutical composition defined herein, and / or the cosmeceutical composition defined herein.

[0032] Also provided is the use of the composition defined herein, the pharmaceutical composition defined herein, or the cosmeceutical composition defined herein in the manufacture of a medicament for the treatment and / or prevention of at least one menopausal symptom in a subject.

[0033] Also provided are a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein for use in treating and / or preventing at least one menopausal symptom in a subject. In some embodiments, the at least one menopausal symptom is optionally selected from the group consisting of hot flashes, night sweats, tingling or itching sensations under the skin, headache, fatigue, frequent urination, vaginal dryness, and mixtures thereof.

[0034] Also provided is a method of hydrating and / or increasing collagen formation in at least a portion of a subject's skin, the method comprising administering to the subject a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein.

[0035] Also provided is the use of a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein for hydrating and / or increasing collagen formation in at least a portion of a subject's skin.

[0036] Also provided is a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein for use in hydrating and / or increasing collagen formation in at least a portion of a subject's skin.

[0037] Also provided is a method of improving or treating the appearance of a subject's skin, the method comprising administering to the skin an effective amount of a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein.

[0038] Also provided is the use of a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceutical cosmetic composition as defined herein for improving and / or treating the appearance of a subject's skin.

[0039] Also provided is a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceuticocosmetic composition as defined herein for use in improving or treating the appearance of the skin of a subject.

[0040] Also provided is a method of treating and / or preventing hair loss in a subject, the method comprising administering to the subject a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceuticocosmetic composition as defined herein, the composition being formulated for topical application and comprising at least one bioactive compound optionally comprising minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof.

[0041] Also provided is the use of a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceuticocosmetic composition as defined herein in the manufacture of a medicament for treating and / or preventing hair loss in a subject, the composition being formulated for topical application and comprising at least one bioactive compound optionally comprising minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof.

[0042] Also provided is a composition as defined herein, a pharmaceutical composition as defined herein, or a pharmaceuticocosmetic composition as defined herein for use in treating and / or preventing hair loss in a subject, the composition being formulated for topical application and comprising at least one bioactive compound optionally comprising minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof. In some embodiments, the at least one bioactive compound comprises minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, or a mixture thereof. In some embodiments, the hair loss is male pattern hair loss.

[0043] Also provided is a method of treating and / or preventing hirsutism in a subject, the method comprising administering a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein, wherein the composition is formulated for topical application and wherein the at least one bioactive compound optionally comprises spironolactone or a derivative thereof.

[0044] Also provided is the use of a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein in the manufacture of a medicament for treating and / or preventing hirsutism in a subject, wherein the composition is formulated for topical application and wherein the at least one bioactive compound optionally comprises spironolactone or a derivative thereof.

[0045] Also provided is a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein for use in treating and / or preventing hirsutism in a subject, wherein the composition is formulated for topical application and wherein the at least one bioactive compound optionally comprises spironolactone or a derivative thereof. In some embodiments, the at least one bioactive compound comprises spironolactone or a derivative thereof.

[0046] Also provided is a method of treating and / or preventing a dermatological condition or disorder in a subject, the method comprising administering to the subject a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein.

[0047] Also provided is the use of a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein in the manufacture of a medicament for treating and / or preventing a dermatological condition or disorder in a subject.

[0048] Also provided are the compositions defined herein, the pharmaceutical compositions defined herein, or the cosmeceutical compositions defined herein for use in treating and / or preventing a dermatological condition or disease in a subject. In some embodiments, the dermatological condition or disease is acne.

[0049] A method for delivering at least one bioactive compound through the stratum corneum of a subject's skin for cosmeceutical purposes, excluding cutaneous malignancies, the method comprising administering a composition defined herein or a cosmeceutical composition defined herein, wherein the bioactive compound is optionally, in the presence of a further hormonal regulator, optionally estradiol, estrone, estriol, or a retinoid.

[0050] Also provided is the use of a composition defined herein, a pharmaceutical composition defined herein, or a cosmeceutical composition defined herein for delivering at least one bioactive compound through the stratum corneum of a subject's skin for cosmeceutical purposes, excluding cutaneous malignancies, wherein the bioactive compound is optionally, in the presence of a further hormonal regulator, optionally estradiol, estrone, estriol, or a retinoid.

[0051] Also provided is a composition defined herein, a pharmaceutical composition defined herein, or a cosmeceutical composition defined herein for use in delivering at least one bioactive compound through the stratum corneum of a subject's skin for cosmeceutical purposes, excluding cutaneous malignancies, wherein the bioactive compound is optionally, in the presence of a further hormonal substance, optionally estradiol, estrone, estriol, or a retinoid.

[0052] In some embodiments, the composition is administered at least once a day for a period of at least one month.

[0053] In some embodiments, the composition is administered with the aid of an applicator as defined herein.

[0054] In some embodiments, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Embodiments of the invention are further described and illustrated by way of example only with reference to the accompanying drawings.

[0056]

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Modes for Carrying Out the Invention

[0057] The present invention describes the following various non-limiting examples.

[0058] General Definitions and Terms In the following description, reference is made to the accompanying drawings which form a part of this specification and illustrate several embodiments by way of example. It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.

[0059] With respect to the definitions provided in this specification, unless otherwise stated or indicated by context, defined terms and phrases include the provided meanings. In addition, unless otherwise expressly stated or not apparent from the context, the following terms and phrases do not exclude the meaning that the term or phrase would be understood by one of ordinary skill in the relevant art. The definitions are provided to assist in the description of specific embodiments and are not intended to limit the claimed invention, as the scope of the present invention is limited only by the claims. Further, unless otherwise required by context, terms in the singular shall include the plural, and terms in the plural shall include the singular.

[0060] All publications discussed and / or referenced in this specification are hereby incorporated by reference in their entirety.

[0061] Throughout this specification, unless otherwise specifically described or the context requires otherwise, references to a single step, composition of matter, group of steps, or group of compositions of matter shall be construed to include one and more (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an", and "the" include plural aspects unless the context clearly dictates otherwise. For example, references to "a" include one as well as two or more, references to "an" include one as well as two or more, references to "the" include one as well as two or more, and so forth.

[0062] One of ordinary skill in the art will understand that the disclosure of this specification is susceptible to variations and modifications other than those specifically described. It is understood that the disclosure includes all such variations and modifications. The disclosure also includes all examples, steps, features, methods, compositions, formulations, articles, uses, coatings, and processes, individually or collectively recited or shown herein, and any and all combinations, or any two or more of the recited steps or features.

[0063] The term "and / or", e.g., the term "X and / or Y", is understood to mean either "X and Y" or "X or Y", and shall be construed to provide explicit support for both meanings or either meaning.

[0064] Unless otherwise indicated, in this specification, terms such as "first", "second", etc. are used merely as labels and are not intended to impose any sequential, positional, or hierarchical requirements on the items they refer to. Further, a reference to a "second" item does not require or exclude the presence of a lower-numbered item (e.g., a "first" item) and / or a higher-numbered item (e.g., a "third" item).

[0065] As used herein, the phrase "at least one of" when used in conjunction with a listing of items means that different combinations of one or more of the listed items may be used, and only one of the items in the listing may be required. An item may be a particular object, thing, or category. In other words, "at least one of" means that any combination of items or some of the items may be used from the listing, but not all of the items in the listing are required. For example, "at least one of item A, item B, and item C" may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, "at least one of item A, item B, and item C" may mean, for example, but not limited to, 2 item As, 1 item B, and 10 item Cs; 4 item Bs and 7 item Cs; or some other suitable combination.

[0066] In the context of separate embodiments, for clarity, it is understood that certain features described herein may also be provided in combination in a single embodiment. Conversely, for brevity, the various features described in the context of a single embodiment may also be provided separately or in any sub-combination.

[0067] Throughout this specification, various aspects and components of the invention may be presented in a range format. This range format is included for convenience only and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, a range description should be considered to specifically disclose all the possible sub-ranges within that range, as well as individual numerical values, unless otherwise specifically indicated. For example, a range description such as 1 to 5 should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., and individual numbers and fractional numbers within the recited range, such as 1, 2, 3, 4, 4.5, and 5, unless integers are required otherwise or indicated from the context. This applies regardless of the width of the disclosed range. When specific values are required, they are indicated in the specification.

[0068] As used herein, the term "topical composition" refers to a composition suitable for application to the surface of a body part of interest or to a localized area of the body. In one embodiment, the surface of the body part includes the skin. In some embodiments, the surface of the body part includes mucous membranes, vagina, oral cavity, lesions, scars, wound sites, etc. As used herein, a composition or topical composition can be in a form including, but not limited to, creams, emulsions, gels, ointments, lotions, pastes, solutions, pastes, plasters, emulsions, sprays, suspensions, foams, etc. In one embodiment, the composition or topical composition can be in the form of a bioadhesive. In one embodiment, the composition or topical composition can be a component such as an impregnated pad and / or article.

[0069] In some embodiments, the invention describes the "topical application" of a composition. As defined herein, "topical application" is the application of a composition to the surface of a body part of interest or to a localized area of the body and can include application to the surface and rubbing in.

[0070] As used herein, the term "cosmetic" refers to an item intended to be rubbed, poured, sprinkled, or sprayed, introduced, or applied to the human body for cleansing, beautifying, enhancing attractiveness, or altering appearance.

[0071] As used herein, "cosmeceutical" refers to a composition capable of providing both cosmetic and / or pharmaceutical effects. Cosmetics can temporarily treat the symptoms of a condition on a certain area of the skin, while cosmeceuticals can treat one or more underlying conditions related to the symptoms. In one example, the cosmeceuticals encompassed by the present disclosure can regenerate the hair of a subject.

[0072] The recipient of a composition of a formulation defined herein may be referred to by the synonymous terms "recipient", "individual", "patient", and "subject". These three terms are used synonymously and refer to any human or animal as defined herein (unless otherwise indicated). In one example, the subject is human. In one example, the human is an adult.

[0073] The recipient of a composition or formulation defined herein can be male or female, human or non-human animal. In one embodiment, the subject is a human subject. In one embodiment, the subject is female. In another embodiment, the subject is female and suffering from menopause. In another embodiment, the subject is male. In one embodiment, the male subject is suffering from hair loss. In another embodiment, the subject is suffering from hirsutism (excessive hair) in a non-scalp area of the body. In one example, a subject with hirsutism has polycystic ovary syndrome.

[0074] As used herein, the term "skin condition" encompasses the conditions, disorders, or diseases of humans and animals that affect the skin. Such skin conditions can include, but are not limited to, conditions involving the epidermis, dermis (including connective tissue, sebaceous glands, and hair follicles), and subcutaneous tissue (hypodermis).

[0075] As used herein, "skin rejuvenation" means a process that reduces, decreases, delays, or reverses one or more signs of skin aging. For example, common signs of skin aging include, but are not limited to, the appearance of fine lines or wrinkles, thin and transparent skin, loss of collagen, or loss of subcutaneous fat. According to the present invention, one or more of the above signs of skin aging can be reduced, decreased, delayed, or even reversed by the compositions and methods of the present invention. In certain embodiments, one or more signs of skin aging that are suitable for reduction, decrease, delay, or even reversal by the compositions and methods of the present invention are associated with the onset of menopause.

[0076] Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising", is understood to imply the inclusion of a stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0077] Throughout this specification, the term "consisting essentially of" is intended to exclude elements that would materially affect the characteristics of the claimed composition.

[0078] In this specification, the terms "comprising", "comprise", and "comprises" are each, in any case, optionally intended to be replaceable with the terms "consisting essentially of", "consist essentially of", "consists essentially of", "consisting of", "consist of", and "consists of".

[0079] As used herein, the term "about" encompasses a 10% tolerance range in any value or values connected to the term.

[0080] As used herein, "weight %" may be abbreviated as "weight % (wt%)" or "weight % (wt.%)".

[0081] Unless otherwise stated directly or not apparent from the context, in this specification, the concentration by percentage of a component may refer to w / w%, v / v%, or w / v%.

[0082] Composition Disclosed herein is a composition comprising: ● a plurality of microparticles; and ● at least one bioactive compound, wherein the at least one bioactive compound is optionally a coating on at least a portion of the plurality of microparticles; and ● optionally, a permeation enhancer, wherein the composition is formulated for topical application. Also disclosed herein is a composition comprising:

[0083] ● a plurality of microparticles; and ● at least one bioactive compound (optionally as a coating on at least a portion of the at least one microparticle); and ● optionally, a permeation enhancer, wherein the composition is formulated for topical application and on the condition that after application of the composition to a portion of the skin of a subject, the bioactive compound is not delivered, or is substantially not delivered, to the bloodstream at all. ● optionally, a permeation enhancer, wherein the composition is formulated for topical application. Also disclosed is a composition for topical application comprising a plurality of microparticles, optionally a permeation enhancer, and at least one bioactive compound that is a ligand of the nuclear receptor superfamily.

[0084]

[0085] ​ The compositions disclosed herein are not particularly limited as long as they are suitable for topical administration (e.g., application to the skin of a subject). Thus, the compositions can be formulated for any form known in the art for topical application. Exemplary forms include, but are not limited to, liquids, aqueous solutions, alcoholic solutions, emulsions, foams, gels, ointments, lotions, creams, waxes, paints, pastes, powders, pastes, bioadhesives, plasters, emulsions, sprays, suspensions, and the like. The compositions disclosed herein can be formulated for application to various body surfaces including the skin, mucous membranes such as the oral mucosa, vaginal or cervical epithelium, or anal canal, and the scalp and hair.

[0086] In one embodiment, the compositions disclosed herein are in liquid form.

[0087] The composition can include one or more solvents. Any suitable solvent or combination of solvents can be used in the composition. Examples of suitable solvents include, but are not limited to, water, alcohol, acetone, methyl alcohol, ethanol, isopropanol, butyl alcohol, ethyl acetate, dimethyl isosorbide, propylene glycol, glycerol, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, or mixtures thereof. In some embodiments, the solvent includes ethanol. In some embodiments, the solvent includes a mixture of water and ethanol. In some embodiments, the solvent includes isopropyl alcohol. Further examples of suitable solvents include lanolin alcohol, fatty alcohols (e.g., cetearyl alcohol, cetyl alcohol), glycols (e.g., propylene glycol, polypropylene glycol), oils and waxes (e.g., mineral oil, paraffin), isopropyl myristate, or oleic acid.

[0088] The compositions of the present specification may include one or more solvents having the same and / or different boiling points. The solvents can be selected based on several factors including, but not limited to, toxicity, density, viscosity, dielectric constant, dipole moment, and / or melting and boiling points. "Solvent" can be classified broadly into low boiling point: boiling point range less than 100 °C; medium boiling point: boiling point range of 100 °C to 150 °C; high boiling point: boiling point range greater than 150 °C according to the boiling temperature at 1 bar. Low boiling point solvents are highly volatile solvents, while high boiling point solvents tend to be less evaporative and can thus be defined as low volatility solvents. The one or more solvents can have a boiling point of less than about, at least about, or about 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, or 150 °C. For example, at least the solvent can have a boiling point in the range of about 40 °C to about 100 °C and / or a high vapor pressure.

[0089] In one embodiment, the solvent is a mixture of water and ethanol such as a mixture of water and ethanol at 95:5 v / v, 90:10 v / v, 85:15 v / v, 80:20 v / v, 75:25 v / v, 70:30 v / v, 65:35 v / v, 60:40 v / v, 55:45 v / v, 50:50 v / v, 45:55 v / v, 40:60 v / v, 35:65 v / v, 30:70 v / v, 25:75 v / v, 20:80 v / v, 15:85 v / v, 10:90 v / v, or 5:95.

[0090] One or more solvents can be present in an amount of from about 2% to about 99.99% based on the total weight of the composition. One or more solvents can be provided in an amount of about 99.99, 99.95, 99.9, 99.5, 99, 98, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or less than 2 (as weight % based on the total weight of the composition). One or more solvents can be provided in an amount of at least about 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, 99, 99.5, 99.9, 99.95, or 99.99 (as weight % based on the total weight of the composition). One or more solvents can be in the range provided by any two of these upper and / or lower limits. In some embodiments, one or more solvents are provided in an amount of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weight % based on the total weight of the composition.

[0091] It will be understood that one or more solvents can preferably be one or more substances that can also act as diluents, permeability enhancers, viscosity enhancers, or film formers. For example, one or more solvents can be provided as permeability enhancing compounds. The carrier material can also include encapsulating materials.

[0092] In one embodiment, the composition includes water. In one embodiment, any water added to the composition is pharmaceutically grade water, for example, water pharmaceutically acceptable according to the British Pharmacopoeia.

[0093] In some embodiments, the composition comprises a buffer. For example, the buffer can be selected from the group consisting of, but not limited to, glycerol, glutathione, phosphate buffers (e.g., sodium hydrogen phosphate and potassium hydrogen phosphate buffers), acetate buffers, phosphate buffers, citrate buffers, Tris buffers, maleate buffers, succinate buffers, histidine buffers, amino acids (e.g., histidine, arginine, and glycine), or mixtures thereof. Other non-limiting examples of suitable buffers can include, but are not limited to, sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.

[0094] One or more pH buffers may be present and, when dissolved in the aqueous component of the composition, can provide a pH in the range of about 5 to about 7. For example, the pH can be a pH of about, at least about, or less than about 5.5, 6, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5. The pH can be in the range of any one of the recited values.

[0095] In some embodiments, the buffer is present in the composition and is provided in an amount of about 0.01 to about 15 weight percent, based on the total weight of the composition. The buffer can be provided in an amount less than about 15, 10, 5, 1, 0.5, 0.1, 0.05, or 0.01 (as weight percent based on the total weight of the composition). The buffer can be provided in an amount of at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, or 15 (as weight percent based on the total weight of the composition). The buffer can be in the range provided by any two of these upper and / or lower limits.

[0096] In another embodiment, the composition comprises a solvent, such as a mixture of water and ethanol.

[0097] In some embodiments, the compositions disclosed herein are in the form of an aqueous solution or an alcohol solution.

[0098] Solutions are generally homogeneous mixtures where one or more components of the composition can be prepared by dissolving them in one or more of the solvents described herein (e.g., water-soluble solvents), such that the components of the composition are dispersed within one or more solvents. Solutions can contain other pharmaceutically and / or cosmetically acceptable chemicals to buffer, stabilize, or preserve the components of the composition. Examples of one or more solvents that can be used in preparing topical compositions include, but are not limited to, water, alcohols (e.g., ethanol, isopropyl alcohol, benzyl alcohol), lanolin alcohol, fatty alcohols (e.g., cetearyl alcohol, cetyl alcohol), glycols (e.g., propylene glycol, polypropylene glycol), oils and waxes (e.g., mineral oil, paraffin), isopropyl myristate, or oleic acid. These can be applied in any manner, such as spraying them onto at least a portion of the skin, or applying or painting them onto at least a portion of the skin.

[0099] In some embodiments, the compositions disclosed herein are formulated as liquid sprays.

[0100] Compositions in the form of liquids, solutions, or liquid sprays can be applied in any suitable manner, such as painting or spraying onto the body surface. Solutions can be applied to the surface using a dropper, cotton swab, spray, etc.

[0101] In some embodiments, the compositions disclosed herein are formulated as gels, liquids, creams, lotions, or ointments.

[0102] In some embodiments, the composition comprises a viscosity enhancer and / or a film-forming agent. The viscosity enhancer increases the viscosity of the composition to inhibit the spread of the composition beyond the site of application. Any suitable viscosity increasing agent may be used to formulate the composition, and combinations of viscosity increasing agents may also be used. In some embodiments, a polymeric moiety of the viscosity increasing agent may be present and can act as a viscoelastic material to hold the composition at the site of application. Examples of viscosity increasing agents include, but are not limited to, copolymers of carboxymethyl cellulose and acrylic acid, N-vinylpyrrolidone, polyalkylene glycols (e.g., poly(ethylene glycol)), polyalkylene oxides (e.g., polyethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, polysiloxanes, poly(vinyl acetate), cellulose, derivatized cellulose, alginates, copolymers thereof, and blends thereof. For example, the thickening agent can be hydroxypropyl cellulose such as Klucel® hydroxypropyl cellulose. It will be understood that the viscosity enhancers described herein may also have gelling and / or cross-linking properties.

[0103] The film-forming agent forms a protective film on the site of application when dried. In addition, the film-forming agent can act as a solvent. The solution that dries to form the film may be referred to as a paint.

[0104] In one embodiment, the composition disclosed herein is in the form of a gel, such as a topical gel.

[0105] Gels, hydrogels are semi-solid suspension-type systems. A single-phase gel contains organic macromolecules that are substantially uniformly distributed throughout the carrier liquid, which can be aqueous but can also include alcohol and optionally oil.

[0106] In some embodiments, the composition optionally comprises at least one gelling agent and / or cross-linking agent, optionally selected from cross-linked acrylic polymers such as those of the "carbomer" family of polymers, such as carboxypolyalkylene commercially available as Carbopol®. Hydrophilic polymers may also be used. For example, polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersing agent such as alcohol or glycerin may be added, or the gelling agent may be dispersed by trituration, mechanical mixing or stirring, or mixtures thereof.

[0107] In some embodiments, the composition comprises at least one gelling agent and / or cross-linking agent, selected from, but not limited to, carboxymethyl cellulose, salts, and mixtures thereof. Examples of salts include calcium chloride. Other salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate; amino acid salts such as alginate, aspartate, glutamate; metal salts such as sodium salt, potassium salt, cesium salt; alkaline earth metal salts such as calcium salt, magnesium salt; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt.

[0108] In some embodiments, the composition comprises at least one carbohydrate that can also act as a gelling agent and / or a crosslinking agent. "Carbohydrate" refers to a sugar or a polymer of sugars. The terms "sugar", "polysaccharide", "carbohydrate", and "oligosaccharide" may be used synonymously. Most carbohydrates are aldehydes or ketones that usually have one hydroxyl group on each carbon atom of many molecules. Carbohydrates generally have the molecular formula C n H 2n O nhaving, wherein n is an integer. The carbohydrate can be a monosaccharide, disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrates are monosaccharides, and examples include glucose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two joined monosaccharides. Examples of disaccharides include sucrose, maltose, cellobiose, trehalose, and lactose. Oligosaccharides can contain 3 to 6 monosaccharide units (e.g., raffinose, stachyose), and polysaccharides can contain 6 or more monosaccharide units. Examples of polysaccharides include starch, glycogen, and cellulose. Carbohydrates can include modified sugar units such as 2'-deoxyribose with a hydroxyl group removed, 2'-fluororibose with a hydroxyl group replaced by fluorine, or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose). Carbohydrates can exist in many different forms, such as conformational isomers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers. For example, polysaccharides can be selected from the group consisting of or comprising dextran sulfate, pectin, modified pectin, insoluble 1,3-β-D glucan, microgranulated 1,3-β-D glucan, soluble 1,3-β-D glucan, phosphorylated 1,3-β-D glucan, aminated 1,3-β-D glucan, and carboxymethylated 1,3-β-D glucan, sulfated 1,3-β-D glucan, insoluble 1,3 / 1,6-β-D glucan, microgranulated 1,3 / 1,6-β-D glucan, soluble 1,3 / 1,6-β-D glucan, phosphorylated 1,3 / 1,6-β-D glucan, aminated 1,3 / 1,6-β-D glucan, and carboxymethylated 1,3 / 1,6-β-D glucan, or sulfated 1,3 / 1,6-β-D glucan.

[0109] In some embodiments, at least one gelling agent and / or crosslinking agent, and / or at least one carbohydrate is used as a coating excipient for the microparticles in the composition.

[0110] In some embodiments, at least one carbohydrate comprises an alginate-based compound, such as alginic acid, an alginic acid derivative, and a salt of alginic acid (alginates), or a salt of the derivative. Alginic acid (sometimes referred to in the literature as "algin" or "alginate") is an anionic polysaccharide widely distributed in the cell walls of algae. Alginic acid is a linear copolymer in which the (1-4)-linked β-D-mannuronic acid (M) and its C-5 epimer α-L-guluronic acid (G) residues are covalently bonded together in different sequences or blocks. The monomers can occur as homopolymer blocks of consecutive G residues (G blocks), consecutive M residues (M blocks), or alternating M and G residues (MG blocks). Alginic acid can form water-soluble salts (alginates) with substitution cations such as alkali metals like sodium, potassium, or lithium, lower amines such as methylamine, ethanolamine, diethanolamine, or triethanolamine, and ammonium. Algininate-based compounds can be water-soluble.

[0111] Non-limiting examples of salts of alginic acid (alginates) include, but are not limited to, sodium alginate, potassium alginate, magnesium alginate, calcium alginate, propylene glycol alginate, ammonium alginate, triethanolamine alginate, or mixtures thereof. In some cases, the composition may comprise alginic acid, sodium alginate, potassium alginate, or mixtures thereof, especially since the composition is particularly water-soluble.

[0112] The amount of gelling agent and / or cross-linking agent, and / or at least one carbohydrate in the composition can vary, but can be about or at least about 0.1 to about 20% by weight, based on the total weight of the composition. The total amount of gelling agent and / or cross-linking agent, and / or at least one carbohydrate in the composition can be about 0.1 to about 15% by weight, about 0.1 to about 10% by weight, about 0.1 to about 5% by weight, about 0.1 to about 4% by weight, about 0.1 to about 3% by weight, about 0.1 to about 2% by weight. The amount can be about 0.5 to about 20% by weight, about 0.5 to about 15% by weight, about 0.5 to about 10% by weight, about 0.5 to about 5% by weight, about 1 to about 20% by weight, about 1 to about 15% by weight, about 1 to about 10% by weight, or about 1 to about 5% by weight, based on the total weight of the composition. In some embodiments, the amount of gelling agent and / or cross-linking agent, and / or at least one carbohydrate in the composition is about 0.1% to about 5% by weight, about 0.2% to about 4% by weight, about 0.3% to about 3% by weight, about 0.4% to about 2% by weight, about 0.5% to about 1% by weight, based on the total weight of the composition.

[0113] The gel can be formulated to have a relatively high level of volatile solvent or excipient. In some embodiments, the weight percent of the volatile is greater than about 55%, or any range therein. In certain embodiments, the weight percent of the volatile is about 55%, 60%, 65%, 70%, 75%, 80%, or 85% by weight.

[0114] In another embodiment, the compositions disclosed herein are formulated as a cream.

[0115] The cream base is washable with water and can include an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, can include petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and can include a humectant. The emulsifier in the cream formulation can include nonionic, anionic, cationic, or amphoteric surfactants.

[0116] In another embodiment, the compositions disclosed herein are formulated as a lotion.

[0117] A lotion is a preparation that is applied to the skin surface without friction and can be a liquid or semi - liquid preparation in which one or more components of the composition are present in an aqueous or alcoholic base. A lotion is usually a suspension of solids and can include an oil - in - water type liquid oil emulsion. Lotions can be used to treat large body areas because of the ease of applying a more fluid composition. Generally, it is necessary to finely divide the insoluble substances in a lotion.

[0118] A lotion can include suspending agents for producing a better dispersion, as well as compounds useful for localizing and retaining one or more components of the composition in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0119] In another embodiment, the compositions disclosed herein are formulated as an ointment.

[0120] An ointment is a semi - solid preparation and can be based on petrolatum or other petroleum derivatives. As will be understood by those skilled in the art, the particular ointment base used provides several desired characteristics, such as emolliency, etc. Ointment bases are generally inert, stable, non - irritating, and non - sensitizing. Ointment bases are classified into four classes: oleaginous bases, emulsifiable bases, emulsion bases, and water - soluble bases (Remington: The Science and Practice of Pharmacy, 19 thSee Ed. (Easton, PA: Mack Publishing Co., 1995), at pages 1399-1404). Examples of oily ointment bases include vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifying ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion or microemulsion ointment bases can be either water-in-oil (W / O) emulsions, biocontinuous emulsions, or oil-in-water (O / W) emulsions, and include, for example, acetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights.

[0121] In some embodiments, the compositions disclosed herein are in the form of a paste or a powder.

[0122] In some embodiments, the composition includes at least one water repelling agent, also referred to as a water repellent. Examples of water repelling agents include silicones such as cyclomethicone, dimethicone, simethicone, C 26 -C 28 alkyldimethicone, C 26 -C 28 alkylmethicone, polyphenylsilsesquioxane, trimethylsiloxysilicate, and a copolymer of cyclopentasiloxane and dimethicone / vinyltrimethylsiloxysilicate, and blends thereof.

[0123] In one embodiment, the compositions disclosed herein are formulated as a paste. The paste is in a semi-solid form, wherein the composition comprises a suitable base. Depending on the nature of the base, the paste is divided into a fatty paste or a paste made from a single-phase aqueous gel. The base in the fatty paste is generally petrolatum or hydrophilic petrolatum, etc. The paste made from a single-phase aqueous gel generally incorporates carboxymethyl cellulose, etc. as a base.

[0124] The compositions disclosed herein can be formulated for application to the skin of a subject, optionally to the stratum corneum of the skin.

[0125] As used herein, the compositions disclosed herein can be formulated as creams, lotions, gels, ointments, pastes, etc., which can be spread on the surface of the skin of a subject. Compositions that can be in the form of a liquid or a solution can be applied in the same manner, but can be carefully applied to the subject (e.g., to the affected area or areas in need thereof) by means of a dropper, a cotton swab, an atomizer, an applicator, etc. The topical application of the compositions disclosed herein to the surface of a body part of a subject or to a localized area of the body can include applying to the surface and rubbing in. The compositions disclosed herein can be applied directly to the target location, for example, in the form of a topical composition such as a liquid, a gel, or a cream, or as part of a bandage, or a dressing, or a patch. In one embodiment, the topical composition excludes the patch form. In another embodiment, the topical composition does not contain a hydrogel. In another embodiment, the topical composition does not form part of a patch.

[0126] The compositions disclosed herein can be formulated as cosmetic, cosmeceutical, and / or pharmaceutical compositions, optionally together with one or more excipients.

[0127] Also disclosed herein is a pharmaceutical composition comprising the composition as defined herein and at least one pharmaceutically acceptable excipient.

[0128] Also disclosed herein is a pharmaceutical-cosmetic composition comprising the composition defined herein and optionally at least one pharmaceutically or cosmetically acceptable excipient.

[0129] Also disclosed herein is a cosmetic composition comprising the composition defined herein and optionally at least one cosmetically acceptable excipient.

[0130] It will be understood that the compositions, pharmaceutical compositions, and / or pharmaceutical-cosmetic compositions disclosed herein may include one or more additional additives known in the art, such as one or more excipients.

[0131] The compositions, pharmaceutical compositions, and / or pharmaceutical-cosmetic compositions disclosed herein may also include conventional excipients well known to those skilled in the art. Examples of other components that may also be excipients include, but are not limited to, colorants, surfactants, preservatives, antioxidants, acid regulators, thickeners, stabilizers, emulsifiers, osmotic pressure increasing agents, pH regulators, fragrances, bulking agents, suspending agents, stabilizers, and / or dispersants, and mixtures thereof.

[0132] Excipients for use in the compositions disclosed herein are well known in the art and examples can be found in the Handbook of Pharmaceutical Excipients (Rowe, R.C. et al., APhA Publications; 5 th ed., 2005). Classes of excipients include, but are not limited to, waxes, softeners, thickeners / viscosity increasing agents, humectants, pH adjusters, water repellents, defoamers, surfactants, solubilizers, wetting agents, permeability enhancing agents, antioxidants, and solvents. Excipients may also be present in topical compositions at any suitable concentration. In some embodiments, the composition comprises the excipient at a concentration in the range of about 1 to about 99.99 weight percent.

[0133] As further examples of excipients for formulating the compositions disclosed herein, any suitable humectant, or combination of humectants, may be mentioned. Examples include, but are not limited to, glycols such as diethylene glycol monoethyl ether, glycerol; sugar polyols such as sorbitol, xylitol, and maltitol; polyols such as polydextrose; chitosan, urea, and blends thereof. In some embodiments, the humectant may include alkylene glycols such as hexylene glycol.

[0134] In addition, other specific skin-beneficial active agents such as, but not limited to, sunscreen agents, skin protectants, skin soothers, moisturizers, skin lightening agents, sunburn accelerators, whitening agents, agents for reducing spots, pigmentation, and scarring, collagen precursors, lipids and small molecule anti-wrinkle agents, and anti-inflammatory agents may also be included in the compositions, pharmaceutical compositions, and / or cosmeceutical compositions disclosed herein.

[0135] The compositions disclosed herein can be in a form that enables delivery of one or more bioactive compounds to at least a portion of the skin of a subject in need thereof via contact with the compositions disclosed herein. The term "in need thereof" includes both pharmaceutical or health-related needs (e.g., treating one or more symptoms of menopause), as well as cosmetic and subjective needs (e.g., changing or improving the appearance of a portion of the skin; improving the elasticity of the skin, the hydration of the skin, the firmness, the skin tone, the skin color, and / or the texture of the skin; increasing the softness of the skin; treating a crawling sensation; strengthening, preventing loss of, and / or regenerating hair).

[0136] The compositions disclosed herein can include components / excipients found in topical pharmaceutical or pharmaceutic-cosmetic compositions that include a dermatologically and / or pharmaceutically acceptable carrier, vehicle, or medium that is compatible with the tissue to which it is applied. As used herein, the term "dermatologically and / or pharmaceutically acceptable" means that the compositions or components so described are suitable for use in contact with these tissues or for use in a patient generally without undue toxicity, incompatibility, instability, allergic response, etc. Optionally, the compositions disclosed herein can include any components conventionally used in the fields considered, particularly in cosmetics and dermatology.

[0137] In some embodiments, the compositions disclosed herein include one or more components / excipients selected from, but not limited to, antioxidants, preservatives, stabilizers, binders, compression agents, lubricants, dispersion enhancers, and / or colorants, and mixtures thereof. For example, the one or more components / excipients can be selected from, but not limited to, antioxidants, preservatives, salts (e.g., NaCl), sugars (e.g., sucrose and trehalose), sugar alcohols (e.g., mannitol and sorbitol), polysaccharides, vitamins, essential oils, rheology modifiers, transdermal compounding or gels, lipoic acid, xanthan gum, and surfactants (e.g., polysorbate 80 (Tween80) and polysorbate 20 (Tween20)).

[0138] In some embodiments, one or more components / excipients include at least one lipid. "Lipid" can include any form of fat, oil, triglyceride, cholesterol, phospholipid, and fatty acid, including free fatty acids. Fats, oils, and fatty acids can be saturated, unsaturated (cis or trans), or partially unsaturated (cis or trans). In some embodiments, the lipid includes at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), tetracosanoic acid (24:0), and mixtures thereof.

[0139] In some embodiments, one or more components / excipients include at least one accessory mineral or mineral source. Examples of minerals include, but are not limited to, chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, and mixtures thereof. Suitable forms of any of the foregoing minerals include, but are not limited to, soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and mixtures thereof.

[0140] In some embodiments, one or more components / excipients include at least one vitamin. The at least one vitamin can be a fat-soluble or water-soluble vitamin. Suitable vitamins include, but are not limited to, vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of vitamins, derivatives of vitamins, compounds having the same or similar activity as vitamins, and metabolites of vitamins. For example, the one or more vitamins can be selected from cholecalciferol, α-tocopherol, β-tocopherol, δ-tocopherol, γ-tocopherol, α-tocotrienol, β-tocotrienol, δ-tocotrienol, γ-tocotrienol, and mixtures thereof. In one embodiment, the at least one vitamin includes vitamin A.

[0141] The compositions disclosed herein may contain a variety of other components / excipients. These include, but are not limited to, antioxidants, astringents, fragrances, preservatives, vitamins, emollients, pigments, dyes, humectants, propellants, and sunscreens, as well as other classes of materials whose presence may be pharmaceutical or desirable. Other non-limiting examples of optional components / excipients are as follows: preservatives such as sorbates; solvents such as isopropanol and propylene glycol; astringents such as menthol and ethanol; emollients such as polyalkylene methyl glucosides; humectants such as glycerin; emulsifiers such as glyceryl stearate, PEG-100 stearate, polyglyceryl-3 hydroxy lauryl ether, and polysorbate 60; sorbitol and other polyhydroxy alcohols such as polyethylene glycol; sunscreens such as octyl methoxycinnamate and butyl methoxybenzoyl methane; antioxidants such as ascorbic acid (vitamin C), α-tocopherol (vitamin E), β-tocopherol, γ-tocopherol, δ-tocopherol, ε-tocopherol, ζ-tocopherol, θ-tocopherol, η-tocopherol, and retinol (vitamin A); essential oils, ceramides, essential fatty acids, mineral oil, vegetable oils (e.g., soybean oil, palm oil, the liquid fraction of shea butter, sunflower oil), animal oils (e.g., squalane), synthetic oils, silicone oils, or waxes (e.g., cyclomethicone and dimethicone), fluorinated oils (generally perfluoropolyethers), fatty alcohols (e.g., cetyl alcohol) and waxes (e.g., beeswax, carnauba wax, and paraffin wax); skin-feel modifiers; and thickeners and components that can conform to the structure of the composition, such as swelling clays and crosslinked carboxy polyalkylenes. For example, the preservative can be methylparaben, sodium methylparaben, propylparaben, sodium propylparaben, potassium sorbate, benzalkonium chloride, benzthonium chloride, or any mixture thereof.For example, the antioxidant can be ascorbic acid, sodium ascorbate, sodium bisulfite, sodium metabisulfite, curcumin, curcumin derivatives, ursolic acid, resveratrol, resveratrol derivatives, alpha-lipoic acid, monothioglycerol, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, epsilon-tocopherol, zeta-tocopherol, theta-tocopherol, eta-tocopherol, retinol, or any mixture thereof. For example, one or more vitamins can be selected from, but are not limited to, cholecalciferol, alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, and mixtures thereof. For example, one or more essential oils can be selected from the group comprising rosemary essential oil, birch essential oil, balsam of Peru essential oil, peppermint essential oil, marjoram essential oil, helichrysum essential oil, thyme essential oil, frankincense essential oil, clove essential oil, turmeric essential oil, orange essential oil, or any mixture thereof.

[0142] The compositions disclosed herein can include materials that condition the skin (e.g., the upper layer of the skin in the stratum corneum), delay the reduction of its water content, and / or protect the skin to keep it soft by protecting the skin. For example, such conditioning and moisturizing agents include, but are not limited to, pyrrolidone carboxylic acid and amino acids; organic antibacterial agents such as 2,4,4'-trichloro-2-hydroxy diphenyl ether (triclosan) and benzoic acid. Further optional additives include, but are not limited to, anti-inflammatory agents such as acetylsalicylic acid and glycyrrhetinic acid; anti-seborrheic agents such as retinoic acid; vasodilators such as nicotinic acid; melanogenesis inhibitors such as kojic acid; and mixtures thereof.

[0143] The compositions disclosed herein may contain alpha-hydroxy acids, alpha-keto acids, high molecular weight hydroxy acids, humectants, collagen, marine extracts, and antioxidants such as ascorbic acid (vitamin C) and / or alpha-tocopherol (vitamin E). Sunscreen may also be included. Additional components such as enzymes, herbs, plant extracts, gland or animal extracts may be added to the composition.

[0144] The compositions disclosed herein may also contain antibacterial agents to prevent spoilage during storage, i.e., to inhibit the growth of microorganisms such as yeast and mold. Suitable antibacterial agents may be selected from the group consisting of, including, or consisting of methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl parabens), sodium benzoate, sorbic acid, imidurea, and mixtures thereof.

[0145] The compositions disclosed herein may also contain soothing additives to minimize or eliminate the potential for skin irritation or skin damage resulting from the administered chemical or other components of the composition. Suitable soothing additives include, for example, alpha-tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; salicylates; ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; capsaicin; and chloroquine. The soothing additives, if present, may be incorporated into the compositions disclosed herein at a concentration effective to soothe irritation or skin damage and may represent about 15 wt% or less, or about 5 wt% or less of the composition.

[0146] The amounts of these various components / excipients are those conventionally used in the skin care field. In some embodiments, one or more components / excipients may be present in the compositions disclosed herein and may be provided in an amount of about 0.01 to about 15 wt% based on the total weight of the composition. One or more components / excipients may be provided in an amount less than about 15, 10, 5, 1, 0.5, 0.1, 0.05, or 0.01 (as wt% based on the total weight of the composition). One or more components / excipients may be provided in an amount of at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, or 15 (as wt% based on the total weight of the composition). One or more components / excipients may be in the range provided by any two of these upper and / or lower limits.

[0147] In some embodiments, the compositions disclosed herein are admixed with existing or known pharmaceutical and / or cosmeceutical formulations, which can be in the form of aqueous solutions, gels, creams, lotions, emulsions, serums, sprays, suspensions, emulsions, etc.

[0148] In some embodiments, the compositions disclosed herein are micro-particles described herein, to which one or more or all of the following apply: - The micro-particles are present at a concentration of about or at least about 150 mg, 145 mg, 140 mg, 135 mg, 130 mg, 125 mg, 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, or 25 mg per ml of the composition, and optionally, the micro-particles are present at a concentration of about or at least about 50 mg to about 150 mg per ml of the composition, and optionally, at a concentration of about 70 mg to about 100 mg per ml, and / or - The microparticles are elongated and have a length of up to about 150 μm, about 140 μm, about 130 μm, about 120 μm, about 110 μm, about 100 μm, or about 90 μm, and optionally, the microparticles have a length in the range of about 90 μm to about 150 μm, optionally, about 100 μm to about 130 μm, and optionally, the microparticles have a dimension with a length of about 100 - 130 μm and a diameter of about 5 - 10 μm, and / or - The microparticles are coated with a coating material, and the coating material is optionally selected from alginate, crosslinked alginate, or carboxymethyl cellulose, or a mixture thereof, the microparticles as described herein, ● At least one bioactive compound, optionally, at least one bioactive compound is a coating on at least a portion of the microparticles, at least one bioactive compound, and / or ● Optionally, a permeability enhancer optionally selected from ethanol, dimethyl sulfoxide, propylene glycol, and / or isopropyl myristate, is included.

[0149] In some embodiments, the compositions disclosed herein are the microparticles as described herein, to which one or more or all of the following apply, - The microparticles are present at a concentration of about or at least about 150 mg, 145 mg, 140 mg, 135 mg, 130 mg, 125 mg, 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, or 25 mg per ml of the composition, and optionally, the microparticles are present at a concentration of about or at least about 50 mg to about 150 mg per ml of the composition, optionally, at a concentration of about 70 mg to about 100 mg per ml, and / or - The microparticles are elongated and have a length of up to about 150 μm, about 140 μm, about 130 μm, about 120 μm, about 110 μm, about 100 μm, or about 90 μm, and optionally, the microparticles have a length in the range of about 90 μm to about 150 μm, optionally, about 100 μm to about 130 μm, and optionally, the microparticles have a dimension of about 5 to 10 μm in diameter at a length of about 100 - 130 μm, and / or - The microparticles are coated with a coating material, and the coating material is optionally selected from alginate, crosslinked alginate, or carboxymethyl cellulose, or a mixture thereof, the microparticles described herein, and / or ● At least one bioactive compound that is a ligand of the nuclear receptor superfamily, and / or ● Optionally, a permeation enhancer optionally selected from ethanol, dimethyl sulfoxide, propylene glycol, and / or isopropyl myristate.

[0150] In one embodiment, the composition disclosed herein is ● The microparticles described herein (optionally present in an amount of about or at least about 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg), and / or ● Ethanol (optionally present in an amount of about or at least about 10%, 20%, or 30%), and / or ● Isopropyl myristate (optionally present in an amount of about or at least about 1%, 2%, 3%, 4%, or 5%), and / or ● Menthol (optionally present in an amount of about or at least about 0.05% or 0.1%), and / or ● Estradiol, estrone, estriol, or a retinoid (optionally present in an amount of about or at least about 0.0005% or 0.001%).

[0151] In one embodiment, the composition disclosed herein is ● The microparticles described in this specification (optionally, the microparticles are elongated and have a length of up to about 150 μm, about 140 μm, about 130 μm, about 120 μm, about 110 μm, about 100 μm, or about 90 μm, optionally, the microparticles have a length in the range of about 90 μm to about 150 μm, optionally, the microparticles have a length in the range of about 100 μm to about 130 μm, optionally, the microparticles have a length of about 100 - 130 μm and a diameter dimension of about 5 - 10 μm, and / or the microparticles are optionally present at a concentration of about or at least about 150 mg, 145 mg, 140 mg, 135 mg, 130 mg, 125 mg, 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, or 25 mg per ml of the composition, optionally, the microparticles are present at a concentration of about or at least about 50 mg to about 150 mg / ml, optionally, about 70 mg to about 100 mg / ml of the composition, and / or the microparticles are coated with a coating material, and the coating material is optionally selected from alginate, cross-linked alginate, or carboxymethyl cellulose, or a mixture thereof), and / or ● Ethanol (optionally present in an amount of about or at least about 10%, 20%, or 30%), and / or ● Isopropyl myristate (optionally present in an amount of about or at least about 1%, 2%, 3%, 4%, or 5%), and / or ● Menthol (optionally present in an amount of about or at least about 0.05% or 0.1%), and / or ● Containing estradiol, estrone, estriol, or a retinoid (optionally present in an amount of about or at least about 0.0005% or 0.001%).

[0152] In one embodiment, the compositions, pharmaceutical compositions, or cosmeceutical compositions disclosed herein are formulated on the condition that after application of the composition to a portion of the subject's skin, little or substantially no bioactive compound is delivered to the bloodstream. For example, in some embodiments, administration of the compositions, pharmaceutical compositions, or cosmeceutical compositions described herein results in limited, reduced, substantially reduced systemic absorption or accumulation of one or more of the bioactive compounds present in the composition, or no systemic absorption or accumulation at all, and thus reduces or avoids systemic toxicity and / or side effects. That is, in certain instances, one or more bioactive compounds delivered via the compositions, pharmaceutical compositions, or cosmeceutical compositions disclosed herein will be localized in the intradermal region of the subject being treated according to the methods disclosed herein.

[0153] The compositions of the present disclosure can be evaluated via various methods to confirm that systemic absorption or accumulation of the bioactive compound is limited or absent. In one example, the compositions disclosed herein are administered to a subject prior to evaluating a representative sample from the subject for the presence of the bioactive compound or its biomarker (e.g., metabolite). Those skilled in the art will understand that the most appropriate sample can be indicated by the bioactivity being delivered. For example, in certain embodiments, the appropriate sample can be a urine sample. In other embodiments, the appropriate sample can be a blood sample.

[0154] In one example, the presence or level of a particular bioactive compound (or its biomarker, e.g., metabolite) is determined in a sample obtained from a subject (e.g., urine sample, blood sample, plasma sample, and / or serum sample), and optionally, the sample is isolated from the subject. For example, the presence or level of a particular bioactive compound (or its biomarker) can be determined in a plasma sample. In another example, the presence or level of a particular bioactive compound (or its biomarker) is determined in a serum sample.

[0155] In one example, the presence or level (e.g., serum level) of a particular bioactive compound or its biomarker (e.g., metabolite) is determined via an analytical method or assay. Analytical methods and assays for determining the presence or level (e.g., serum level) of a bioactive compound or its biomarker are well known to those of ordinary skill in the art. Such methods include, for example, high performance liquid chromatography (HPLC) / mass spectrometry, HPLC / ultraviolet (UV), mass spectrometry (MS)-based methods, gas chromatography (GC) / electron capture detection (ECD), thin layer chromatography (TLC) / densitometry, electron spin resonance spectroscopy, enzyme-linked immunosorbent assay (ELISA), and various immunoassays such as those described in Hermida J et al., Clin Biochem. 2002, 35(3), 251, Zhao X et al., Analyst. 2003, 128(4), 357, Draisci R et al., Analyst. 2001, 126(11), 1942, and Giese RW, J Chromatogr A. 2003, 1000(1-2), 401. For example, endogenous hormone levels, including serum estradiol levels, can be measured in serum samples using a range of serum assays such as radioimmunoassay.

[0156] In certain instances, the compositions of the present disclosure can be evaluated prior to administration to confirm that their systemic absorption or accumulation of the bioactive compound is limited or absent.

[0157] In other instances, it may be necessary to monitor the subject following administration of the compositions disclosed herein. In one example, the monitoring involves evaluating a sample obtained from the subject (e.g., a sample isolated from the subject) for the presence or level of a bioactive compound or its biomarker (e.g., metabolite). Exemplary samples, although briefly considered above, may include blood samples. Thus, in one example, it may be necessary to periodically monitor the blood of the subject to confirm that the bioactive compound has not entered the bloodstream in a significant amount. For example, a normal blood sample can be obtained from the subject being treated and evaluated for the presence of the bioactive compound. The methods and assays referenced above for confirming the presence or level of a particular bioactive compound are equally applicable to such examples.

[0158] Administration The compositions disclosed herein can be administered by a physician or other healthcare professional, such as a healthcare professional specializing in topical treatment, or under their direction. They can be administered as a single treatment or a series of treatments over time. The concentration and treatment timescale depend on several factors, such as the form and / or concentration of the components of the composition, the subject, the severity of the condition, and / or the specific treatment being performed on the subject in need thereof.

[0159] As used herein, "administering" the compositions disclosed herein means applying the composition to the required body surface area. In some embodiments, "applying" the compositions disclosed herein means applying the composition to a biological barrier, such as the skin surface, and subsequently rubbing or massaging the composition into the biological barrier, for example, by circular or back-and-forth linear motions, such that at least a portion of the composition penetrates the biological barrier.

[0160] In the context of the present disclosure, "biological barrier" can refer to the skin, the surface of the skin, or a particular portion of the skin, such as the stratum corneum. Other biological barriers include, for example, mucous membranes such as oral mucosa, vaginal or cervical epithelium, or anal canal, as well as the scalp, hair, and nails.

[0161] In some embodiments, the biological barrier is the skin surface. In some embodiments, the biological barrier is the stratum corneum of the skin. In one embodiment, the biological barrier is the stratum corneum of human skin.

[0162] In some embodiments, the compositions disclosed herein penetrate only the stratum corneum of the skin. In some embodiments, the compositions disclosed herein penetrate only the stratum corneum and the viable epidermis of the skin.

[0163] The compositions disclosed herein can be administered, for example, by applying a force to the composition on a biological barrier such as the surface of the skin so that at least a portion of the composition penetrates the biological barrier, to facilitate local delivery of one or more bioactive compounds. For example, the compositions or portions thereof disclosed herein can penetrate only the stratum corneum of the skin, or only the stratum corneum and the viable epidermis of the skin, to facilitate local delivery of one or more bioactive compounds. In some embodiments, the compositions or portions thereof disclosed herein penetrate only the stratum corneum of the skin to facilitate local delivery of one or more bioactive compounds.

[0164] To deliver and / or administer the compositions described herein, a force may be applied, for example, by hand or by use of an applicator. In some embodiments, the compositions disclosed herein are administered by rubbing or massaging the composition on a biological barrier such as the skin by means of the hand or an applicator. In some embodiments, the compositions disclosed herein are rubbed or massaged on a biological barrier such as the skin by means of an applicator.

[0165] In some embodiments, the applicator is a textured applicator.

[0166] In some embodiments, the applicator is a microtextured applicator. The microtextured applicator can be of various sizes suitable for a desired surface area and can be made of different suitable materials such as biocompatible and non-allergenic materials and can be manufactured, for example, using 3D printing.

[0167] In some embodiments, the applicator is the applicator described in Patent Application No. WO2014 / 094067A1, the entire content of which is incorporated herein by reference.

[0168] Following administration, the number of microparticles of the compositions disclosed herein in the body can decrease over time as they are excreted from the body. The microparticles of the compositions disclosed herein can be completely excreted from the body after about 1, 2, or 3 weeks. Potential mechanisms of microparticle elimination can be associated with natural skin turnover (desquamation). In humans, over approximately 3 weeks, new skin cells (keratinocytes) are generated within the basal layer of the epidermis. Keratinocytes move upward and form the cellular living epidermis. As the cells approach the surface of the skin, they ultimately differentiate (lose their cell nuclei) and begin to flatten. This process renews the stratum corneum and aids in the natural removal of foreign substances within the skin.

[0169] Bioactive compound As defined above, the compositions disclosed herein include at least one bioactive compound.

[0170] As used herein, the terms "bioactive compound," "bioactive agent," "bioactive molecule," or "biomolecule" refer to any organic or inorganic therapeutic, prophylactic, or diagnostic agent that actively or passively affects a biological system. Such agents can also be referred to as "drugs."

[0171] The compositions disclosed herein may include one, or two or more bioactive compounds. In some embodiments, one bioactive compound is present. In other embodiments, a plurality of bioactive compounds, e.g., 2, 3, 4, or 5 bioactive compounds, or at least 2, 3, 4, or 5 bioactive compounds are present.

[0172] In one embodiment, at least one bioactive compound forms at least a part of a coating on the microparticles or has the ability to form at least a part of a coating on the microparticles. In one example, the composition includes microparticles coated with different bioactive compounds. In another example, the microparticles in the composition are coated with the same bioactive compound. In some embodiments, at least one bioactive compound and the microparticles are formulated as a mixture.

[0173] In one embodiment, at least one bioactive compound in the compositions disclosed herein is coated on at least a part of the surface of at least a part of the microparticles. When the compound is coated on the microparticles, the compound is delivered with the microparticles when the microparticles penetrate the biological barrier. The microparticles can be mixed with the compound and then coated on at least a part of the surface of the microparticles, for example, by freezing or air-drying the microparticles.

[0174] At least one bioactive compound can be formulated for topical application to a body surface (e.g., skin) as a single formulation having microparticles. For example, the formulation can be pre-formed and stored. Alternatively, the formulation may be formed immediately prior to application. Advantageously, an existing or known formulation of at least one bioactive compound can be mixed with the microparticles for either storage or immediate topical application.

[0175] In some embodiments, at least one bioactive compound in the compositions disclosed herein is formulated to be applied to a body surface (e.g., skin) separately from the microparticles, such as after application of the microparticles. In some embodiments, at least one bioactive compound can be in the form of an existing or known formulation of the at least one bioactive compound.

[0176] As used herein, a bioactive compound or compounds can be selected by one of ordinary skill in the art for a particular treatment and / or purpose.

[0177] In some embodiments, at least one bioactive compound is selected from, but not limited to, therapeutic compounds, cosmeceuticals, pharmaceuticals, nutraceuticals, diagnostics, vaccines, nucleic acids, and mixtures thereof. In some embodiments, at least one bioactive compound is selected from therapeutic compounds, cosmeceuticals, pharmaceuticals, nutraceuticals, diagnostic agents, and mixtures thereof.

[0178] In some embodiments, at least one bioactive compound is a hormone modulator having cosmeceutical and / or pharmaceutical uses. As used herein, "hormone modulator" refers to an agent that modulates a hormone receptor. Hormone modulators include, for example, any hormone therapy agent that includes an agonist or antagonist of a hormone, such as a steroid hormone or a vitamin.

[0179] In one embodiment, at least one bioactive compound is a hormone modulator for cosmeceutical purposes, excluding skin malignancies.

[0180] In some embodiments, at least one bioactive compound is a ligand of the superfamily of ligand-activated nuclear receptor transcription factors and is a modifier of ligand or transcription factor function. Nuclear receptors bind to and respond to certain steroids, as well as other signaling molecules such as vitamin D3, thyroid hormones, and retinoids. For example, at least one bioactive compound can be selected from the list of known nuclear receptor ligands shown in Table 1 of E.R. Weikum et al., “The nuclear receptor superfamily: A structural perspective”, Protein Science, vol. 27, pp. 1876-1892, 2018, the content of which is incorporated herein by reference.

[0181] In some embodiments, at least one bioactive compound is a steroid. Examples of steroids include, but are not limited to, estradiol, finasteride, corticosteroids, human growth hormone, testosterone, phytoestrogens, hormonally active peptides, and mixtures thereof.

[0182] In some embodiments, at least one bioactive compound is a retinoid. As used herein, the term “retinoid” refers to any natural or synthetic retinoid, or derivative thereof, including any low molecular weight chemical that acts on retinoic acid receptors (RAR). Examples of retinoids include, but are not limited to, vitamin A, retinoic acid, retinol, retinal, tretinoin, tazarotene, tazarotenic acid, adapalene, isotretinoin, and acitretin, or derivatives thereof, and mixtures thereof.

[0183] In some embodiments, at least one bioactive compound is selected from, but not limited to, tretinoin, tazarotene, tazarotenic acid, adapalene, isotretinoin, or acitretin, and mixtures thereof.

[0184] In some embodiments, at least one bioactive compound is a vitamin A derivative. In one example, the vitamin A derivative is retinol or retinoic acid. In another example, at least one bioactive compound is a retinoid. Examples of retinoids include, but are not limited to, tretinoin, retinoic acid, and mixtures thereof. Other examples of bioactive compounds include, but are not limited to, retinyl acetate, retinyl linoleate, retinyl palmitate, and retinyl propionate, and mixtures thereof. In one example, at least one bioactive compound is tretinoin or acitretin. In another example, at least one bioactive compound is a topical retinoid, and / or a topical antibiotic, and / or benzoyl peroxide.

[0185] In one embodiment, the vitamin A derivative is tretinoin having the following structure:

[0186]

Chemical formula

[0187] or a pharmaceutically acceptable salt thereof.

[0188] Suitable salts of the bioactive compounds described herein and encompassed by the present disclosure include those formed with organic or inorganic acids or bases. As used herein, the terms "pharmaceutically acceptable salts" or "pharmaceutically effective salts" refer to pharmaceutically acceptable organic or inorganic salts. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate acid salt, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethyl-propylamine, or mono-, di-, or trihydroxy lower alkylamines such as mono-, di-, or triethanolamine. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterions. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Further, pharmaceutically acceptable salts may have two or more charged atoms in their structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, they may have multiple counterions. Thus, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counterions.Also, pharmaceutically unacceptable salts may fall within the scope of the present disclosure as they may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transportation.

[0189] One of ordinary skill in the art will also understand that many bioactive compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates" and are encompassed by the present disclosure. For example, complexes with water are known as "hydrates". As used herein, the terms "pharmaceutically acceptable solvate", "pharmaceutically effective solvate", or "solvate" refer to an adduct of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0190] In some embodiments, at least one bioactive compound is vitamin D3, A, B, C, and / or E, niacinamide, hyaluronic acid, bacitracin, resveratrol, minoxidil, or minoxidil sulfate, or derivatives thereof. In one embodiment, at least one bioactive compound is vitamin D3, A, B, C, and / or E. In one embodiment, at least one bioactive compound is niacinamide. In one embodiment, at least one bioactive compound is hyaluronic acid. In one embodiment, at least one bioactive compound is bacitracin. In one embodiment, at least one bioactive compound is resveratrol. In one embodiment, at least one bioactive compound is or minoxidil, minoxidil sulfate, or derivatives thereof.

[0191] As described herein, the compositions disclosed herein may include any one or more combinations of these bioactive compounds. Thus, the compositions disclosed herein may include any one or more combinations of vitamin D3, A, B, C, and / or E, nicotinamide, hyaluronic acid, bacitracin, resveratrol, minoxidil, minoxidil sulfate, or derivatives thereof. In some embodiments, the compositions disclosed herein include any one or more combinations of vitamin D3, A, B, C, and / or E, nicotinamide, hyaluronic acid, bacitracin, and resveratrol. In some embodiments, the compositions disclosed herein include any one or more combinations of retinoids optionally selected from the group consisting of vitamin D3, A, B, C, and / or E, nicotinamide, hyaluronic acid, bacitracin, resveratrol, and retinoic acid, tretinoin, and mixtures thereof.

[0192] In some embodiments, at least one bioactive compound is a keratolytic such as adapalene, azelaic acid, benzoyl peroxide, clindamycin and clindamycin phosphate, doxycycline, erythromycin, salicylic acid and retinoic acid (“Retin-A”), norgestimate, organic peroxides, retinoids such as isotretinoin and tretinoin, topical anti-acne agents such as sodium sulfacetamide, tazarotene, or mixtures thereof. In some embodiments, the anti-acne agent is selected from, but not limited to, adapalene, azelaic acid, benzoyl peroxide, clindamycin (e.g., clindamycin phosphate), doxycycline (e.g., doxycycline monohydrate), erythromycin, isotretinoin, norgestimate, sodium sulfacetamide, tazarotene, etretinate, or acitretin, or mixtures thereof.

[0193] In some embodiments, at least one bioactive compound is an estrogen hormone or an estrogen derivative. Non-limiting examples of estrogen hormones or derivatives include, for example, estradiol, estrone, estriol, estetrol, esterified estrogens, 17β-estradiol, estradiol benzoate, 17β-estradiol valerate, estradiol 17β-cypionate, estrone, estropipate (piperazine estrone sulfate), and 17β-ethinyl estradiol. In some embodiments, at least one bioactive compound is selected from estradiol, estrone, and estriol, or derivatives thereof.

[0194] In any of the embodiments herein, a "derivative" of a bioactive compound includes, for example, esters, ethers, amides, carbamates, phosphates, anhydrides, or sulfonamide derivatives of the compound, and / or stereoisomers, enantiomers, diastereomers, geometric isomers, racemates, tautomers, zwitterions, active metabolites, or prodrugs of the compound, or pharmaceutically acceptable salts or solvates thereof.

[0195] In one embodiment, at least one bioactive compound is estradiol or a derivative thereof.

[0196] As used herein, a derivative of estradiol can refer to a compound having the following general estradiol structure, in which one or more available carbon atoms of the general estradiol skeleton are substituted with moieties other than hydrogen:

[0197]

Chemical formula

[0198] In some embodiments, a carbon atom is substituted at the 1, 2, 4, 6, 7, 8, 9, 11, 12, 14, 15, 16, or 17 position. In another embodiment, a carbon atom is substituted at the 1, 2, 4, 6, 7, 11, 12, 15, 16, or 17 position. In yet another embodiment, a carbon atom is substituted at the 17 position. In yet another embodiment, one or more carbon atoms are one or two C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl substituted. In other embodiments, one or more carbon atoms are C 1-6 alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, one or more carbon atoms are C 2-6 alkenyl such as ethenyl, propenyl, butenyl, pentenyl, or hexenyl. In other embodiments, one or more carbon atoms are C 2-6 alkynyl such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl substituted.

[0199] In another embodiment, at least one bioactive compound is finasteride or a derivative thereof having the following general structure. Finasteride (i.e., (1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-tert-butyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroinden[5,4-f]quinoline-1-carboxamide) is sold, inter alia, under the names Proscar® and Propecia®, and is a medicament for the treatment of hair loss and benign prostatic hyperplasia in men.

[0200] As used herein, a derivative of finasteride is a compound having the following general finasteride structure in which one or more available carbon atoms of the general finasteride skeleton are substituted with moieties other than hydrogen:

[0201] [Chemical formula]

[0202] may refer to or its pharmaceutically acceptable salts.

[0203] In some embodiments, a carbon atom is substituted at the 1, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, or 17 position. In another embodiment, a carbon atom is substituted at the 1, 6, 7, 8, 10, 13, 14, 15, 16, or 17 position. In yet another embodiment, one or more carbon atoms are one or two C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, which are substituted. In other embodiments, one or more carbon atoms are C 1-6 alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, one or more carbon atoms are C 2-6 alkenyl such as ethenyl, propenyl, butenyl, pentenyl, or hexenyl. In other embodiments, one or more carbon atoms are C 2-6 alkynyl such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl, which are substituted.

[0204] In some embodiments, at least one bioactive compound is minoxidil or a derivative thereof. Minoxidil having the following structure (i.e., 2,4-diamino-6-piperidinyl-pyrimidine-3-oxide) is the active ingredient of Rogaine (registered trademark) and is commercially available for the treatment and prevention of androgenetic alopecia (male pattern baldness and female pattern baldness).

[0205]

Chemical formula

[0206] or its pharmaceutically acceptable salts.

[0207] In one embodiment, at least one bioactive compound is minoxidil sulfate (i.e., (2,6-diamino-4-piperidin-1-ylpyrimidin-1-ium-1-yl) sulfate) having the following structure or a derivative thereof:

[0208]

Chemical formula

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, at least one bioactive compound is a steroid. Non-limiting examples of steroids include estradiol, 5α-dihydrotestosterone, estrone, estriol, and finasteride. In some embodiments, the steroid is a corticosteroid. Non-limiting examples of corticosteroids include cortisone and spironolactone.

[0211] In some embodiments, at least one bioactive compound is spironolactone having the following structure (i.e., S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5’-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2’-oxolane]-7-yl] ethanethioate), or a derivative thereof. Spironolactone is sold under names such as Aldactone, Spiractin, Verospiron, etc., and is frequently used in the treatment of various skin chemical conditions where androgen plays a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women.

[0212]

Chemical formula

[0213] or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, at least one bioactive compound is 5α-dihydrotestosterone (DHT, or 5α-DHT) having the following structure (i.e., ((1S,3aS,3bR,5aS,9aS,9bS,11aS)-1-hydroxy-9a,11a-dimethylhexadecahydro-7H-cyclopenta[a]phenanthren-7-one) or a derivative thereof:

[0215]

Chemical formula

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, at least one bioactive compound is estrone having the following structure (i.e., (3aS,3bR,9bS,11aS)-7-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-1-one) or a derivative thereof:

[0218]

Chemical formula

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, at least one bioactive compound is estriol having the following structure (i.e., (1R,2R,3aS,3bR,9bS,11aS)-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-1,2,7-triol) or a derivative thereof:

[0221]

Chemical formula

[0222] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, at least one bioactive compound is cortisol having the following structure (i.e., 17α,21-dihydroxy-preg-4-ene-3,11,20-trione; or (1R,3aS,3bS,9aR,9bS,11aS)-1-hydroxy-1-(hydroxyacetyl)-9a,11a-dimethyl-2,3,3a,3b,4,5,8,9,9a,9b,11,11a-dodecahydro-7H-cyclopenta[a]phenanthrene-7,10(1H)-dione) or a derivative thereof:

[0224] [Chemical formula]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] As described herein, the compositions disclosed herein may include any one or more combinations of the bioactive compounds described herein. Thus, the compositions disclosed herein may include any one or more combinations of estradiol, 5α-dihydrotestosterone, estrone, estriol, finasteride, cortisol, and spironolactone. In some embodiments, the compositions disclosed herein include any one or more combinations of estradiol, 5α-dihydrotestosterone, estrone, estriol, and finasteride. In some embodiments, the compositions disclosed herein include a combination of cortisol and spironolactone.

[0227] The concentration of the one or more bioactive compounds will depend on the particular nature of the bioactive compound and / or the end use of the composition.

[0228] In one embodiment, the composition is formulated such that the concentration of a bioactive compound (e.g., estradiol) of about 10 ng to about 1000 ng is delivered by application to skin of 2×2 cm 2 The concentration of the bioactive compound (e.g., estradiol) can be in an amount of about or at least about 10 ng, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 550 ng, 600 ng, 650 ng, 700 ng, 750 ng, 800 ng, 850 ng, 900 ng, 950 ng, or 1000 ng.

[0229] In another embodiment, the composition is formulated such that the concentration of one or more bioactive compounds that permeate a sample of the skin to which the composition is applied is at least about 27 ng / cm 2 In another embodiment, the composition is formulated such that the concentration of one or more bioactive compounds that permeate a sample of the skin to which the composition is applied is about, at least about 25 ng / cm 2 , 30 ng / cm 2 , 35 ng / cm 2 , 40 ng / cm 2 , 45 ng / cm 2 , 50 ng / cm 2 , 55 ng / cm 2 , 60 ng / cm 2 , 65 ng / cm 2 , 70 ng / cm 2 , 75 ng / cm 2 , 80 ng / cm 2 , 85 ng / cm 2 , 90 ng / cm 2 , 95 ng / cm 2 , 100 ng / cm 2 , 105 ng / cm 2 , 110 ng / cm 2 , 115 ng / cm 2 , 120 ng / cm 2 , 125 ng / cm 2 , 130 ng / cm 2 , 135 ng / cm 2 , 140 ng / cm 2, 145 ng / cm 2 , or 150 ng / cm 2 and is formulated to be so.

[0230] In yet another embodiment, the composition has a concentration of one or more bioactive compounds of about, or about 1000 ng / cm 2 , 990 ng / cm 2 , 980 ng / cm 2 , 970 ng / cm 2 , 960 ng / cm 2 , 950 ng / cm 2 , 940 ng / cm 2 , 930 ng / cm 2 , 920 ng / cm 2 , 910 ng / cm 2 , 900 ng / cm 2 , 890 ng / cm 2 , 880 ng / cm 2 , 870 ng / cm 2 , 860 ng / cm 2 , 850 ng / cm 2 , 840 ng / cm 2 , 830 ng / cm 2 , 820 ng / cm 2 , 810 ng / cm 2 , 800 ng / cm 2 , 790 ng / cm 2 , 780 ng / cm 2 , 770 ng / cm 2 , 760 ng / cm 2 , 750 ng / cm 2 , 740 ng / cm 2 , 730 ng / cm 2 , 720 ng / cm 2 , 715 ng / cm 2 , or 710 ng / cm 2 and is formulated to be provided at such a concentration.

[0231] In some embodiments, in a subject being treated, an additional step of testing the serum levels of one or more of the bioactive compounds of the compositions disclosed herein and determining that the serum levels of one or more of the bioactive compounds in the subject are normal or not substantially elevated compared to the serum levels of one or more of the bioactive compounds in subjects of the same gender and age group as the subject being treated may involve monitoring the systemic levels (e.g., serum levels) of one or more bioactive compounds over time by periodic follow-up (e.g., by routine blood or urine tests). For example, routine blood or urine samples can be obtained from the subject being treated and evaluated for the presence of bioactive compounds as discussed above.

[0232] Permeation enhancer The compositions disclosed herein may include one or more permeation enhancers, such as chemical permeation enhancers. Thus, in some embodiments, there are provided permeation enhancers for increasing the permeability of skin or mucosal tissue for topical administration of at least one bioactive compound. Ideally, such a permeation enhancer (or "penetration enhancer") is a compound that is harmless and functions to simply facilitate the diffusion of the bioactive compound through the stratum corneum.

[0233] In one embodiment, one or more permeation enhancers are compounds that penetrate the skin of a subject, interact with skin components, facilitate or increase the flux of one or more bioactive compounds, and / or reversibly decrease the barrier resistance of the skin to which the compositions described herein are applied.

[0234] In another embodiment, one or more permeation enhancers in the compositions disclosed herein facilitate or increase the flux of one or more bioactive compounds and / or reversibly decrease the barrier resistance of the skin to which the composition is applied compared to a similar composition without the added permeation enhancer.

[0235] In yet another embodiment, the permeability enhancer increases the delivery of one or more bioactive compounds through the skin to which the composition is applied, but does not deliver the one or more bioactive compounds to the bloodstream.

[0236] A variety of compounds for improving skin permeability are known in the art and can be used in the compositions disclosed herein. Compounds used for improving skin permeability include, but are not limited to, sulfoxides such as dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (commercially available as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyl trimethyl ammonium bromide, benzalkonium chloride, poloxamers (231, 182, 184), Tweens (20, 40, 60, 80), and lecithin (U.S. Patent No. 4,783,450); 1-substituted azacycloheptan-2-ones, particularly 1-n-decyl-cyclazacycloheptan-2-one (trademark Azone® available from Nelson Research & Development Co., Irvine, Calif., see U.S. Patent Nos. 3,989,816, 4,316,893, 4,405,616, and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl alcohol; fatty acids such as lauric acid, oleic acid, and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; polyols and their esters such as propylene glycol (PG), ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, for example, U.S. Patent No. 4,568,343); amides, and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and its salts, citric acid, and succinic acid.

[0237] One or more permeability enhancers can be selected from, but are not limited to, nonpolar solvents, polar protic solvents, aprotic polar solvents, alcohols (optionally, polyols), ionic surfactants, nonionic surfactant solvents, aliphatic hydrocarbons, fatty acids, and mixtures thereof.

[0238] In one embodiment, one or more permeability enhancers include, but are not limited to, water, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol (PG), a common excipient in topically applied dosage forms), surfactants (also common in dosage forms), fatty acids, and terpenes and terpenoids. It will be understood that one or more of the solvents described herein can also have permeability enhancing properties.

[0239] In one embodiment, one or more permeability enhancers can be selected from, but are not limited to, ethanol, dimethyl sulfoxide, propylene glycol, isopropanol, polyoxyethylene (20) sorbitan monooleate, urea, sodium dodecyl sulfate, menthol, limonene, oleic acid, isopropyl myristate, undecanoic acid, and mixtures thereof. In some embodiments, one or more permeability enhancers are ethanol, dimethyl sulfoxide, propylene glycol, and / or isopropyl myristate.

[0240] The concentration of one or more permeability enhancers can depend on several factors, including the permeability enhancer or type of permeability enhancer used, the type of microparticles utilized, and / or the selection of one or more bioactive compounds.

[0241] In one embodiment, the permeability enhancer as defined herein is used in combination with at least one bioactive compound that is estradiol or a derivative thereof.

[0242] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound selected from 5α-dihydrotestosterone, estrone, estriol, or cortisone, or derivatives thereof.

[0243] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound that is finasteride or a derivative thereof.

[0244] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound that is spironolactone or a derivative thereof.

[0245] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound that is minoxidil, minoxidil sulfate, or a derivative or mixture thereof.

[0246] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound that is a vitamin selected from vitamins A, B, C, D3, and / or E, or derivatives thereof.

[0247] In one embodiment, the permeability enhancer defined herein is used in combination with at least one bioactive compound that is a retinoid. In certain embodiments, the retinoid is selected from retinoic acid, tretinoin, and derivatives or mixtures thereof.

[0248] In one embodiment, the permeability enhancer contains ethanol.

[0249] In one embodiment, the permeability enhancer contains dimethyl sulfoxide.

[0250] In one embodiment, the permeability enhancer contains propylene glycol.

[0251] In one embodiment, the permeability enhancer contains isopropanol.

[0252] In one embodiment, the permeability enhancer contains polyoxyethylene (20) sorbitan monooleate (Tween80).

[0253] In one embodiment, the permeability enhancer contains urea.

[0254] In one embodiment, the permeability enhancer contains sodium dodecyl sulfate.

[0255] In one embodiment, the permeability enhancer contains menthol.

[0256] In one embodiment, the permeability enhancer contains limonene.

[0257] In one embodiment, the permeability enhancer contains oleic acid.

[0258] In one embodiment, the permeability enhancer contains isopropyl myristate.

[0259] In one embodiment, the permeability enhancer contains undecanoic acid.

[0260] One or more permeability enhancers may be present in the compositions disclosed herein in the range of from about 0.1% to about 30% (v / v% or w / v%), for example, about or at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by amount. In some embodiments, one or more permeability enhancers are present in the composition in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, or about 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2% by amount. In some embodiments, one or more permeability enhancers are present in an amount of about 0.01 wt% to about 3 wt%, 4 wt%, or 5 wt% based on the total weight of the composition. In some embodiments, one or more permeability enhancers are present in an amount of about 5 wt% to about 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, or 15 wt% based on the total weight of the composition. The permeability enhancer may be provided in an amount of less than about 15, 10, 5, 1, 0.5, 0.1, 0.05, or 0.01 (as wt% based on the total weight of the composition). The permeability enhancer may be provided in an amount of at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, or 15 (as wt% based on the total weight of the composition). One or more permeability enhancers may be in the range provided by any two of these upper and / or lower limits. In some embodiments, one or more permeability enhancers are present in the compositions disclosed herein.

[0261] Micro-particles As defined above, the compositions disclosed herein comprise a plurality of micro-particles.

[0262] The microparticles in the compositions disclosed herein can be composed of any suitable material known in the art. In one embodiment, the microparticles comprise a material having sufficient strength and rigidity to be able to penetrate biological barriers. Examples of such materials include, but are not limited to, silicon, glass, metal, polymers, ceramics, cellulose-derived materials, and mixtures thereof.

[0263] In the context of the present disclosure, a "biological barrier" can refer to the skin, the surface of the skin, or a particular part of the skin such as the stratum corneum of the skin. Other biological barriers include, for example, mucous membranes such as oral mucosa, vaginal or cervical epithelium, or anal canal, as well as the scalp, hair, and nails.

[0264] In some embodiments, the biological barrier is the skin surface. In some embodiments, the biological barrier is the stratum corneum of the skin. In one embodiment, the biological barrier is the stratum corneum of human skin.

[0265] In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum of the skin. In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum and the living epidermis of the skin.

[0266] In part of the present disclosure, the microparticles can be referred to as Foroderm.

[0267] In some embodiments, the microparticles are composed of biocompatible materials that can be safely applied to the skin, such as silicon, carbohydrates, or polymers. In some embodiments, the material is biodegradable. In some embodiments, the material is inert.

[0268] As used herein, a "biocompatible" material is generally a material that does not cause a significant adverse reaction (e.g., a toxic response or an antigenic response) in the body, whether it degrades in the body, remains in the body for a long period of time, or is excreted entirely. A "biodegradable" material is a material that degrades relatively easily under biological conditions.

[0269] In one embodiment, the microparticles comprise, consist essentially of, or consist of a material selected from, but not limited to, silicon, silica, and mixtures thereof. In another embodiment, the microparticles comprise, consist essentially of, or consist of a material having mechanical properties similar to at least one material selected from silicon, silica, and mixtures thereof. However, other suitable materials such as metals, plastics (e.g., biocompatible polymers), cellulose-derived materials, or ceramic materials may also be used.

[0270] In one embodiment, the microparticles comprise, consist essentially of, or consist of silica. Silica can be conveniently used due to its biocompatibility, suitable mechanical properties, relatively low cost, and availability. Microparticles formed from silica can advantageously be chemically and / or biologically inert.

[0271] To fabricate the microparticles, various polymeric materials such as poly-l-lactic acid, poly-glycolic acid, poly-carbonate, poly-lactic acid-co-glycolic acid (PLGA), poly-dimethylsiloxane, copolymers of methyl vinyl ether and maleic anhydride, and cellulose-derived materials such as carboxymethyl cellulose, maltose, dextrin, and galactose can all be used.

[0272] In some embodiments, the microparticles comprise a material having sufficient strength and rigidity to withstand an applied force of at least 13 MPa.

[0273] In some embodiments, the microparticles are eliminated or dissolved after application. Depending on the composition of the microparticles, the microparticles that penetrate the skin barrier can remain within the skin barrier for 3 to 4 weeks and can be removed by natural skin turnover. For example, it has previously been shown that microparticles made of silica are well tolerated in human patients and eventually flake off.

[0274] Microparticles can be fabricated in different sizes depending on the application.

[0275] In some embodiments, the microparticles are sized to penetrate through the stratum corneum of the skin. The size can vary depending on the material of the microparticles.

[0276] Microparticles can take on any geometric form known in the art. In one embodiment, the microparticles are cylindrical or substantially cylindrical.

[0277] In one embodiment, at least a portion of the microparticles, substantially all of the microparticles, or all of the microparticles are not spherical. In another embodiment, at least a portion of the microparticles, substantially all of the microparticles, or all of the microparticles are not substantially spherical.

[0278] In one embodiment, all of the microparticles comprise, consist essentially of, or consist of the same material, such as silicon or silica. In another embodiment, at least a portion of the microparticles, substantially all, or all are hydrophilic. In another embodiment, at least a portion of the microparticles, substantially all, or all are hydrophobic. In yet another embodiment, the compositions described herein comprise, consist essentially of, or consist of one type of microparticle (e.g., comprising or consisting of the same material). In yet another embodiment, the compositions described herein comprise, consist essentially of, or consist of a plurality of different types of microparticles (e.g., comprising or consisting of at least two different materials).

[0279] In some embodiments, at least a portion of the microparticles comprises a circular, substantially circular, or elliptical face having a diameter or length in the range of about 5 μm to about 15 μm, such as 6 μm to about 12 μm. The diameter or length can be about or at least about 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, or 15 μm. In some embodiments, the microparticles have a diameter in the range of about 4 μm to about 15 μm, about 5 μm to about 15 μm, about 6 μm to about 14 μm, about 6 μm to about 13 μm, about 6 μm to about 12 μm, about 7 μm to about 11 μm, about 8 μm to about 10 μm. The microparticles can have a diameter of about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, about 12 μm, about 13 μm, about 14 μm, or about 15 μm, such as, for example, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, or about 12 μm.

[0280] The microparticles may be elongated.

[0281] In some embodiments, at least a portion of the microparticles has a length of about or at least about 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, 105 μm, 110 μm, 115 μm, 120 μm, 125 μm, 130 μm, 135 μm, 140 μm, 145 μm, 150 μm, 155 μm, 160 μm, 165 μm, 170 μm, 175 μm, 180 μm, 185 μm, 190 μm, 195 μm, 200 μm, 205 μm, 210 μm, 215 μm, or 220 μm. In some embodiments, at least a portion of the microparticles has a length of about or at least about 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, 105 μm, 110 μm, 115 μm, 120 μm, 125 μm, 130 μm, 135 μm, 140 μm, 145 μm, or 150 μm.

[0282] In some embodiments, the microparticles have a length of up to about 250 μm, 240 μm, 230 μm, 220 μm, 210 μm, 200 μm, 190 μm, 180 μm, 170 μm, 160 μm, 150 μm, 140 μm, 130 μm, 120 μm, 110 μm, 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, or 30 μm. In some embodiments, the microparticles have a length of up to 220 μm, 210 μm, 200 μm, 190 μm, 180 μm, 170 μm, 160 μm, 150 μm, 140 μm, 130 μm, 120 μm, 110 μm, 100 μm, or 90 μm. In some embodiments, the microparticles have a length of up to 180 μm, 170 μm, 160 μm, 150 μm, 140 μm, 130 μm, 120 μm, 110 μm, 100 μm, or 90 μm. In some embodiments, the microparticles have a length of up to 150 μm, 140 μm, 130 μm, 120 μm, 110 μm, 100 μm, or 90 μm.

[0283] In some embodiments, the microparticles have a length in the range of from about 20 μm to about 220 μm, from about 30 μm to about 210 μm, from about 30 μm to about 200 μm, from about 40 μm to about 190 μm, from about 50 μm to about 180 μm, from about 60 μm to about 170 μm, from about 70 μm to about 160 μm, from about 80 μm to about 150 μm, from about 90 μm to about 140 μm, from about 100 μm to about 130 μm, from about 110 μm to about 130 μm, or from about 110 μm to about 120 μm. In some embodiments, the microparticles have a length in the range of from about 30 μm to about 100 μm, from about 60 μm to about 120 μm, or from about 60 μm to about 170 μm, or from about 40 μm to about 90 μm, from about 70 μm to about 110 μm, or from about 70 μm to about 160 μm, for example, from about 50 μm to about 80 μm, from about 80 μm to about 100 μm, or from about 80 μm to about 150 μm. In certain embodiments, the microparticles have a length in the range of from about 100 μm to about 130 μm.

[0284] In some embodiments, the microparticles have a width or diameter of less than about 30 μm, about 25 μm, or about 20 μm. In some embodiments, the width or diameter is less than about 19 μm, about 18 μm, about 17 μm, about 16 μm, or about 15 μm. In some embodiments, the width or diameter of the elongated microparticles is about 15 μm, about 14 μm, about 13 μm, about 12 μm, about 11 μm, about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, about 1 μm, for example, about 13 μm, about 12 μm, about 11 μm, about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, or about 5 μm. In some materials, the width can be less than about 12 μm, such as in the range of about 5-10 μm for silica.

[0285] In some embodiments, at least a portion of the microparticles is elongated. For example, at least a portion of the microparticles has a length that is longer than the perpendicular cross-section of the microparticles. In some embodiments, at least a portion of the microparticles includes an aspect ratio of greater than about 1 in this specification, and in some embodiments, at least a portion of the microparticles, substantially all of the microparticles, or all of the microparticles are elongated. For example, at least, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the microparticles are elongated.

[0286] In some embodiments, the microparticles are elongated and have an aspect ratio (e.g., length:width) of about or at least about 10:1, 9.5:1, 9:1, 8.5:1, 8:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, or 1.1:1.

[0287] In some embodiments, the microparticles are elongated with a high aspect ratio. The aspect ratio (e.g., length:width) can be about or at least about 10:1, such as about or at least about 11:1, 12:1, 13:1, 14:1, or 15:1. In some embodiments, the aspect ratio (e.g., length:width) is higher than about 20:1. The upper limit for the aspect ratio (e.g., length:width) can be approximately about 200:1, such as about 150:1. In some embodiments, the maximum aspect ratio (e.g., length:width) is about 100:1. In some embodiments, the aspect ratio (e.g., length:width) is from about 5:1 to about 50:1. In some embodiments, the aspect ratio (e.g., length:width) is from about 5:1 to about 20:1, such as from about 10:1 to about 20:1. In some embodiments, the microparticles have an aspect ratio (e.g., length:width) of about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, or about 5:1.

[0288] In some embodiments, the microparticles have dimensions of a length of about 50 - 80 μm and a diameter of about 6 μm, a length of about 50 - 90 μm and a diameter of about 7 μm, a length of about 60 - 100 μm and a diameter of about 8 μm, a length of about 60 - 100 μm and a diameter of about 8 μm, a length of about 70 - 100 μm and a diameter of about 9 μm, a length of about 80 - 120 μm and a diameter of about 9 μm, a length of about 90 - 130 μm and a diameter of about 9 μm, a length of about 80 - 140 μm and a diameter of about 10 μm, a length of about 80 - 150 μm and a diameter of about 10 μm, a length of about 80 - 150 μm and a diameter of about 11 μm, or a length of about 80 - 150 μm and a diameter of about 12 μm. In some embodiments, the microparticles have dimensions of a length of about 100 - 130 μm and a diameter of about 5 - 10 μm.

[0289] The microparticles can be mixtures of different types described herein.

[0290] In one embodiment, the microparticles are of substantially uniform size. At least about 50% or at least about 70% of the microparticles can have a length within about 80% of the median length. In one embodiment, at least about 80% of the microparticles have a length within about 80% of the median length.

[0291] The microparticles can be formed by any process known in the art, such as various microfabrication techniques.

[0292] The microparticles can be used immediately after synthesis or can undergo one or more processes to change one or more of the following characteristics: topography, structure, content, coating, and mixtures thereof.

[0293] The microparticles can be manufactured by grinding and / or cutting.

[0294] The microparticles can be prepared using chemical isotropic etching, injection molding, reactive ion etching, surface / bulk micromachining, microforming, and lithography - electroforming - replication.

[0295] For example, the microparticles can be generated by a fabrication process that includes steps of fabricating pillars using deep reactive ion etching (DRIE), inspecting the etching results, and removing residues using a piranha solution in lithography (patternizing a design on a substrate).

[0296] The microparticles can be processed, e.g., etched, by processes known in the art. The process can be chemical, utilizing chemical processes with compounds such as, for example, sodium hydroxide and / or piranha solution, or can be physical means such as reactive ion etching.

[0297] The microparticles may be coated with one or more materials. The materials may be cross-linked or the materials may not be cross-linked. The one or more materials may form a dry coating. The one or more materials may be selected from, but are not limited to, celluloses such as alginates, cross-linked alginates, chitosan, sugars, or carboxymethylcellulose, and mixtures thereof. In some embodiments, the microparticles are coated with a coating material selected from alginates, cross-linked alginates, or carboxymethylcellulose, or mixtures thereof.

[0298] In some embodiments, the microparticles are coated. In some embodiments, the coating comprises at least one bioactive compound. In some embodiments, the microparticles and the at least one bioactive compound are formulated as a mixture.

[0299] In some embodiments, the microparticles are admixed with at least one bioactive substance as a single formulation prior to topical application to a body surface (e.g., skin). The formulation may be pre-formed and stored or may be formed immediately prior to application. Advantageously, the microparticles may be admixed with an existing or known formulation of the at least one bioactive compound.

[0300] In some embodiments, the at least one bioactive compound is formulated to be applied to the body surface (e.g., skin) separately from the microparticles, such as after application of the microparticles. For example, the at least one bioactive compound may be in the form of an existing or known formulation of the at least one bioactive compound.

[0301] The microparticles can be hollow, substantially hollow, solid, substantially solid, or mixtures thereof.

[0302] At least a portion of the microparticles can have one or more flat, or substantially flat, ends. In one embodiment, at least a portion of the microparticles has a tapered end geometry. The microparticles can have a terminal angle of less than about 180° (e.g., less than about 170°, 160°, 150°, 140°, 130°, 120°, 110°, 100°, 90°, 80°, 70°, 60°, 50°, 40°, or 30°), and can be less than about 20°, such as less than about 10°.

[0303] At least a portion of the microparticles can have one or more convex ends.

[0304] The microparticles can be of uniform size or can be of a range of sizes.

[0305] The microparticles can be used at concentrations known to those skilled in the art. The final concentration can depend on several factors, including the selection of one or more bioactive compounds, one or more permeability enhancers, the particular microparticles selected, and / or the end use of the composition containing the microparticles.

[0306] In one embodiment, less than about 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, or 90 wt% of at least one bioactive compound is present within at least a portion, substantially all, or all of the microparticles. In yet another embodiment, about or at least about 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, or 90 wt% of at least one bioactive compound is present on at least one outer surface of at least a portion, substantially all, or all of the microparticles (e.g., as one or more coatings).

[0307] In the compositions described herein, a single coating may be present on at least a portion of the microparticles. In some embodiments, multiple coatings may be present on at least a portion of the microparticles. For example, at least a portion of the microparticles may comprise multiple coating layers. In another embodiment, microparticles having different coatings may be mixed together.

[0308] In some embodiments, the microparticles are present in the compositions disclosed herein at a concentration of about or at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg per ml of the composition. In some embodiments, the microparticles are present in the compositions disclosed herein at a concentration of up to about 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, or 1 mg per ml of the composition. In some embodiments, the concentration of the microparticles is about 150 mg, 145 mg, 140 mg, 135 mg, 130 mg, 125 mg, 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, or 25 mg per ml of the composition, such as about 150 mg to about 50 mg, 140 mg to about 60 mg, 130 mg to about 70 mg, 120 mg to about 80 mg, 110 mg to about 90 mg, or about 100 mg per ml of the composition. In some embodiments, the microparticles are present in the composition at a concentration of about or at least about 50 mg to about 150 mg per ml of the composition, optionally at a concentration of about 70 mg to about 100 mg per ml.

[0309] In some embodiments, the microparticles are about or at least about 1 cm 2 , 2 cm2 , 3 cm 2 , 4 cm 2 , 5 cm 2 , 6 cm 2 , 7 cm 2 , 8 cm 2 , 9 cm 2 , 10 cm 2 , 11 cm 2 , 12 cm 2 , 13 cm 2 , 14 cm 2 , 15 cm 2 , 16 cm 2 , 17 cm 2 , 18 cm 2 , 19 cm 2 , 20 cm 2 , 21 cm 2 , 22 cm 2 , 23 cm 2 , 24 cm 2 , 25 cm 2 , 26 cm 2 , 27 cm 2 , 28 cm 2 , 29 cm 2 , 30 cm 2 , 31 cm 2 , 32 cm 2 , 33 cm 2 , 34 cm 2 , 35 cm 2 , 36 cm 2 , 37 cm 2 , 38 cm 2 , 39 cm 2 , 40 cm 2 can be applied to the body surface area such as the skin having an area of. In some embodiments, the surface area is about 1 to about 15 cm 2 , about 5 to about 20 cm 2 , about 10 to about 25 cm 2 , about 15 to about 30 cm 2 , about 20 to about 35 cm 2 , about 25 to about 40 cm 2 , about 30 to about 45 cm 2 , about 35 to about 50 cm 2 , about 40 to about 55 cm 2 , about 45 to about 60 cm 2 , about 50 to about 65 cm 2 , about 55 to about 75 cm 2, about 60 to about 80 cm 2 , about 65 to about 85 cm 2 , about 70 to about 90 cm 2 , about 75 to about 95 cm 2 , about 80 to about 100 cm 2 , about 85 to about 105 cm 2 , about 90 to about 110 cm 2 , about 95 to about 115 cm 2 , about 100 to about 120 cm 2 , about 110 to about 130 cm 2 , about 120 to about 140 cm 2 , about 130 to about 150 cm 2 It is. In some embodiments, the surface area is about 100 to about 150 cm 2 , about 120 to about 180 cm 2 , about 140 to about 200 cm 2 , about 150 to about 220 cm 2 , about 160 to about 240 cm 2 , about 180 to about 260 cm 2 , about 200 to about 300 cm 2 , or about 200 to about 400 cm 2 It is. In some embodiments, the microparticles cover all or substantially all of the area on the body surface, approximately 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1% of the area on the body surface. In some embodiments, the surface area to which the composition is applied is less than 500 cm 2 . For example, the surface area is 300 cm 2 , 200 cm 2 , 100 cm 2 , 50 cm 2 , 40 cm 2 , 30 cm 2 , 20 cm 2 , 10 cm 2 , and 5 cm 2 less than.

[0310] In yet another embodiment, for application to at least a portion of the surface, about or at least about 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of the microparticles are per cm of the body surface (e.g., skin) 2 mixed with about or at least about 5 μL, 10 μL, 15 μL, 20 μL, 25 μL, 30 μL, 35 μL, 40 μL, 45 μL, 50 μL, 55 μL, 60 μL, 70 μL, 80 μL, 90 μL, or 100 μL of a liquid.

[0311] In some embodiments, the amount of the microparticles is at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg per cm of the body surface area (e.g., skin). 2

[0312] Applicator The compositions disclosed herein can be administered, for example, to promote the topical delivery of one or more bioactive compounds, by applying force to the composition on a biological barrier such as the surface of the skin so that at least a portion of the composition penetrates the biological barrier. For example, the compositions disclosed herein or portions thereof can penetrate only the stratum corneum of the skin, or only the stratum corneum and the viable epidermis of the skin, to promote the topical delivery of one or more bioactive compounds. In some embodiments, the compositions disclosed herein or portions thereof penetrate only the stratum corneum of the skin to promote the topical delivery of one or more bioactive compounds. In some embodiments, the compositions disclosed herein or portions thereof penetrate only the stratum corneum and the viable epidermis of the skin to promote the topical delivery of one or more bioactive compounds.

[0313] ​Force can be applied by hand or by using an applicator. In some embodiments, the compositions disclosed herein are administered by rubbing or massaging the composition on a biological barrier such as the skin, by means of the hand or an applicator. In some embodiments, the compositions disclosed herein are rubbed or massaged on a biological barrier such as the skin, by means of an applicator.

[0314] Accordingly, in another aspect of the disclosure, an applicator adapted to administer (or capable of administering) the compositions disclosed herein is provided. As used herein, an applicator can be adapted to apply the compositions disclosed herein to a biological barrier such that at least a portion of the composition penetrates the biological barrier.

[0315] In some embodiments, the applicator is a textured applicator having at least one textured surface. The textured surface can be configured to engage and orient microparticles in the compositions disclosed herein at an angle to facilitate penetration of a biological barrier such as the skin surface. In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum of the skin. In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum and the living epidermis of the skin.

[0316] In some embodiments, the applicator is a microtextured applicator having at least one microtextured surface. The microtextured surface can be configured to engage and orient microparticles in the compositions disclosed herein at an angle to facilitate penetration of a biological barrier such as the skin surface. In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum of the skin. In some embodiments, the microparticles in the compositions disclosed herein penetrate only the stratum corneum and the living epidermis of the skin.

[0317] The microtextured applicator can be of various sizes suitable for a desired surface area, can be made of different suitable materials such as biocompatible and non-allergenic materials, and can be manufactured using, for example, 3D printing, photolithography, or deep reactive ion etching.

[0318] In some embodiments, the applicator is the applicator described in Patent Application No. WO2014 / 094067A1, the entire content of which is incorporated herein by reference.

[0319] For example, in some embodiments, the applicator can include a microtextured surface configured to engage and orient the microparticles of the compositions disclosed herein at an angle to promote the penetration of biological barriers. The compositions disclosed herein can be applied to biological barriers using an applicator that includes a microtextured surface such that at least a portion of the composition penetrates the biological barrier, which includes the step of engaging and orienting the microparticles of the composition at an angle using the applicator to promote the penetration of the biological barrier.

[0320] The applicator is an instrument for use in applying the compositions disclosed herein, but may not be intended to be a permanent support for the compositions disclosed herein. The compositions disclosed herein are provided separately from the applicator. Some of the microparticles of the compositions disclosed herein can be temporarily adhered to the microtextured surface of the applicator, such as the applicator head, during and after use. However, generally, the applicator is removed after delivery of the composition.

[0321] In some embodiments, the microtextured surface of the applicator is treated with a composition disclosed herein (such as by coating with the composition) that is intended to be delivered through a biological barrier such as the skin surface. In such cases, the compositions disclosed herein can be applied simultaneously to the biological barrier and can be at least partially delivered through the biological barrier with the aid of the applicator.

[0322] In some embodiments, the microparticles of the composition disclosed herein are applied to the skin in a first step in the absence of one or more bioactive compounds of the composition disclosed herein. The microparticles of the composition disclosed herein are thought to form microchannels in the skin as they penetrate the skin under manual force applied by the applicator surface. In a subsequent step, one or more bioactive compounds of the composition disclosed herein can be applied to the skin (with or without massaging or rubbing in of the bioactive compounds) while forming the composition disclosed herein in situ, and at least a portion of the bioactive compounds can penetrate through the microchannels formed in the skin, thereby delivering the bioactive compounds.

[0323] The applicator can be held in the operator's hand, and the microtextured surface can be manually massaged or rubbed over the area of skin to which the composition disclosed herein is to be applied. Manual massaging or rubbing can facilitate the penetration of at least a portion of the composition disclosed herein through the skin.

[0324] In one embodiment, the applicator includes a body and an applicator head having a microtextured surface thereon. In another embodiment, the applicator comprises a glove or finger sack that includes a microtextured surface on its fingertip region.

[0325] In another embodiment, the applicator includes a microtexturing on both the head and the body. For example, the applicator can be of a substantially cylindrical shape. The cylindrical applicator can have a body in the form of a shaft and a head in the form of the tip of the shaft. The cylinder can have a microtextured surface on the shaft and the tip. In one embodiment, the cylindrical applicator can be a rod or a baton. This embodiment is suitable for use when a biological barrier is provided in a body cavity and the applicator is inserted into the body cavity during use. At least a portion of the shaft intended for insertion can have a microtextured surface. The body cavity can be, for example, a vaginal canal.

[0326] The applicator is intended for manual use, however, there can be mechanical and / or electronic incorporations within the applicator. For example, there can be a mechanical agitation part on the microtextured surface of the applicator. The agitation can be vibration and / or oscillation. The applicator can include a sonophoresis or electrophoresis probe, or the like, that provides a "non-invasive" force to improve delivery. Any agitation part can operate in conjunction with manual massage or rubbing application techniques.

[0327] The handheld applicator can further include a force controller. The force controller allows the user to vary the force with which the applicator is manually applied to the skin so that an optimal force for skin penetration can be achieved. The force controller can also include an added force gauge that indicates to the user when the optimal manual force is achieved.

[0328] By the applicator surface, the force applied to the compositions disclosed herein is a force within the range that can be manually applied by a human operator. In one embodiment, the force can be greater than 0.01 newtons, such as at least 0.1 newtons. In one embodiment, the applied force is at least 0.2 newtons. In one embodiment, the applied force is 2.5 newtons. The maximum force can be 10 newtons.

[0329] When the compositions disclosed herein are applied using an applicator, for example, by rubbing in with a finger, they can exhibit improved permeability of biological barriers, such as the stratum corneum of the skin, compared to manual application without using an applicator. For example, when the composition is applied using an applicator, intradermal delivery of the compositions disclosed herein can be improved.

[0330] As used herein, the term "microtextured" means that the surface has been raised and / or lowered on a micrometer to millimeter scale relative to the plane of the surface.

[0331] In one embodiment, the textured surface includes angled surfaces that define a space for receiving the microparticles of the compositions disclosed herein during use of the applicator. The angled surfaces may be flat or curved. In the use of the applicator of this embodiment, at least the end regions of each microparticle of the compositions disclosed herein are received in a space such that at least one angled surface engages the end of the microparticle and defines the orientation of the microparticle. The spaces may each be defined by one or more angled surfaces.

[0332] In one embodiment, the spaces may be defined between protrusions on the textured surface. The protrusions may comprise a series of laterally spaced elongate or dispersed fine protrusions or fine ridges, each protrusion or ridge providing two or more generally inwardly angled surfaces. The first surface can engage the end of the microparticle of the compositions disclosed herein, and an adjacent second surface can define the orientation of the microparticle. There may be a base or valley formed between the ridges.

[0333] In another embodiment, the space can be defined by recesses in the textured surface. The recesses can comprise a series of laterally spaced elongated or dispersed fine recesses. The fine recesses can be a series of indentations. In one embodiment, each recess provides two or more inwardly angled surfaces. One of the surfaces can engage the ends of the microparticles of the compositions disclosed herein, and the other can define the orientation of the microparticles. The geometry of the microtextured portion is adapted such that the microparticles cannot be received into and trapped within the space between the textured portions, e.g., the surfaces.

[0334] The surface that defines the orientation of the microparticles of the compositions disclosed herein can be angled and dimensioned to provide support to at least the end sections of the microparticles. In this embodiment, at least the end sections of the microparticles can extend across the width of the surface. Thus, each microparticle can extend beyond the surface and the width of the surface can be less than the minimum length of the microparticles of the compositions disclosed herein so that the microparticles can penetrate the biological barrier during use of the applicator. The width of this surface can be at least 8 microns. The maximum width of this surface can be 1 mm.

[0335] There can be some geometries of the microtextured portion that are optimal for engaging and orienting the individual microparticles of the compositions disclosed herein, and other geometries of the microtextured portion that are optimal for engaging aggregates of the microparticles of the compositions disclosed herein. The type of microtextured portion on the surface of the applicator can vary across the surface. The type of microtextured portion can vary to provide optimal penetration of single particles and aggregates of particles. Single particles can be best oriented by relatively small surfaces in the microtextured portion. In one embodiment, the peripheral circumferential edge of a generally cylindrical applicator surface can have a first geometry of the microtextured portion and the upper surface of the cylinder can have a different geometry of the microtextured portion.

[0336] On the surface of the applicator, there may be a smooth area without a micro-textured portion. The micro-textured portion on the surface of the applicator can be in the range of about 1 to 100%. In one embodiment, at least about 75%, 77%, 80%, 85%, 90%, or 95% of the applicator surface comprises a micro-textured portion, and the area between the micro-textured portions is substantially smooth. In one embodiment, the surface of the applicator comprises 100% micro-textured portion and has no smooth area. Different amounts of the compound can be delivered depending on the different amounts of the micro-textured portion. In one embodiment, different amounts of the micro-textured portion can be selected to control the dose delivery at a given concentration of the compound in the composition or formulation. For example, 95% of the micro-textured portion of the applicator surface can provide 95% of the available dose of the compound of the composition, while 50% of the micro-textured portion on the applicator surface can provide 50% of the available dose of the compound in the composition.

[0337] After application of the composition disclosed herein, due to the fine size diameter of the microparticles of the composition disclosed herein and the elastic properties of the skin, it is assumed that the disruption to the skin is of a negligible extent. The micro-channels formed by the microparticles of the composition disclosed herein are considered to close after their permeation. This attribute of the rapid closure of the path created by the microparticles of the composition disclosed herein after application is beneficial considering potential foreign body (microorganism) infiltration.

[0338] At least a portion of the applicator with a textured surface is constructed from a material harder than the skin because the microparticles of the composition disclosed herein may be embedded in the applicator rather than the skin.

[0339] The micro-textured portion on the surface of the applicator can engage and align the microparticles of the compositions disclosed herein. The base or valleys within the textured surface are believed to be the most common areas that provide resistance to the microparticles of the compositions disclosed herein when pressing them against the skin.

[0340] In some embodiments, for engaging and orienting the microparticles, the material of the applicator surface can be selected or adapted to attract the microparticles of the compositions disclosed herein. For example, to provide an attraction to the areas of the micro-textured portion, the material of the applicator can vary at any base, valley, or indentation within the micro-textured portion. The attraction can be provided in the form of an adhesive material and / or a magnetic material. Where a portion of the micro-textured portion attracts, it may be possible to attract the microparticles to the applicator head and then align them, for example, by the ridges of the textured portion.

[0341] In one embodiment, the material in which the micro-textured portion is formed is soft and / or malleable. A soft material may allow for deeper penetration of the compositions disclosed herein. If the material in which the micro-textured portion is formed is too hard, some of the microparticles of the compositions disclosed herein can be destroyed, for example, by crumbling, which is undesirable. The material can include a UV curable polymer.

[0342] The micro-textured surface of the applicator can be formed by any method that results in surface micro-texturing. The method can be 3D printing, photolithography, or deep reactive ion etching.

[0343] In some embodiments, it is advantageous when the microparticles of the compositions disclosed herein penetrate the biological barrier at an angle. The angle may be sufficiently oblique to allow the microparticles to penetrate the stratum corneum, but not so deep that the microparticles penetrate the dermis. Without being bound by theory, the importance of the angled penetration profile may also be that, to deliver one or more bioactive compounds of the compositions disclosed herein, the microparticles of the compositions disclosed herein can create microchannels with a larger surface area compared to (skin-)perpendicular or 90-degree penetration. This may mean that the delivery methods described herein are advantageous over the prior art such as microneedles and gas jet injectors. The angled penetration of the microparticles of the compositions disclosed herein can disrupt a larger area of the living epidermis while increasing its permeability, but is hypothesized to be minimally invasive by minimizing damage to the dermal-epidermal junction, dermal capillaries, and pain receptors.

[0344] During use of the applicator, an angled surface can be oriented on the microtextured surface such that the microparticles of the compositions disclosed herein can be oriented at an acute angle to the surface of a biological barrier, such as the skin, to facilitate penetration of the biological barrier. In one embodiment, the microparticles of the compositions disclosed herein can be oriented to penetrate the skin at an angle greater than 0 degrees and less than about 45 degrees, such as, for example, in the range of about 5 to about 30 degrees, such as, for example, in the range of about 7 to about 25 degrees. In some embodiments, it is expected that the angle of penetration will rarely exceed 45 degrees. If the microparticles of the compositions disclosed herein are in a mass, or if the skin is deformed around the applicator, the angle may exceed 45 degrees. For example, skin in which collagen and elastin have been degraded (e.g., aged skin) can potentially deform around the applicator, and during massage, the microparticles can penetrate at nearly perpendicular (90 degrees).

[0345] The textured surface can generally have a convex, concave, rectangular, V-shaped, or other profile during use. In one embodiment, the microtextured surface is generally convex. In experiments using different applicator designs, it has generally been found that a convex textured surface can better align the microparticles of the compositions disclosed herein into an orientation that allows them to penetrate the skin than either a smooth convex surface or a concave textured surface that can cause poor transmission, for example. Due to the elasticity of the skin, when force is applied, the skin stretches and moves. Thus, generally, a convex profile is thought to allow for optimal contact between the textured surface and the skin when the applicator is manually pressed against the skin. In one embodiment, a portion of the applicator comprising the microtextured surface can be made of a deformable material that can start as concave and become convex when force is applied.

[0346] The applicator surface can cause the penetration of about 1 to about 100 microparticles of the compositions disclosed herein per mm of a biological barrier such as the skin surface. In some embodiments, the applicator surface can cause the penetration of about 40, about 50, about 60, about 70, or about 80 microparticles per mm. 2 2

[0347] The applicator can cause the penetration of the microparticles of the compositions disclosed herein to a depth of at least 40 μm, up to a maximum of 50 μm, for example up to a maximum of 60 μm. The microparticles of the compositions disclosed herein cannot penetrate deeper than 60 μm after application to the skin. Without being bound by theory, this may be due to the skin collagen acting as a physical penetration barrier to the microparticles.

[0348] It is proposed that with the aid of the applicator, an average maximum of about 15%, such as 10 - 15% of the microparticles of the compositions disclosed herein provided to the skin, can penetrate the dermis.

[0349] The number of microparticles of the compositions disclosed herein within the body will decrease over time as they are excreted from the body. In some embodiments, it is expected that the microparticles of the compositions disclosed herein can be completely excreted from the body after about 1, 2, or 3 weeks. Potential mechanisms of microparticle elimination may be associated with natural skin turnover (desquamation). In humans, over the course of approximately 3 weeks, new skin cells (keratinocytes) are generated within the epidermal basal layer. Keratinocytes migrate upward and form the cellularly viable epidermis. As the cells approach the surface of the skin, they ultimately differentiate (lose their nuclei) and begin to flatten. This process renews the stratum corneum and aids in the natural removal of foreign substances within the skin.

[0350] An applicator can be provided as part of a kit that includes the compositions disclosed herein. Accordingly, in a further aspect of the disclosure, a kit is provided that includes the applicator described herein and the compositions disclosed herein. In some embodiments, at least a portion of the surface of the applicator is coated with the composition described herein. The kit can be provided together with instructions for use.

[0351] Method of treatment In certain aspects of the present disclosure, the compositions disclosed herein are administered in a method of treatment or prevention. As used herein, the terms "treating," "treat," or "treatment" include administering the compositions of the present disclosure to reduce or eliminate at least one symptom of the condition being treated thereby. In one example, treatment includes administering the compositions disclosed herein to the skin of a subject. In one example, a treatment response is determined by comparison to a baseline measurement prior to treatment. In another example, a treatment response is determined by comparison to a control patient population. As used herein, the terms "prevent," "preventive treatment," "preventive," or "prophylactic," or "preventing" refer to treating a subject who does not yet exhibit symptoms of a disease or condition but is susceptible to or at risk of a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition by the treatment. In some embodiments, the compositions disclosed herein are administered to cure, ameliorate, delay the progression of, prevent, or reduce the likelihood of onset of an identified disease or condition, or to exhibit a detectable therapeutic or prophylactic effect.

[0352] In one example, one or more bioactive compounds of the compositions disclosed herein are administered in combination with a permeation enhancer. Suitable permeation enhancers will be apparent to those skilled in the art based on the bioactive compound and the condition being treated. In one embodiment, combinations of permeation enhancers may be used in conjunction with one or more bioactive compounds of the compositions disclosed herein.

[0353] The compositions disclosed herein are particularly advantageous for the topical delivery of bioactive compounds. Accordingly, the present disclosure also provides a method of treatment comprising administering to a subject the compositions disclosed herein, the pharmaceutical compositions disclosed herein, or the cosmeceutical compositions disclosed herein.

[0354] Without being bound by theory, it is proposed that the microparticles in the compositions disclosed herein preferentially penetrate biological barriers such as the skin, e.g., the stratum corneum of the skin, or the stratum corneum of the skin and the outer portion of the living epidermis, enabling localized absorption of bioactive compounds such as localized intradermal absorption. For example, absorption can involve the partitioning of the bioactive compound from the applied composition into the stratum corneum and the epidermis. In this way, the compositions of the present disclosure can achieve, for example, local delivery of the bioactive compound across the stratum corneum and retention within the skin such that most of the bioactive compound does not enter the bloodstream in a significant amount. Such improved localized topical delivery is particularly suitable for the topical administration of bioactive compounds that act on the nuclear receptor superfamily, e.g., steroids, thyroid hormones, retinoids, vitamins, etc., and the treatment of associated conditions. In particular, the methods disclosed herein are suitable for the local delivery of steroid hormones and compounds that act on steroid hormone regulation. In some embodiments, the methods disclosed herein are particularly suitable for the local delivery of one or more bioactive compounds selected from the group consisting of steroids or corticosteroids optionally selected from the group consisting of estradiol, estrone, estriol, 5α-dihydrotestosterone, finasteride, cortisone, spironolactone, or mixtures thereof; minoxidil, minoxidil sulfate, or derivatives or mixtures thereof; vitamins optionally selected from the group consisting of vitamin A, B, C, D3, and / or E; or retinoids optionally selected from the group consisting of retinoic acid, tretinoin, and mixtures thereof. Other bioactive compounds can include 5-aminolevulinic acid hydrochloride, diclofenac sodium, fluorescein sodium, or mixtures thereof.

[0355] In some embodiments, the compositions and methods of treatment described herein result in limited systemic absorption or accumulation of one or more of the administered bioactive compounds, or no systemic absorption or accumulation at all. In other words, in certain instances, the bioactive compounds localize to the intradermal region of a subject being treated according to the methods disclosed herein. In such embodiments, it may be necessary to periodically monitor the blood of the subject to confirm that the bioactive compounds are not present in significant amounts in the bloodstream. For example, the presence of the bioactive compounds can be evaluated by obtaining a normal blood sample from the treated subject and using methods known to those of skill in the art and readily available.

[0356] Accordingly, in some embodiments, the methods of the present disclosure further include, after the administration step, an additional step of testing for the presence or level of one or more bioactive compounds of the compositions disclosed herein in the treated subject. In some embodiments, the additional step includes testing the serum level of one or more bioactive compounds in the subject.

[0357] The additional step can include determining the concentration of one or more bioactive compounds in a sample from the subject, and optionally, the sample is isolated from the subject. In some embodiments, the sample is a urine sample, a blood sample, a serum sample, or a plasma sample.

[0358] As will be apparent to those skilled in the art, endogenous bioactive compounds may be present at certain normal (e.g., baseline) levels in the body of a treated subject in subjects of the same gender and / or age group. In the context of the present disclosure, an "endogenous" compound refers to a compound that has its origin within the body, such as a hormone. In such instances, it may not be practical to rely solely on the mere presence of the bioactive compound as an indicator of whether the bioactive compound has entered the bloodstream of the treated subject after administration of the compositions disclosed herein. In such instances, the level (e.g., serum level) of the bioactive compound in the treated subject may be compared to a control. In one example, the control may be the level (e.g., serum level) of the bioactive compound in the treated subject prior to treatment. In another example, the control may be the level (e.g., serum level) of the bioactive compound observed in an untreated subject of the same gender. In a particular example, the control may be the level (e.g., serum level) of the bioactive compound observed in an untreated subject of the same gender and age. Typically, control levels of endogenous bioactive compounds in untreated subjects will be readily available to those skilled in the art from the literature.

[0359] As used herein, a "normal" level of a bioactive compound is a level (e.g., serum level) of the bioactive compound that is relatively close to the average level of the bioactive compound in subjects of the same gender and / or same age group. For example, in some embodiments, the methods disclosed herein may also include, after the administration step, testing the serum estradiol level of a treated female subject of a particular age group and determining that the serum estradiol level of the treated female subject is normal for females of the same age group as the treated female subject. In some embodiments, the female subject is a postmenopausal female subject.

[0360] Moreover, it will be apparent to those skilled in the art that an exogenous bioactive compound may not normally be present in a substantial amount in the body of a treated subject prior to administration of such an exogenous bioactive compound. In the context of the present disclosure, an "exogenous" compound is a compound that does not have an origin within the body, such as a small molecule drug. After administering the compositions disclosed herein, if the mere presence of the bioactive compound is an indicator of whether the bioactive compound has entered the bloodstream of the treated subject, the baseline level of the exogenous bioactive compound in the treated subject can be approximately zero. In other examples, the subject may have been previously treated with an exogenous bioactive compound. In such examples, the level (e.g., serum level) of the bioactive compound in the treated subject may be compared to a control, where the control is the level (e.g., serum level) of the bioactive compound observed in the subject prior to administering the treatment.

[0361] For example, in some embodiments, the methods disclosed herein may also include, after the administration step, testing the serum level of minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof in a treated male subject, and determining that the serum level of minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof in the treated male subject has not increased substantially as compared to the control serum level of minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof in the subject.

[0362] In one embodiment, provided herein is a method of treating and / or preventing at least one menopausal symptom, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein. In some embodiments, at least one bioactive compound in the composition disclosed herein comprises estradiol, estrone, estriol, or a retinoid, or a derivative thereof. In some embodiments, at least one bioactive compound in the composition disclosed herein comprises estradiol or a derivative thereof. As used herein, at least one menopausal symptom that can be alleviated by the composition or method disclosed herein can be selected from, but is not limited to, hot flashes, night sweats, a crawling or itching sensation under the skin, headache, fatigue, frequent urination, vaginal dryness, and mixtures thereof. In some embodiments, menopausal symptoms that can be alleviated by the composition or method disclosed herein include loss of skin thickness and elasticity. In some embodiments, the compositions and methods disclosed herein are useful for increasing epidermal hydration, skin elasticity, skin thickness, and / or reducing skin wrinkles in menopausal subjects. Further, in some embodiments, the compositions and methods disclosed herein are useful for improving the collagen content and quality, as well as the level of angiogenesis.

[0363] In another embodiment, provided herein is a method of hydrating and / or increasing collagen formation in at least a portion of the skin, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein. In some embodiments, at least one bioactive compound in the composition disclosed herein comprises estradiol, estrone, estriol, or a retinoid, or a derivative thereof. In some embodiments, at least one bioactive compound in the composition disclosed herein comprises estradiol or a derivative thereof. The methods described herein, including topical administration, are applicable, for example, to maintaining the condition of the skin and / or stimulating / increasing collagen formation, rejuvenating the skin, and increasing the thickness and / or elasticity of the skin. The method can alleviate changes resulting from aging that occur in human skin, such as the appearance of fine lines (wrinkles), loss of elasticity (sagging), and changes in skin color, texture, thickness, and moisture content.

[0364] In another embodiment, provided herein is a method of treating and / or preventing hair loss, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical-cosmetic composition disclosed herein, wherein the composition is formulated for topical application. In one embodiment, at least one bioactive compound in the composition disclosed herein comprises minoxidil or a derivative thereof. In one embodiment, at least one bioactive compound comprises minoxidil sulfate or a derivative thereof. In one embodiment, at least one bioactive compound comprises finasteride or a derivative thereof. In one embodiment, the method relates to the treatment of male subjects. In one embodiment, the hair loss of the subject is self-diagnosed. In one embodiment, the hair loss is diagnosed by a clinician treating the subject. In one embodiment, the treatment is performed on the head of the subject. In some embodiments, the hair loss is male hair loss. In one embodiment, the hair loss is male pattern hair loss. In one embodiment, the hair loss is treated in female subjects. In some embodiments, the hair loss is caused by androgenetic alopecia (AGA). In one embodiment, the treatment is prophylactic.

[0365] In another embodiment, provided herein is a method of treating and / or preventing hirsutism (excessive hair growth), such as excessive hair growth in non-scalp areas of the body, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical-cosmetic composition disclosed herein, wherein the composition is formulated for topical application. In some embodiments, at least one bioactive compound in the composition disclosed herein comprises spironolactone or a derivative thereof. In embodiments, the method relates to the treatment of female subjects. The excessive hair may be on non-scalp areas of the subject, such as the face, chest, and / or back. In embodiments, the method relates to the treatment of male subjects.

[0366] In another embodiment, provided herein is a method of treating and / or preventing a dermatological condition or disease, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein, wherein the composition is formulated for topical application. Examples of dermatological conditions or diseases suitable for treatment by the methods described herein include, but are not limited to, the aging condition of the skin, seborrheitis, psoriasis, and dermatitis. The compositions disclosed herein are also suitable for the treatment and / or prevention of a crawling sensation.

[0367] In some embodiments, the dermatological condition or disease is acne. As used herein, the term "acne" refers to a skin condition that occurs when hair follicles become clogged with oil and / or dead skin cells. The condition generally causes whiteheads, blackheads, or blemishes on the skin of the subject. In one embodiment, the acne is common acne. In another example, the acne is cystic acne. Other types of acne include acne with papules, pustules, or nodules, acne mechanica caused by heat and friction, and acne conglobata. In one embodiment, the composition disclosed herein is applied directly to the zone of acne occurrence. In another example, the composition is applied prophylactically in the absence of acne. In one example, the composition is applied to a subject who has previously presented with acne or symptoms thereof.

[0368] In some embodiments, at least one bioactive compound in the compositions disclosed herein, the pharmaceutical compositions disclosed herein, or the pharmaceutical cosmetic compositions disclosed herein that are suitable for the treatment of acne comprises a vitamin A derivative. In one embodiment, the vitamin A derivative is retinol or retinoic acid. Other examples of suitable bioactive compounds include retinyl acetate, retinyl linoleate, retinyl palmitate, and retinyl propionate. In one embodiment, at least one bioactive compound is tretinoin. In other examples, at least one bioactive compound is a topical retinoid, adapalene, salicylic acid, azelaic acid, and alpha hydroxy acids, and / or a topical antibiotic, and / or benzoyl peroxide. In one embodiment, at least one bioactive compound is a steroid. In another embodiment, at least one bioactive compound is tetracycline. In another embodiment, at least one bioactive compound is spironolactone.

[0369] Examples of topical anti-acne bioactive compounds suitable for the methods disclosed herein further include keratolytics such as adapalene, azelaic acid, benzoyl peroxide, clindamycin and clindamycin phosphate, doxycycline, erythromycin, salicylic acid and retinoic acid (e.g., "Retin-A"), norgestimate, organic peroxides, retinoids such as isotretinoin and tretinoin, sodium sulfacetamide, and tazarotene. Specific anti-acne agents include adapalene, azelaic acid, benzoyl peroxide, clindamycin (e.g., clindamycin phosphate), doxycycline (e.g., doxycycline monohydrate), erythromycin, isotretinoin, norgestimate, sodium sulfacetamide, tazarotene, etretinate, and acitretin.

[0370] In another embodiment, provided herein is a method of improving or treating the appearance of a subject's skin, the method comprising administering a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein. The compositions disclosed herein are suitable for addressing cosmetic and subjective needs such as, for example, changing or improving the appearance of a portion of the skin, improving the elasticity of the skin, moisturizing the skin, firmness, skin color, skin color and / or texture, increasing the softness of the skin, and the like.

[0371] In one embodiment, a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein is administered by a treating clinician. In another example, the composition is self-administered by the subject.

[0372] In one embodiment, treatment comprises two or more doses (or applications) of a composition disclosed herein, a pharmaceutical composition disclosed herein, or a pharmaceutical cosmetic composition disclosed herein. For example, a composition disclosed herein can be administered periodically, such as daily, weekly, bi-weekly, or monthly. In some embodiments, a composition disclosed herein is administered at least once a day for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In some embodiments, a composition disclosed herein is administered at least once a day for a period of at least 18 months, at least 24 months, or at least 36 months.

[0373] In the context of the disclosed methods, "administering" a composition means applying the compositions disclosed herein for the topical delivery of at least one bioactive compound to the required body surface area. In some embodiments, "applying" includes applying the composition to the required body surface, such as the skin, and then rubbing or massaging the applied composition onto the surface, for example, by circular or back-and-forth movement of the hand or an applicator. In some embodiments, application is achieved by using an applicator. In some embodiments, the applicator is a textured applicator. In some embodiments, the applicator is a micro-textured applicator. Micro-textured applicators can be of various sizes suitable for the desired surface area and can be made of different suitable materials such as biocompatible and non-allergenic materials and can be manufactured, for example, using 3D printing. In some embodiments, the applicator is the applicator described in Patent Application No. WO2014 / 094067A1, the entire content of which is incorporated herein by reference. In some embodiments, the compositions disclosed herein are delivered to the skin by rubbing or massaging onto the skin using a micro-textured applicator such as the applicators described herein. For example, the applicator can be used to locally apply and massage the composition onto the skin using circular or linear back-and-forth movement for a suitable period of time.

[0374] In some embodiments, the microparticles and at least one bioactive compound are applied to the body surface (e.g., skin) as a single formulation. The formulation can be pre-formed and stored or can be formed immediately prior to application. Advantageously, the microparticles can be commingled with an existing or known formulation of the at least one bioactive compound.

[0375] In some embodiments, at least one bioactive compound is formulated to be applied separately from the microparticles to the body surface (e.g., skin), such as after application of the microparticles. For example, at least one bioactive compound can be in the form of an existing or known formulation of the at least one bioactive compound.

[0376] The appropriate dosage of at least one bioactive compound administered as part of the compositions disclosed herein will be determined by a skilled professional in topical therapy and / or hormonal therapy. Generally, the dosage will depend on the concentration of the bioactive substance in the composition, the amount of the composition placed on the surface such as the skin, the area covered by the composition for topical delivery of the bioactive compound, and the frequency of application of the topical treatment.

[0377] In other embodiments, disclosed herein is a method for delivering at least one bioactive compound through the stratum corneum of the skin of a subject for cosmeceutical purposes, excluding cutaneous malignancies, the method comprising applying a composition that administers a composition as defined herein, a pharmaceutical composition as defined herein, or a cosmeceutical composition as defined herein to the subject, wherein the bioactive compound is optionally estradiol, optionally in the presence of a further hormonal modulator.

[0378] The microparticles of the compositions disclosed herein can be eliminated or dissolved after application. Depending on the composition of the microparticles, microparticles that penetrate the skin barrier can remain within the skin barrier for 1, 2, or 3 weeks and can be removed by natural skin turnover. For example, it has previously been shown that microparticles made of silica are well tolerated in human patients and eventually flake off.

Example

[0379] Example 1 - Generation of Foroderm Microparticles In some embodiments, the microparticles of the compositions disclosed herein are referred to as Foroderm. Examples of the generation of Foroderm microparticles are provided below.

[0380] Twelve wafers of silicon in the form of micropillars were fabricated by the South Australian Node of the Australian National Fabrication Facility (ANFF-SA). Four micropillars with a diameter of 12 μm, four with a diameter of 9 μm, and four with a diameter of 6 μm were generated, having a target height of 115 μm ± 10%.

[0381] Microparticles referred to as fiber glass Foroderm were manufactured from silicon wafers called "etched microparticles". A photomask was designed and fabricated to cover a diameter of 5 inches out of 6 inches of the silicon wafer. The wafer was coated with a photoresist via spin coating. Bosch etching was used to generate pillars with a diameter of 10 μm and a height of 150 μm. Each etched wafer was washed to remove the photoresist, and then the pillars were harvested from the wafer to generate microparticles.

[0382] The etched micro-particles (Foroderm) were removed from the silicon wafer using a blade, and the surface of the wafer was washed with absolute ethanol. This procedure was repeated twice to collect most of the micro-particles. The micro-particles were collected in a 15 mL tube and centrifuged at 2500 rpm for 5 minutes. The clear supernatant was removed, and the precipitate (micro-particles) was washed three times with acetone, followed by three times with absolute ethanol, and finally three times with distilled water. For each wash, 5 ml of the solvent was added, gently shaken, and then centrifuged at 2500 rpm for 5 minutes. The clear supernatant was removed each time and replaced with fresh washing solvent. After the final washing procedure, the wet micro-particles were transferred to a pre-weighed 1.5 mL microtube and left in an incubator at 60 °C for 24 hours. The weight of the microtube was measured several times until no weight change was observed. The dried micro-particles were stored at room temperature for future work and their sterilization.

[0383] To determine the size of the micro-particles, bright-field images were taken and the images were analyzed by ImageJ.

[0384] A total of 291 mg of micro-particles with a diameter of 12 μm, 297 mg of micro-particles with a diameter of 9 μm, and 85 mg of micro-particles with a diameter of 6 μm were collected from the corresponding wafers. Table 1 shows the length of each Foroderm, and the length of Foroderm in the three diameter groups of sizes is approximately the same as the target size provided by ANFF-SA.

[0385]

Table 1

[0386] Example 2 - Estradiol Assay Verification Estradiol 17β-[4- 14 C] (E2-14C) with a specific activity of 0.01 mCi / mL and 55 mCi / mmol was purchased from American Radiolabeled Chemicals Inc., USA.

[0387] A specific volume of E2-14C stock solution containing 1 and 2 μl (corresponding to 0.01 μCi and 0.02 μCi respectively) was separately added to 1 mL of water. Various volumes of the prepared E2-14C aqueous solution containing 10, 20, 30, 40, and 50 μL were placed into 1.5 mL Eppendorf tubes to which 1.2 mL of scintillation fluid (Ultima Gold™ XR, Perkin Elmer Inc., USA) was added and vortexed thoroughly. Then, the samples were counted using a microplate counter, MicroBeta® (model 2450, PerkinElmer, Singapore Pte. Ltd) for 4 minutes. The value of counts per minute (CPM) was converted to disintegrations per minute (DPM) and subsequently to μCi. Equation 1 was used to calculate the percentage of E2-14C efficiency (Equation 1).

[0388]

Number

[0389] The radiolabeling efficiency of E2-14C was also determined in digested skin. A 2 μl volume of E2-14C stock solution was added to 1 mL of water. Two series of digested skin experiments were considered. Skin biopsies were taken using a microsampling device with a 6 mm diameter. In series 1, one human full-thickness skin biopsy was placed into a 4 mL scintillation tube, followed by the addition of 500 μL of Solvable™ solution. Various volumes of the prepared E2-14C aqueous solution containing 10, 20, 30, 40, and 50 μL were added to each tube, and the samples were left in an incubator at 60 °C to digest the skin overnight. In series 2, two skin biopsy pieces and 800 μL of Solvable™ were placed into each vial, various volumes of the prepared E2-14C aqueous solution were added to each tube, and they were left in an incubator at 60 °C overnight.

[0390] To measure the amount of E2-14C in each tube, scintillation fluid was added, filling the 4 mL tubes, and vortexed vigorously. The samples were analyzed using a microplate counter. The efficiency percentage was calculated using Equation 1.

[0391] The radiolabeling efficiency in the E2-14C aqueous solution was shown to be 40%. The radiolabeling efficiencies in the presence of one piece of skin and two pieces of skin were 25% and 14%, respectively. These values were used in subsequent experiments as the counting efficiency for converting CPM to DPM (Equation 2).

[0392]

Number

[0393] Example 3 - Estradiol Assay Verification Estradiol 17β-[4- 14 C] (E2-14C) with activities of 0.01 mCi / mL and 55 mCi / mmol was purchased from American Radiolabeled Chemicals Inc., USA. β-Estradiol (E2) was purchased from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Australia).

[0394] E2 is a low water solubility drug with a molecular weight of 272.4 g / mol, Log P 4, and a water solubility of 3.9 mg / L at 27 °C. It is very soluble in ethanol, acetone, and dioxane (https: / / pubchem.ncbi.nlm.nih.gov / compound / Estradiol#section). -1 To develop a validated assay for E2, radiolabeled E2 was selected and a calibration range of E2 with digested skin added was presented to cover skin from 1 - 1000 mol / cm

[0395] (0 - 272.4 ng / cm 2 ) 2 .

[0396] A series of E2 standard solutions (STD) were prepared in a water:ethanol mixture in the range of 0 - 30 μg / mL. The presented STD concentrations were based on a dose - volume application of 10 μL of formulation per cm of skin. 2 Table 2 shows the stock solutions required to prepare the various STD solutions.

[0397] [Table 2]

[0398] Table 3 shows the concentration and volume of each stock solution and water in the final STD solutions containing E2 and E2 - 14C.

[0399] [Table 3]

[0400] Each 100 μL volume of the STD solutions was transferred to 1.5 mL Eppendorf tubes, followed by the addition of 1.2 mL of scintillation fluid (Ultima Gold™ XR, Perkin Elmer Inc., USA) and vortexed thoroughly. The samples were then counted using a microplate counter, MicroBeta® (model 2450, PerkinElmer, Singapore Pte. Ltd) for 4 minutes.

[0401] The radiolabeling efficiency of the E2 - 14C stock solution in water was also calculated (Equation 1) and used to convert CPM to DPM (Equation 2). The DPM values were used to calculate the E2 - 14C activity based on μCi, and subsequently the amount of E2 - 14C in μg (Equations 3 and 4). Equation 5 was used to calculate the final E2 in each STD.

[0402] [Equation]

[0403] [Number]

[0404] [Number]

[0405] [Number]

[0406] The counting efficiency was 23% and was used to convert CPM to DPM. Figure 1 shows two different ranges, an E2 to E2-14C ratio of 86 (Table 3) for E2 STD (A: 10 - 30 μg / mL) and an E2 to E2-14C ratio of 8.6 (Table 3) for Figure 1B (0.5 - 5 μg / mL). Both plots show an r 2 showing a good correlation of about 0.99.

[0407] The total E2 concentration in each STD was calculated using Equations 2 - 5 and plotted against the E2 STD concentration (Table 3), which is shown in Figure 2. There is a good correlation between the two concentrations, suggesting that radiolabeled E2 can be used for the sensitive quantification of E2 in a water-ethanol mixture.

[0408] Example 4 - Estradiol Assay Validation in Digested Skin 0 - 272.4 ng / cm 2To prepare the calibration range of E2 with added skin in the range of 0 to 30 μg / mL in water:ethanol (90:10), 12 calibration standards of E2 were prepared. In the next step, 3 skin biopsies were placed into 4 ml scintillation tubes, followed by the addition of 1.5 ml of Solvable™, and left overnight in an incubator at 60 °C to prepare 14 digested skins. Once the digested skin was ready, 10 μL of each STD in the water-ethanol mixture was added to 1.5 mL of the digested skin (Table 4). The total volume of 1.5 mL of E2 with added digested skin was divided into 700 μL volumes and placed into separate 4 mL scintillation tubes, followed by the addition of scintillation liquid (Ultima Gold™ XR, Perkin Elmer Inc., USA). Two digested skin samples were used as controls without the addition of E2. All tubes were vortexed vigorously and the E2-14C content was measured by a 4-minute microplate counter, MicroBeta® (Model 2450, PerkinElmer, Singapore Pte. Ltd). The radio-labeling efficiency of E2-14C in the digested skin was also calculated (Equation 1) and used as the counting efficiency for converting CPM to DPM (Equation 2). Using the DPM values, the E2-14C activity based on μCi, and subsequently the amount (μg) of E2-14C was calculated (Equations 3 and 4). Equation 5 was used to calculate the final E2 in each STD.

[0409]

Table 4

[0410] The target skin dose in this study expected to be delivered and measured is highlighted in Table 3. As an example of the added solution preparation from the 2700 ng / mL (2.7 μg / mL) STD solution, digested skin was added to 10 μL containing 27 ng of E2 and 4.1 ng of E2-14C.

[0411] The range of E2-14C in the added solution is 1.2 ng / 1.5 mL to 5.8 ng / 1.5 mL.

[0412] The counting efficiency of E2-14C in the presence of digested skin was 17%, which was used to calculate DPM (Equation 2), and Equations 3, 4, and 5 were used to add skin samples to the total E2 recovered at each E2.

[0413] According to Figure 3A, radiolabeled E2 showed a limited ability to be used at high concentrations of E2 (r 2 = 0.8389). This partial defect can be explained by the limited solubility of E2 in aqueous solutions and digested skin, and thus the precipitation of E2 in the final solution. However, at lower concentrations (Figure 3B), a good linear relationship was observed between E2 concentration and DPM (r 2 = 0.99).

[0414] According to Figure 4A, the top four concentrations of E2 do not align with the rest of the E2 STD with added skin. However, a good correlation (r 2 = 0.99) was observed between the E2 STD concentration and the observed E2 concentration with added digested skin in the defined range of 5 - 150 ng / cm 2 (Figure 4B). Considering the point where the skin target dose is defined as 27.2 ng / cm 2 , radiolabeled E2 can be used as a sensitive and specific assay method in this study.

[0415] Example 5 - Validation of Estradiol Assay in Tape-Stripped Skin Estradiol 17β-[4- 14 14C] (E2 14C) with activities of 0.01 mCi / mL and 55 mCi / mmol was purchased from American Radiolabeled Chemicals Inc., USA. β-Estradiol (E2) was purchased from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Australia).

[0416] A solution of E2 14C was prepared by adding 6 μL of E2 14C to 100 μL of water:ethanol (9:1) and mixing thoroughly. The prepared solution contained 300 ng of E2 14C. Another solution was prepared by adding 3 μL of E2 14C to 100 μL of water:ethanol (9:1) containing 1.5 μg / mL of E2. The prepared solution contained 150 ng of E2 14C and 150 ng of E2.

[0417] Full-thickness human skin was obtained from a female patient (40 years old) after surgical abdominoplasty. Skin with a surface area of 1.3 cm 2 was marked, followed by 20 tape strippings (D-Squame tape, 22 mm in diameter) to remove the stratum corneum. The prepared E2 solution was applied to the tape-stripped skin and placed in a water bath at 37 °C for 90 minutes. At the end of the experiment, the residual material was removed from the surface by wetting a cotton swab three times. Then, the skin was biopsied using a microsampling device with a diameter of 6 mm. Each biopsy piece was placed in a 4 mL scintillation tube, followed by the addition of 500 μL of Solvable™ solution (Perkin Elmer Inc., USA). The sample was placed in an incubator at 60 °C to digest the skin overnight. To measure the amount of E2 14C in each, scintillation fluid (Ultima Gold™ XR, Perkin Elmer Inc., USA) was added to fill the 4 mL tube and vortexed vigorously. The samples were analyzed using a microplate counter, MicroBeta® (model 2450, PerkinElmer, Singapore Pte. Ltd). The experiment was conducted three times.

[0418] Table 5 shows the CPM obtained from analyzing one skin biopsy with an area of 0.28 cm 2 . A counting efficiency of 25% was considered to calculate the DPM.

[0419]

Table 5

[0420]

Number

[0421] In the experiment, a target of 100 CPM is considered. In this experiment, since the stratum corneum, the main barrier, was removed, the CPM value was high. In the presence of the stratum corneum, a significant reduction in the CPM value was expected, and therefore, it seems reasonable to incorporate at least 6 μL of stock E2-14C into 100 μL of the formulation. By reducing the volume of E2-14C in the solution containing E2-14C + E2, approximately half of the CPM measured from the E2-14C solution was obtained, indicating that the radiolabeled E2-14C is sensitive and specific for the quantification of E2 delivery.

[0422] Example 6 - Foroderm Coating Characterization Evaluation β-Estradiol (E2), sodium alginate salt from brown algae, low viscosity (Na Alg), calcium chloride (CaCl2), and sodium carboxymethyl cellulose (low viscosity) were purchased from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Austaria).

[0423] Sodium alginate (Na Alg), one of the most commonly used natural polysaccharides, was used as a coating excipient for Foroderm. A sodium alginate solution (1%) was prepared by adding 100 mg of Na to a water:ethanol (90:10) mixture containing 25 μg / mL of E2 and continuously stirring at 400 rpm for about 30 minutes using a magnetic stir bar to completely dissolve the alginate.

[0424] A solution of Na Alg (1%) containing 12.5 μg / mL of E2 was also prepared by dissolving 100 mg of Na Alg in 10 mL of water:ethanol for comparison.

[0425] The gelation of Na Alg is Ca 2+This can be achieved by introducing cations such as [[ID=]], and forming a gel by replacing sodium ions (Abbasalizade et al., 2020). A CaCl2 solution was prepared by dissolving an appropriate amount of CaCl2 in water to obtain the desired concentrations of 0.2, 0.4, 0.6, 0.8, 1, and 2 mg / mL. The CaCl2 solution was added to the Na Alg (1%) solution at a volume ratio of 1:1 and vortexed at 2000 rpm for 10 seconds to obtain a cross-linked gel. The final concentration of Na Alg in the prepared gel was 0.5%, while the concentration of CaCl2 was in the range of 0.1 - 1 mg / mL. All the prepared gels contained 12.5 μg / mL of E2. A 0.5% Na Alg solution was prepared by adding 1 mL of a water:ethanol mixture.

[0426] Various carboxymethylcellulose (CMC) gels (0.5, 1, 1.5, 2, 2.5, and 5%) were prepared by adding a specific amount of CMC to a 12.5 μg / mL E2-containing water:ethanol (90:10) mixture. The mixture was continuously mixed at 300 rpm and room temperature using a magnetic stir bar until a transparent gel was obtained.

[0427] Fiberglass Foroderm with a length of 124.3 ± 56.0 μm was used to coat with three prepared coating materials. An amount of 10 mg of Foroderm was added to 50 μL of the Na Alg solution, Na Alg cross-linked gel, and CMC gel to prepare freeze-dried samples. The samples were then mixed with Foroderm using a vortex and immediately frozen in liquid nitrogen for several seconds. The frozen samples were transferred to a freeze dryer and left overnight. A water:ethanol (90:10) solution containing 12.5 μg / mL of E2 was used as a control. Two freeze-dried samples were prepared for each. The ease of disintegration of the freeze-stained samples was evaluated by gently touching the samples with a finger to break them up and imaging them under optical microscopy.

[0428] The coated particles were studied by optical microscopy and bright-field microscopy. Scanning electron microscopy (SEM) (Zeiss Merlin FEG SEM equipped with SDD EDS) was performed to characterize the morphology and particle coating of Foroderm. The freeze-dried samples were placed on carbon-coated copper grids. An ultrathin coating (1 nm) of conductive metal was applied. SEM images were obtained using an EHT of 2 KV and two different magnifications of 100x and 1500x.

[0429] All CMC gels were homogeneous and fluid, however, the viscosity increased as the CMC concentration increased.

[0430] The first consideration was to evaluate the ease of disintegration of the freeze-dried samples under the small pressure of the finger. The ease of disintegration was as follows: E2 solution > Na Alg (0.5%) > Na Alg (0.5%) + CaCl 2( 0.1 mg.mL) ≧ Na Alg (0.5%) + CaCl 2( 0.2 mg.mL) > Na Alg (0.5%) + CaCl 2( 0.3 mg.mL) > Na Alg (0.5%) + CaCl 2( 0.4 mg.mL) > Na Alg (0.1%) > Na Alg (0.5%) + CaCl 2( 0.5 mg.mL) > Na Alg (0.5%) + CaCl2 (1 mg.mL).

[0431] The disintegration ease test of the CMC gels showed that only the 0.5% and 1% gels could disintegrate under finger pressure, and the rest of the samples remained as lumps of dry gel.

[0432] Considering the disintegration test and SEM images, for preparing dry formulations, 0.5% Na Alg solution, 0.5% Na Alg + 0.2 mg / mL CaCl2, and 0.5% CMC could be potential coating agents for Foroderm.

[0433] Example 7 - Evaluation of Foroderm Delivery Characteristics β-Estradiol (E2) was obtained from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Australia) as estradiol 17β-[4- 14 C](E2-14C) with a specific activity of 0.01 mCi / mL and 55 mCi / mmol, purchased from American Radiolabeled Chemicals Inc., USA.

[0434] An ethanol-water mixture (30:70) was selected to dissolve E2. Three different E2 concentrations containing 5, 10, and 30 μg / mL were prepared. A 24 μL volume of the E2-14C stock solution was added to 400 μL of the ethanol-water mixture (30:70) containing E2 and mixed thoroughly.

[0435] Abdominal full-thickness human skin from a 26-year-old female was used. The skin was stained with an aqueous methylene blue solution (50 μg / mL) by immersing it for 5 minutes, followed by washing under running water for 1 minute and gently drying it using tissue. The skin was pinned onto a foam board with a wet cloth attached underneath. An undamaged area of skin with a surface area of 2 × 2 cm was marked and left in a water bath set at 37 °C for 30 minutes. Ethanol solutions of E2 (10 and 30 μg / mL) and E2-14C with a volume of 50 μL, containing 5 mg of fiberglass Foroderm (applicator + Foroderm; "Foroderm") and without Foroderm (applicator only; "control"), were massaged onto the skin for 30 seconds in small circular motions using a micro-textured pen applicator. After administering the formulation to the skin, the foam was floated on the surface of a covered water bath at 37 °C (skin surface 32 °C) for 90 minutes. At the end of the experiment, the residual material on the skin surface was removed by wetting a cotton swab, followed by 5 tape strippings (D-Squame tape, diameter 22 mm). Then, the skin was biopsied using a microsampling device with a diameter of 6 mm. One biopsy from the group with Foroderm and 2 biopsies from the group without Foroderm were placed into 4 mL scintillation tubes, followed by adding 500 μL and 800 μL of Solvable™ solution (Perkin Elmer Inc., USA) to the samples respectively. The samples were left in an incubator at 60 °C to digest the skin overnight. To measure the amount of E2-14C in each, scintillation fluid (Ultima Gold™ XR, Perkin Elmer Inc., USA) was added to fill the 4 mL tubes and vortexed vigorously. The samples were analyzed using a microplate counter, MicroBeta® (model 2450, PerkinElmer, Singapore Pte. Ltd). The experiment was conducted 3 times. An experiment was carried out to test an initial dose of 5 μg / mL of E2, but the volume application dose was reduced to 40 μL for 4 cm 2 with respect to 40 μL. All skin experiments were conducted 3 times.

[0436] Table 6 shows the E2 dosage applied to the skin surface area and the percentage of the final dosage of total E2 in the solution.

[0437]

Table 6

[0438] The amount that permeated through the skin increased as the initial concentration of E2 increased. After applying the solution containing 10 μg / ml of E2, a total of about 50 ng of E2 was found in the skin. Therefore, the third concentration of E2 (5 μg / mL) was also tested, resulting in an average value of 37 ng / cm 2 (Table 7). The target dosage was presented as 27.2 ng / cm 2 , but it was determined to proceed at this E2 concentration in order to study the effect of the chemical permeation enhancer in combination with Foroderm.

[0439]

Table 7

[0440] Figure 5 shows the DPM found in each biopsy and the amount calculated considering the ratio of E2 / E2-14C in the solution.

[0441] Example 8 - Preparation of a liquid topical formulation containing a chemical permeation enhancer A series of chemical permeation enhancers (CPE) were selected as chemical permeation enhancers and in combination with Foroderm as a physical permeation enhancer to prepare the topical formulations to be tested. The formulations were prepared with and without E2.

[0442] β-Estradiol (E2), dimethyl sulfoxide, ethanol, propylene glycol, isopropyl alcohol, urea, sodium dodecyl sulfate, R-(+)-limonene, isopropyl myristate, oleic acid, undecanoic acid were purchased from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Australia). Tween® 80 was purchased from Chem-supply (Chem-supply Pty Ltd, SA, Australia), and menthol was provided by Plant essentials (QLD, Australia).

[0443] Estradiol 17β-[4- 14 C] (E2-14C) having a specific activity of 0.01 mCi / mL and 55 mCi / mmol was purchased from American Radiolabeled Chemicals Inc., USA.

[0444] Table 8 shows the CPE by the percentage used. The percentage of each CPE in the formulation was selected in such a way that it was below the maximum potency per unit dose provided by the Food and Drug Administration (FDA) (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm).

[0445]

Table 8

[0446] To prepare 1 mL of each CPE solution, first, the CPE was dissolved in an appropriate solvent (Table 9), then the remaining components were added, and subsequently the solution was mixed for 30 seconds using a vortex.

[0447] In the case of urea and SDS, a specific weight was dissolved in water before adding ethanol. Due to the low percentage of menthol in the final formulation, a 1% menthol solution in ethanol was prepared and used for addition to the final formulation.

[0448] A formulation containing E2 was prepared by preparing an ethanol solution of E2 at 100 μg / mL. The volume / amount of each component is presented in Table 8. The final E2 concentration in each CPE solution is 5 μg / mL and 30% ethanol.

[0449] Table 9 shows the final composition of each formulation in 1 mL of the formulation containing E2 and 1 mL of the formulation not containing E2.

[0450]

Table 9

[0451] Example 9 - Evaluation of various chemical permeation enhancers for improved estradiol delivery by Foroderm Abdominal full-thickness human skin from a 26-year-old female was used. As a control, an ethanol-aqueous solution was selected.

[0452] β-Estradiol (E2), dimethyl sulfoxide, ethanol, propylene glycol, isopropyl alcohol, urea, sodium dodecyl sulfoxide, R-(+)-limonene, isopropyl myristate, oleic acid, undecanoic acid were purchased from Sigma-Aldrich (Sigma-Aldrich Pty Ltd., NSW, Australia). Tween® 80 was purchased from Chem-supply (Chem-supply Pty Ltd, SA, Australia), and menthol was provided by Plant essentials (QLD, Australia).

[0453] Estradiol 17β-[4- 14C](E2-14C) was purchased from American Radiolabeled Chemicals Inc., USA.

[0454] Before the skin evaluation test, 18 μL of the E2-14C stock solution was added to 300 μL of the liquid formulation (Table 10) containing CPE and mixed thoroughly.

[0455] The skin was stained with an aqueous methylene blue solution (50 μg / mL) by immersing it for 5 minutes, followed by washing under running water for 1 minute and gently drying it using tissue. The skin was pinned onto a foam board with a damp cloth attached below. Marks were made on non-damaged areas of the skin with a surface area of 2×2 cm and left in a water bath set at 37 °C for 30 minutes. The transepidermal water loss (TEWL) of each marked area was measured three times using a vaporimeter (Delfin Technologies Ltd, Finland). Various CPE solutions with a volume of 40 μL containing E2-14C and E2, including 5 mg of Foroderm (applicator + Foroderm) and Foroderm-free (applicator only), were massaged onto the skin in small circular motions for 30 seconds using a micro-textured pen applicator. After administering the formulation to the skin, the foam was floated on the surface of a covered water bath and left at 37 °C (skin surface 32 °C) for 90 minutes. At the end of the experiment, the residual material on the skin surface was removed by wetting a cotton swab. The TEWL was measured, followed by five tape strippings (D-Squame tape, 22 mm in diameter). Then, the skin was biopsied using a microsampling device with a 6 mm diameter. One biopsy from the group with Foroderm and two biopsies from the group without Foroderm were placed in 4 mL scintillation tubes, followed by adding 500 μL and 800 μL of Solvable™ solution (Perkin Elmer Inc., USA) to the samples respectively. The samples were left in an incubator at 60 °C to digest the skin overnight. To measure the amount of E2-14C in each, scintillation fluid (Ultima Gold™ XR, Perkin Elmer Inc., USA) was added to fill the 4 mL tubes and vortexed vigorously. The samples were analyzed using a microplate counter, MicroBeta® (model 2450, PerkinElmer, Singapore Pte. Ltd). The experiment was conducted three times.

[0456] The TEWL of human skin measured before and after treatment is shown in Figure 6. Treatment of the skin with Foroderm resulted in an increase in TEWL (Figure 6A), but there was no significant change in the skin after treatment with only the CPE formulation and the applicator (Figure 6B).

[0457] Total amount of E2 (ng / cm 2 ) permeated through the skin is presented in Table 10. Since the variability of the amount obtained from the PG skin samples was high, this permeation enhancer was repeated.

[0458] The results showed that Foroderm increased the permeability of E2 compared to the corresponding control group. Among CPE + Foroderm, ethanol 30% (alone), DMSO, and PG showed the highest skin permeation amount by Foroderm. Among the CPE groups without Foroderm, ethanol and limonene showed the highest amount of E2 in the skin.

[0459]

Table 10

[0460] Figure 7 shows the DPM found in each biopsy in two groups and the amount of E2 calculated considering the ratio of E2 / E2-14C in the CPE solution.

[0461] Example 10 - Clinical trial to investigate the topical administration of an estradiol-containing Foroderm composition to postmenopausal women Method This trial was conducted in July 2022 at a specialized women's health clinic affiliated with the University of Adelaide, South Australia. Three postmenopausal women attending the clinic were selected according to the inclusion / exclusion criteria, including not receiving skin or systemic hormone therapy and having serum estradiol levels below 88 pmol / L, the minimum level detectable by radioimmunoassay. The skin thickness and hardness were evaluated using an Aixplorer ultrasound system (Supersonic Imagine, France) equipped with a 4-15-MHz linear probe. Using this scanning technique, the average skin thickness of the 54-year-old women was (0.9 - 3.3 mm), and the skin elasticity was 13 - 32 kPa. Dermoscopic photography was performed at baseline and at each of the subsequent blood samplings at 4, 24, 72, and 168 hours. Five milligrams of microparticles (9 μm in diameter and 113 ± 13 μm in length) were applied to the skin, followed by 70 μl of the formulation (30% ethanol, 5% isopropyl myristate, 0.1% menthol, 0.001% estradiol) to the same area. The micro-textured curved applicator head was printed using a 3D printer to create a convex surface. "Micro-textured" means that the surface has surface facets raised and / or lowered on a micro-meter to millimeter scale. The skin was then immediately massaged for 30 seconds using the applicator. Excess microparticles and formulation were removed with an alcohol wipe. A final blood sampling was performed on day 40 to confirm no delay in depot release from the microparticle insertion. A single-dose topical application of microparticles coated with estradiol (0.4 μg) was applied from the lower lateral surface of the earlobe to the angle of the jaw for 4 cm 2It was applied once to the area. The microparticles (silica) were fabricated by deep reactive ion etching in an ISO-certified clean room. The length is the length measured using a microscope. The dose of estradiol was selected to reproduce the preclinical evaluation of skin concentration achieved by the application of 50 mcg (micrograms) of estradiol, a dose commonly used in the application of hormone replacement therapy (HRT).

[0462] Results The average age of the female patients was 68.5 years, and the average number of years since menopause was 16.5 years. By shear wave ultrasound examination, the average skin thickness was 0.65 mm, and the skin elasticity was 11.2 kPa, revealing very thin and fragile skin. The measured serum estradiol levels are shown in Table 11 and Figure 8. The results indicate that there was no increase in estradiol beyond what was expected in postmenopausal women. In contrast, Patient #2, who had received Estradot® (50 mcg of estradiol; twice a week) for transdermal HRT (reproduction of the dose used in the study) two years prior to the study, demonstrated a serum estradiol level of 294 pmol / L with that medication. Patient #2 had discontinued that therapy two years prior to this study.

[0463] Other blood chemistry tests remained within normal ranges, and there were no adverse events associated with the application, including no abnormalities or irritation associated with the skin at the application site. There was no discomfort associated with the application. Skin photographs revealed the onset of natural skin shedding of the microparticles starting 7 days after application, which was only visible under magnified photographs.

[0464]

Table 11

[0465] Summary This pilot study in women with very thin and fragile skin demonstrated that clinically significant doses of estradiol can be delivered to the dermis of the face of women with very low skin thickness without systemic absorption of the hormone. The application was painless, there were no harmful skin reactions either early or late in the test, and there was no delay in the depot secretion of estradiol on day 40.

[0466] Example 11 - Optimization of Foroderm Application These experiments were conducted to determine an improved application procedure for the microparticles of the compositions disclosed herein.

[0467] Experiments An applicator micro-patterned using a micromill at UniSA-ANFF was fabricated and Foroderm was applied. Applicators micro-patterned with ridge spacings of 20 - 200 μm were fabricated. The interaction between different solvents and the applicator head was also tested. These applicators were used to apply Foroderm particles (fiberglass) to excised human skin using our standard application parameters: 30 seconds of application, the weight on the applicator during application, and 5 mg of Foroderm. The skin was then imaged and the micro-particles were counted per mm 2 The level of barrier disruption was determined using transepidermal water loss (TEWL).

[0468] Materials and Methods Profile Parameters The solvents tested were ethanol, DMSO (dimethyl sulfoxide), Tween-80, and UDA (undecanoic acid). The applicators were profiled by Olympus OLS5000 laser confocal microscopy. The microscope settings were LM 20x lens, 3D fine plus color scanning mode, and 1x zoom. The selected roughness profiles across the peaks and dips (Ra) were measured individually. The roughness profile (Ra) and the area roughness of a 500 μm width across the total scan area (Sa) were also measured.

[0469] Application of Applicators on Human Skin Ex Vivo For visualization in 70% ethanol + 5 mg Foroderm (0.02%), these applicators were applied to human skin ex vivo with 50 μl of rhodamine 6G. The treated skin was incubated for 60 minutes and excess particles and solution were gently removed with a cotton swab. TEWL was measured immediately. Then, the treated skin was tape-stripped 5 times to remove the stratum corneum (skin surface) before imaging under a confocal microscope.

[0470] Results Comparison of Roughness Figures 9 to 13 show applicator profiles including roughness and height histograms. Figure 9 shows the default profile (scanning area) of the applicator head. When the applicator head was interacted with ethanol and UDA, the head roughness decreased slightly (Figures 10 and 13), however, when DMSO and Tween-80 were used, the head roughness increased slightly (Figures 11 and 12). Table 12 shows an overview of the roughness in each solvent in a quantitative manner.

[0471] [Table 12]

[0472] Measurement of Trans-epidermal Water Loss (TEWL) These applicators were used to apply Foroderm containing rhodamine 6G (Rh6G) (for visualization). 5 mg of Foroderm was massaged onto the skin with an application force of 800 g for 30 seconds by the applicator. TEWL was measured immediately after application (Table 13). Regions 2, 3, and 5 show disrupted surface skin by Foroderm + applicator, which resulted in delivery of Rh6G beneath the skin surface (Figure 14).

[0473] [Table 13]

[0474] Result Quantitative data were generated to show the effects of applicator head profile and surface roughness by interacting with some commonly used percutaneous permeation enhancers. Based on the TEWL values and delivery profiles, the protocol defined for the use of 3D printed applicators was to use 5 mg of Foroderm with the applicator for 30 seconds by applying a weight of 800 g to the applicator during application.

[0475] It will be understood by those skilled in the art that numerous variations and / or modifications may be made to the embodiments described above without departing from the broad general scope of the present invention. Accordingly, the embodiments are to be regarded in all respects as illustrative and not restrictive.

Claims

1. A composition, Multiple microparticles, At least one bioactive compound, wherein the at least one bioactive compound is optionally a coating on at least a portion of the plurality of microparticles, It contains a permeability enhancer, A composition wherein the aforementioned composition is formulated as a topical composition.

2. A topically applied composition comprising a plurality of microparticles, at least one bioactive compound that is a ligand for the nuclear receptor superfamily, and a permeability enhancer.

3. The composition according to claim 1, wherein the composition is formulated as a topical composition, and after application of the composition to a portion of the target skin, the bioactive compound is not delivered to the bloodstream at all, or substantially not at all.

4. The composition according to any one of the prior claims, wherein at least a portion, substantially all, or all of the microparticles are elongated.

5. The composition according to claim 1, wherein the microparticles have an aspect ratio of about 5:1 to 50:

1.

6. The composition according to claim 1, wherein the microparticles are cylindrical or substantially cylindrical.

7. The at least one bioactive compound is Steroids or corticosteroids optionally selected from the group consisting of estradiol, estrone, estriol, 5α-dihydrotestosterone, finasteride, cortisone, spironolactone, or mixtures thereof; or Minoxidil, minoxidil sulfate, or derivatives or mixtures thereof; or Vitamins optionally selected from vitamins A, B, C, D3, and / or E; or A retinoid, optionally selected from the group consisting of retinoic acid and tretinoin; or The composition according to claim 1, including mixtures thereof.

8. The composition according to claim 1, wherein the permeability enhancer is selected from the group consisting of nonpolar solvents, polar proton solvents, aproton polar solvents, alcohols, polyols, ionic surfactants, nonionic surfactant solvents, aliphatic hydrocarbons, fatty acids, and mixtures thereof, and the permeability enhancer is optionally selected from the group consisting of ethanol, dimethyl sulfoxide, propylene glycol, isopropanol, polyoxyethylene (20) sorbitan monooleate, urea, sodium docecil sulfate, menthol, limonene, oleic acid, isopropyl myristate, undecanoic acid, and mixtures thereof.

9. The composition according to claim 1, wherein the microparticles include or consist of silicon, silica, and mixtures thereof.

10. The composition according to claim 1, wherein the microparticles are coated with a material, the material being optionally a dry coating selected from the group consisting of alginates, crosslinked alginates, carboxymethylcellulose, and mixtures thereof.

11. The composition according to claim 1, wherein the coating component comprises a bioactive compound.

12. The composition may be in the form of a liquid, gel, ointment, cream, lotion, paste, ointment, spray, or any mixture thereof. The composition is At least one solvent selected from the group consisting of water, ethanol, and mixtures thereof, and / or The composition according to claim 1, comprising a gelling agent and / or crosslinking agent optionally selected from the group consisting of carboxymethylcellulose, salts, and mixtures thereof, wherein the salt further comprises a gelling agent and / or crosslinking agent optionally selected from the group consisting of calcium chloride and mixtures thereof.

13. The composition according to claim 12, wherein at least a portion of the bioactive compound is dispersed in a liquid, gel, ointment, cream, lotion, paste, ointment, spray, or any mixture thereof.

14. The composition according to claim 1, wherein the composition is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, or as a medicated cosmetic composition comprising at least one excipient, optionally at least one pharmaceutically acceptable excipient.

15. An applicator configured to dispense a composition according to any one of claims 1 to 14, wherein the applicator has a microtextured surface.

16. The applicator according to claim 15, wherein the microtextured surface includes an angled surface that defines a space for receiving the microparticles during use of the applicator.

17. The applicator according to claim 16, wherein the space is formed between micro-protrusions, micro-ridges, or micro-recesses arranged at lateral intervals on a micro-textured surface, the intervals between these micro-protrusions, micro-ridges, or micro-recesses being approximately 20 μm to approximately 200 μm.

18. A composition according to any one of claims 1 to 14 for treating and / or preventing at least one menopausal symptom in a subject, A composition in which at least one menopausal symptom is optionally selected from the group consisting of hot flashes, night sweats, crawling or itching under the skin, headache, fatigue, frequent urination, vaginal dryness, and mixtures thereof.

19. A composition according to any one of claims 1 to 14 for hydrating and / or increasing collagen formation in at least a portion of the skin; and / or for improving or treating the appearance of the skin.

20. A composition according to any one of claims 1 to 14 for improving or treating the appearance of the target skin, The composition is a topical composition, wherein the at least one bioactive compound optionally comprises minoxidil or a derivative thereof, minoxidil sulfate or a derivative thereof, finasteride or a derivative thereof, or a mixture thereof, and optionally the hair loss is male hair loss.

21. A composition according to any one of claims 1 to 14 for treating and / or preventing hirsutism in a subject, The composition is a topical composition, wherein the at least one bioactive compound optionally comprises spironolactone or a derivative thereof.

22. A composition according to any one of claims 1 to 14 for treating and / or preventing a dermatological condition or disease in a subject, wherein the dermatological condition or disease is acne.

23. A method for delivering at least one bioactive compound through the stratum corneum of a target skin for medicinal cosmetic purposes, excluding skin malignancies, wherein the method comprises administering a composition according to any one of claims 1 to 14, wherein the bioactive compound is optionally selected from estradiol, estrone, estriol, and retinoids, optionally in the presence of an optionally further hormone regulator.

24. A kit comprising a composition according to any one of claims 1 to 14, and means for topically administering the preceding composition, wherein the means is optionally selected from a dropper, cotton swab, spray, pad, bandage, adhesive bandage, patch and applicator.

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