阅读说明：本技术 活性剂在皮肤内的递送和保留 (Delivery and retention of active agents within the skin ) 是由 S·米特拉约特里 E·施彭格勒 D·莱文森 D·R·沃古斯 于 2020-04-17 设计创作，主要内容包括：本申请描述了包括能够渗透皮肤的药剂的系统的合成、调配物和用途。(The present application describes the synthesis, formulation and use of systems comprising agents capable of penetrating the skin.)

1. A system comprising an osmotic agent of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

A is the payload portion;

b is a carrier moiety;

l is a linker; and is

n is 1 to 100.

2. The system of claim 1, wherein B has a structure that is or includes formula (II):

wherein

R¹independently-H, -halogen, -CN, optionally substituted C_1-6Aliphatic, optionally substituted 5-to 10-membered heterocyclyl, optionally substituted 6-to 10-membered aryl, or optionally substituted 5-to 10-membered heteroaryl;

R²is-H, halogen, -CN, optionally substituted C_1-6Aliphatic, optionally substituted 5-to 10-membered heterocyclyl, optionally substituted 6-to 10-membered aryl, or optionally substituted 5-to 10-membered heteroaryl; and is

m is 1 to 4.

3. The osmotic agent according to claim 1, wherein the osmotic agent is (I-b):

or a pharmaceutically acceptable salt thereof.

4. The osmotic agent according to claim 1, wherein the osmotic agent is (I-d):

or a pharmaceutically acceptable salt thereof.

5. The osmotic agent of claim 1 wherein L is a chemical bond through any one of the groups.

6. The osmotic agent of claim 1, wherein L is optionally substituted C_1-6An alkylene chain wherein one, two or three methylene units of L are optionally and independently replaced by-NH-, -O-, -S-or-C (O) -.

7. The system of claim 1, wherein a is a nanoparticle, wherein the nanoparticle encapsulates one or more therapeutic agents.

8. The system of claim 1, wherein m is greater than 1.

9. The system of claim 1, wherein a is selected from agents for treating cosmetic conditions.

10. The system of claim 1, wherein a is selected from agents for treating dermatological conditions.

11. The system of claim 1, wherein L is degradable under biological conditions.

12. The system of claim 1, wherein a is a sunscreen.

13. The system of claim 1, wherein the active agent is a vitamin, a retinoic acid derivative, a colorant, or a exfoliatin.

14. A method of treating a subject in need thereof by administering the system of claim 1 to the subject.

Disclosure of Invention

The present disclosure provides various insights related to vehicles for delivering and retaining molecules that confer therapeutic or cosmetic activity in the skin. The ability to deliver and/or retain cosmetic or therapeutic agents within the skin is highly desirable. In many cases, enhancing the delivery and/or retention of such agents can significantly increase the efficacy and safety of treatment. The present disclosure provides, among other things, the use of 6-amino-2-Cyanobenzothiazole (CBT) and analogs thereof to enhance the delivery and/or retention of such actives.

Drawings

FIG. 1 includes panels A-C, showing CBT-functionalized entities: examples of particles decorated with CBT (a), actives functionalized with a single CBT moiety (B), and actives functionalized with multiple CBT moieties (C).

FIG. 2 shows the chemical structures of gly-CBT and HA-CBT for skin penetration studies.

FIG. 3 includes columns A-F showing bright field (column A, C, E) and fluorescence (column B, D, F) images of a section of porcine skin after application of PBS (column A, B), gly-CBT (column C, D), and HA-CBT (column E, F).

FIG. 4 shows quantification and microscopy of gly-CBT distribution after application on epidermal-X tissue inserts: fraction of applied gly-CBT detected by absorbance in donor solution, recipient solution and extracted from tissue inserts after 6 hours incubation (a); bright field (left) and fluorescence image (right) of frozen sections of tissue after PBS application (B); and bright field (left) and fluorescence image (right) of frozen sections of tissue after gly-CBT application (C).

FIG. 5 includes panels A-D showing the distribution of CBT species extracted from tissue inserts in the donor and acceptor compartments and after application of gly-CBT (A) and gly-Luc (B) as measured by HPLC; a fraction (C) of gly-CBT and gly-Luc that was not detected after application of the formulation; and images (D) of the tissue inserts (PBS (left) and gly-CBT (right)) under UV lamp after extraction of CBT species.

FIG. 6 shows cell viability of epidermal tissue treated with positive control (5% SDS), HA-CBT and gly-CBT relative to tissue treated with PBS. Based on the EPI-200-SIT guidelines, relative cell viability of greater than 50% indicates no irritation.

FIG. 7 includes panels A and B, showing fluorescence images of human skin sections treated with IR-labeled HA (A) and IR-labeled HA-CBT (B). Autofluorescence of the skin was observed in both samples (GFP filter), while IR-labeled HA species were only observed in samples treated with IR-labeled HA-CBT (Cy5 filter).

Definition of

About: when used herein to refer to values, the term "about" refers to values that are similar in context to the recited values. In general, those skilled in the art who are familiar with the context will understand the relative degree of difference encompassed by "about" in that context. For example, in some embodiments, the term "about" can encompass values within a range of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value.

Application: as used herein, the term "administering" generally refers to administering a composition to a subject or system to effect delivery of an agent as or contained in the composition. One of ordinary skill in the art will recognize a variety of routes that may be used to administer to a subject, e.g., a human, where appropriate. For example, in some embodiments, administration can be ocular, oral, parenteral, topical, and the like. In some particular embodiments, administration may be bronchial administration (e.g., by bronchial instillation), buccal administration, dermal administration (which may be or include, for example, topical to one or more of the dermis, intradermal, interputaneous, transdermal, etc.), enteral administration, intraarterial administration, intradermal administration, intragastric administration, intramedullary administration, intramuscular administration, intranasal administration, intraperitoneal administration, intrathecal administration, intravenous administration, intraventricular administration, intra-specific (e.g., intrahepatic) administration, mucosal administration, nasal administration, oral administration, rectal administration, subcutaneous administration, sublingual administration, topical administration, tracheal administration (e.g., by intratracheal instillation), vaginal administration, vitreous administration, and the like. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve the application of a fixed number of doses. In some embodiments, administration may involve administration that is intermittent (e.g., multiple doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time). In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

The analogues: as used herein, the term "analog" refers to a substance that shares one or more specific structural features, elements, components, or parts with a reference substance. Generally, "analogs" show significant structural similarity to a reference substance, such as sharing a core or consensus structure, but also differ in some discrete manner. In some embodiments, an analog is a substance that can be generated from a reference substance, for example, by chemically manipulating the reference substance. In some embodiments, an analog is a substance that can be produced by performing a synthetic process that is substantially similar (e.g., shares multiple steps) to the synthetic process that produces the reference substance. In some embodiments, the analog is or may be generated by performing a different synthetic process than the synthetic process used to generate the reference substance.

Medicament: generally, as used herein, the term "agent" may be used to refer to any chemical class of compound or entity, including, for example, polypeptides, nucleic acids, carbohydrates, lipids, small molecules, metals, or combinations or complexes thereof. Where appropriate, the term may be used to refer to an entity that is or includes a cell or organism or a fraction, extract or component thereof, as will be clear to the skilled person from the context. Alternatively or additionally, as will be clear from the context, the term may be used to refer to natural products as they exist in and/or are derived from nature. In some cases, again as will be clear from context, the term may be used to refer to one or more man-made entities as they are designed, engineered, and/or produced by the actions of a human hand and/or are not present in nature. In some embodiments, the agent may be utilized in isolated or pure form; in some embodiments, the agent may be utilized in a natural form. In some embodiments, the potential agents may be provided as, for example, a collection or library of active agents that may be screened to identify or characterize therein. In some cases, the term "agent" may refer to a compound or entity that is or includes a polymer; in some cases, the term may refer to a compound or entity that includes one or more polymeric moieties. In some embodiments, the term "agent" may refer to a compound or entity that is not a polymer and/or is substantially free of any polymer and/or one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety.

Aliphatic: as used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon of aromatic nature (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but does not have a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 carbon atoms. In some embodiments, the aliphatic group contains 1-4 carbon atoms. In some embodiments, aliphatic groups contain 1-3 carbon atoms, and in some embodiments, aliphatic groups contain 1-2 carbon atoms. In some embodiments, "carbocyclic" (or "alicyclic" or "carbocycle" or "cycloalkyl") refers to a monocyclic aromatic ring C that is fully saturated or contains one or more units of unsaturation, but does not have a single point of attachment to the rest of the molecule₃-C₈A hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

Alkylene group: the term "alkylene" refers to a divalent alkyl group. The "alkylene chain" being a polymethylene groupI.e., - (CH)₂)_n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

Aryl: the term "aryl", used alone or as part of a larger moiety as used in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to aromatic ring systems, and exemplary groups include phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthylimino, phenanthridinyl, or tetrahydronaphthyl, and the like.

And (3) correlation: two events or entities are "related" to each other if the presence, level, and/or form of one event or entity is related to the presence, level, and/or form of another event or entity, as that term is used herein. For example, a particular entity (e.g., a polypeptide, genetic signature, metabolite, microorganism, etc.) is considered to be associated with a particular disease, disorder, or condition if its presence, level, and/or form is associated with the incidence and/or susceptibility of the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are "associated" with each other physically if they interact, directly or indirectly, such that they are and/or remain in physical proximity to each other. In some embodiments, two or more entities physically associated with each other are covalently linked to each other; in some embodiments, two or more entities that are physically associated with each other are not covalently linked to each other, but are non-covalently associated, for example, by hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

Biocompatible: as used herein, the term "biocompatible" refers to a material that does not cause significant damage to such a component when placed in contact with living tissue, for example, in vivo. In certain embodiments, a material is "biocompatible" if it is not toxic to cells. In certain embodiments, a material is "biocompatible" if its addition to cells in vitro results in less than or equal to 20% cell death and/or its administration in vitro does not induce significant inflammation or other such adverse effects.

The method comprises the following steps: as used herein, the term "equivalent" refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to each other but are sufficiently similar to allow comparisons to be made therebetween such that one of skill in the art will appreciate that a reasonable conclusion may be drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, situation, individual, or population is characterized by a plurality of substantially identical features and one or a small number of different features. One of ordinary skill in the art will understand, in this context, how to what degree of identity two or more such agents, entities, situations, sets of conditions, etc., are considered to be rather desirable in any given instance. For example, one of ordinary skill in the art will appreciate that groups of situations, individuals, or populations are equivalent to one another when characterized by substantially the same features in sufficient numbers and types to warrant a reasonable conclusion as follows: differences in the results or observed phenomena obtained under or with different groups of situations, individuals or populations are caused by or indicative of changes in those characteristics that are altered.

Corresponding to … …: as used herein in the context of polypeptides, nucleic acids, and chemical compounds, the term "corresponding to … …" designates the position/identity of a structural element, e.g., an amino acid residue, a nucleotide residue, or a chemical moiety, in a compound or composition by comparison with an appropriate reference compound or composition. For example, in some embodiments, a monomer residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) can be identified as "corresponding to a residue in an appropriate reference polymer. For example, one of ordinary skill in the art will understand that, for simplicity, a canonical numbering system based on a reference related polymer can be used to designate residues in the polymer such that, for example, a residue that "corresponds to a residue at position 190 of the reference polymer" need not actually be the 190 th residue in the polymer of interest, but rather refers to a residue that corresponds to a residue at position 190 in the reference polymer; one of ordinary skill in the art will readily understand how to identify "corresponding" residues in the polymer (e.g., using sequence comparison software for commercially available polypeptides and nucleic acid polymers; optionally manually for other polymers).

Designing: as used herein, the term "designed" refers to (i) an agent whose structure is or has been selected manually; (ii) agents produced by processes requiring manual labor; and/or (iii) agents other than natural substances and other known agents.

The preparation formulation is as follows: one skilled in the art will appreciate that the term "dosage form" may be used to refer to a physically discrete unit of an agent (e.g., a therapeutic, diagnostic, or cosmetic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of medicament. In some embodiments, such amounts are unit doses (or intact portions thereof) suitable for administration according to a dosing regimen that has been determined to be relevant for the desired or beneficial (e.g., therapeutic and/or cosmetic) result when administered to a relevant population (i.e., utilizing a therapeutic dosing regimen). In some embodiments, such amounts are unit doses (or intact portions thereof) suitable for administration according to a regimen that has been determined to be relevant to the desired or beneficial cosmetic result (e.g., providing visual and/or tactile improvement to the skin) when administered to the relevant population. One of ordinary skill in the art will appreciate that the total amount of a composition or medicament administered to a particular subject is determined by one or more attending professionals (e.g., physicians, nurses, or other licensed professionals) and may involve administration of a variety of dosage forms. In some embodiments, the dosage form may be provided in the form of a formulation that is or includes a cream, gel, liquid, lotion, mist, mask, matrix, particle, paste, patch, powder, serum, solid, spray (or collection thereof), or a combination thereof.

The administration scheme is as follows: one skilled in the art will appreciate that the term "dosing regimen" may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by a period of time. In some embodiments, a given agent has a recommended dosing regimen that may involve one or more agents. In some embodiments, the dosing regimen comprises a plurality of doses, each dose of the plurality of doses being separated in time from the other doses. In some embodiments, the individual agents are separated from each other by periods of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses. In some embodiments, all agents within a dosing regimen have the same unit dose. In some embodiments, different agents within a dosing regimen have different amounts. In some embodiments, a dosing regimen comprises a first dose of a first dose followed by one or more additional doses of a second dose that is different from the first dose. In some embodiments, the dosing regimen comprises a first dose of a first dose followed by one or more additional doses of a second dose that is the same as the first dose. In some embodiments, the dosing regimen is associated with a desired or beneficial result when administered across a relevant population.

Excipient: as used herein, the term "excipient" refers to a non-active (e.g., not a therapeutic active such as a cosmetic active) agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.

Halogen: the term "halogen" means F, Cl, Br or I.

Heteroaryl group: the terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having from 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups that share 6, 10, or 14 pi electrons in the ring array; and/or groups having from one to five heteroatoms in addition to carbon atoms, wherein the term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur as well as any quaternized form of basic nitrogen. Exemplary heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, where the group or point of attachment is on the heteroaromatic ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2,3-b ] -1, 4-oxazin-3 (4H) -one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms encompass optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

Heterocyclic ring: as used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms in addition to carbon atoms, as defined above. The term "nitrogen" when used in reference to a ring atom of a heterocyclic ring includes substituted nitrogens. By way of example, in the range of 0-3 optionsFrom saturated or partially unsaturated rings of heteroatoms of oxygen, sulfur or nitrogen, the nitrogen being N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or⁺NR (as in N-substituted pyrrolidinyl). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazacycloyl, oxazaheterocyclyl, thiazaheterocyclyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl group", "heterocyclic moiety" and "heterocyclic group" are used interchangeably herein and also encompass groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the group or point of attachment is on the heterocyclyl ring. The heterocyclic group may be monocyclic or bicyclic. The term "heterocycloalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

"improve", "increase", "inhibit" or "decrease": as used herein, the terms "improve," "increase," "inhibit," "decrease," or grammatical equivalents thereof indicate a value relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may be or include a measurement in a particular system (e.g., in a single individual) in the absence (e.g., before and/or after) of a particular agent or treatment, or in the presence of an appropriate comparable reference agent, under otherwise comparable conditions. In some embodiments, an appropriate reference measurement may be or include a measurement in a comparable system that is known or expected to respond in a particular manner in the presence of the relevant agent or treatment.

Separating: as used herein refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when originally produced (whether in nature and/or in an experimental setting), and/or (2) artificially designed, produced, prepared, and/or manufactured. An isolated substance and/or entity may be separated from other components with which it is initially associated by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99%. In some embodiments, the isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. In some embodiments, as will be understood by those skilled in the art, a substance may still be considered "isolated" or even "pure" after combination with certain other components, e.g., one or more carriers or excipients (e.g., buffers, solvents, water, etc.); in such embodiments, the isolation or purity percentage of a substance is calculated without including such carriers or excipients.

A linker: as used herein, to refer to the portion of the multi-element medicament that connects different elements to each other.

A marker: a marker, as used herein, refers to an entity or moiety whose presence or level is characteristic of a particular state or event. In some embodiments, the presence or level of a particular marker may be characteristic of the presence, state, or stage of a disease, disorder, or condition.

Optionally substituted: as used herein, a compound may sometimes contain an "optionally substituted" moiety. In general, the term "substituted" whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "substituted" applies to one or more hydrogens either explicitly or implicitly in the structure (e.g.,means at leastAnd isMeans at least Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, at each position, the substituents may be the same or different. The combinations of substituents contemplated by the present invention are preferably combinations of substituents that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to one or more conditions of interest that allow for its production, detection, and, in certain embodiments, recovery, purification, and use for the purposes disclosed herein. Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently: halogen; - (CH) ₂)_0-4R°；-(CH₂)_0-4OR°；-(CH₂)_0-4R°、-O-(CH₂)_0-4C(O)OR°；-(CH₂)_0-4CH(OR°)₂；-(CH₂)_0-4SR°；-(CH₂)_{0- 4}Ph, which may be substituted by R °; - (CH)₂)_0–4O(CH₂)_0–1Ph, which may be substituted by R °; -CH ═ CHPh, which may be substituted by R °; - (CH)₂)_0–4O(CH₂)_0–1-pyridyl, which may be substituted by R °; -NO₂；-CN；-N₃；-(CH₂)_0-4N(R°)₂；-(CH₂)_0-4N(R°)C(O)R°；-N(R°)C(S)R°；-(CH₂)_0-4N(R°)C(O)NR°₂；-N(R°)C(S)NR°₂；-(CH₂)_0-4N(R°)C(O)OR°；-N(R°)N(R°)C(O)R°；-N(R°)N(R°)C(O)NR°₂；-N(R°)N(R°)C(O)OR°；-(CH₂)_0-4C(O)R°；-C(S)R°；-(CH₂)_0-4C(O)OR°；-(CH₂)_0-4C(O)SR°；-(CH₂)_0-4C(O)OSiR°₃；-(CH₂)_0-4OC(O)R°；-OC(O)(CH₂)_0-4SR-、SC(S)SR°；-(CH₂)_0-4SC(O)R°；-(CH₂)_0-4C(O)NR°₂；-C(S)NR°₂；-C(S)SR°；-SC(S)SR°、-(CH₂)_0-4OC(O)NR°₂；-C(O)N(OR°)R°；-C(O)C(O)R°；-C(O)CH₂C(O)R°；-C(NOR°)R°；-(CH₂)_0-4SSR°；-(CH₂)_0-4S(O)2R°；-(CH₂)_0-4S(O)2OR°；-(CH₂)_0-4OS(O)₂R°；-S(O)₂NR°₂；-(CH₂)_0-4S(O)R°；-N(R°)S(O)₂NR°₂；-N(R°)S(O)₂R°；-N(OR°)R°；-C(NH)NR°₂；-P(O)₂R°；-P(O)R°₂；-OP(O)R°₂；-OP(O)(OR°)₂；SiR°₃；-(C_1-4Straight-chain or branched alkylene) O-N (R DEG)₂(ii) a Or- (C)_1-4Straight or branched alkylene) C (O) O-N (R DEG)₂Wherein each R DEG may be substituted as defined below and is independently halogen, C_1-6Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph、-CH₂- (5 to 6 membered heteroaryl ring) or a 5 to 6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R ° taken together with their intervening atoms form a 3 to 12 membered saturated, partially unsaturated or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which heteroatoms may be nitrogen, oxygen or sulfurSubstituted as defined below. Suitable monovalent substituents on R ° (or a ring formed by two independently occurring R ° -together with their intervening atoms) are independently halogen, - (CH)₂)_{0- 2}R^·- (halogenated R)^·)、-(CH₂)_0-2OH、-(CH₂)_0-2OR^·、-(CH₂)_0-2CH(OR^·)₂(ii) a -O (halo R)^·)、-CN、-N₃、-(CH₂)_0-2C(O)R^·、-(CH₂)_0-2C(O)OH、-(CH₂)_0-2C(O)OR^·、-(CH₂)_0-2SR^·、-(CH₂)_0-2SH、-(CH₂)_{0- 2}NH₂、-(CH₂)_0-2NHR^·、-(CH₂)_0-2NR^· ₂、-NO₂、-SiR^· ₃、-OSiR^· ₃、-C(O)SR^·、-(C_1-4Straight OR branched alkylene) C (O) OR^·or-SSR^·Wherein each R is^·Is unsubstituted or, in the case of the preceding "halo", substituted by one or more halogens only and is independently selected from C _1-4Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R ° include ═ O and ═ S. Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: o ("oxo"), ═ S, ═ NNR ═ n₂、＝NNHC(O)R*、＝NNHC(O)OR*、＝NNHS(O)₂R*、＝NR*、＝NOR*、-O(C(R*₂))_2-3O-or-S (C (R)₂))_2-3S-, wherein each independently occurring R is selected from hydrogen, C which may be optionally substituted as defined below_1-6Aliphatic or unsubstituted 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to a substitutable carbon in the ortho position of the "optionally substituted" groupComprises the following steps: -O (CR;)₂)_2-3O-, wherein each independently occurring R is selected from hydrogen, C which may be substituted as defined below_1-6Aliphatic or unsubstituted 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on the aliphatic radical of R include halogen, -R^·- (halogenated R)^·)、-OH、-OR^·-O (halo R)^·)、-CN、-C(O)OH、-C(O)OR^·、-NH₂、-NHR^·、-NR^· ₂or-NO₂Wherein each R is^·Is unsubstituted or, in the case of the preceding "halo", substituted by one or more halogen(s) only, and is independently C _1-4Aliphatic, -CH₂Ph、-O(CH₂)_{0- 1}Ph or a 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include OrEach of whichIndependently hydrogen, C which may be substituted as defined below_1-6Aliphatic, unsubstituted-OPh or an unsubstituted 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring, although defined aboveTogether with their central atoms form a 3-to 12-membered saturated moiety having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfurUnsaturated or aryl monocyclic or bicyclic rings.Suitable substituents on the aliphatic radical of (a) are independently halogen, R^·- (halogenated R)^·)、-OH、-OR^·-O (halo R)^·)、-CN、-C(O)OH、-C(O)OR^·、-NH₂、NHR^·、-NR^· ₂or-NO₂Wherein each R is^·Is unsubstituted or, in the case of the preceding "halo", substituted by one or more halogen(s) only, and is independently C_1-4Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Physiological conditions: as used herein, reference to conditions is taken to have its meaning understood in the art under the conditions in which a cell or organism lives and/or propagates. In some embodiments, the term refers to conditions of the external or internal environment that an organism or cellular system may present in nature. In some embodiments, the physiological conditions are those conditions present in a human or non-human animal, particularly those conditions present at and/or within a target moiety of interest. Physiological conditions typically include, for example, one or more of a temperature in the range of 20-40 ℃ (and specifically about 37 ℃), an atmospheric pressure of 1, a pH of 6-8, a 1-20mM glucose concentration, an oxygen concentration at atmospheric level, and the gravitational forces encountered on the earth.

Reference: as used herein, standards or controls are described with respect to which comparisons are performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with a test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, the reference or control is determined or characterized under conditions or circumstances comparable to those under evaluation, as will be understood by those skilled in the art. One skilled in the art will understand when sufficient similarity exists to demonstrate reliance on and/or comparison to a particular possible reference or control.

Sample preparation: as used herein, the term "sample" generally refers to an aliquot of material obtained from or derived from a source of interest. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest may be or include a cell or organism such as a microorganism, plant, or animal (e.g., human). In some embodiments, the source of interest is or includes a biological tissue or fluid. In some embodiments, the sample is a "primary sample" obtained directly from a source of interest by any suitable means. In some embodiments, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components from the primary sample and/or by adding one or more pharmaceutical agents to the primary sample), as will be clear from the context. Such "treated samples" may include, for example, material extracted from a sample or obtained by subjecting a primary sample to one or more techniques such as chromatography, extraction, precipitation, and the like.

Subject: as used herein, the term "subject" refers to any organism to which a provided system is or can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, the subject is a human. In some embodiments, the subject is suffering from and/or susceptible to one or more disorders or conditions. In some embodiments, the subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the subject has been diagnosed with one or more disorders or conditions. In some embodiments, the disorder or condition is or comprises the presence of a cancer or one or more tumors. In some embodiments, the subject is receiving or has received certain therapies to diagnose and/or treat a disease, disorder, or condition. In some embodiments, a subject refers to a person seeking cosmetic benefit and/or improvement such as improvement in skin appearance and/or feel.

Substantial structural similarity: as used herein, the term "substantial structural similarity" refers to the presence of shared structural features at a particular location. In some embodiments, the term "substantial structural similarity" refers to the presence and/or identity of structural elements such as: a loop, a sheet, a helix, an H-bond donor, an H-bond acceptor, a glycosylation pattern, a salt bridge, a disulfide bond, and combinations thereof. In some embodiments, the term "substantial structural similarity" refers to the three-dimensional arrangement and/or orientation of atoms or moieties relative to one another (e.g., the distance and/or angle between or within an agent of interest and a reference agent).

Therapeutic agents: as used herein, the phrase "therapeutic agent" generally refers to any agent that, when administered to an organism, elicits a desired pharmacological effect (which, in some embodiments, may be or include a cosmetic effect). In some embodiments, an agent is considered to exhibit an effect (i.e., be a therapeutic agent) if it exhibits a statistically significant effect across the appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by specific criteria such as certain age groups, gender, genetic background, pre-existing clinical conditions, and the like, or combinations thereof. In some embodiments, a therapeutic agent is a substance that can be used to reduce, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and/or reduce the incidence of one or more symptoms or features of a disease, disorder, and/or condition. In some embodiments, the therapeutic agent is a therapeutic agent that achieves a cosmetic effect (i.e., is a cosmetic agent). In some embodiments, the therapeutic agent may be used to achieve an improvement in the appearance and/or feel of the skin and/or another cosmetic benefit.

Treatment: as used herein, the terms "treat," "treating," or "treating" refer to a partial or complete reduction, amelioration, delay of onset, inhibition, prevention, alleviation, and/or reduction in the incidence and/or severity of one or more symptoms or features of a disease, disorder, and/or condition, or the achievement of another desired physiological effect (e.g., a desired cosmetic effect such as an improvement in the appearance and/or feel of the skin, such as an improvement in the visual and/or tactile feel of the skin). In some embodiments, the treatment comprises administering an agent that produces a physiological effect. In some embodiments, the treatment comprises a cosmetic treatment that improves the physical appearance upon administration in the manner described herein. In some embodiments, the treatment may be administered to a subject who does not exhibit signs or characteristics of a disease, disorder, and/or condition (e.g., may be prophylactic). In some embodiments, treatment may be administered to a subject who exhibits only early or mild signs or features of a disease, disorder, and/or condition, e.g., for the purpose of reducing the risk of developing a pathology associated with the disease, disorder, and/or condition. In some embodiments, the treatment may be administered to a subject exhibiting established, severe, and/or advanced signs of a disease, disorder, or condition.

Detailed Description

As described herein, the present disclosure provides certain techniques related to enhancing penetration and/or retention of a payload (e.g., which may be or include an active agent) at a target site, which may be, for example, a site in or on the skin, such as on, at, in, or below the stratum corneum, epidermis, dermis, or underlying hypodermal tissue. In some embodiments, the present disclosure provides a system capable of delivering and/or enhancing delivery of a payload across a skin surface and into a target site. In some embodiments, the present disclosure provides an osmotic agent that permeates into and/or is retained at the target site. In some embodiments, the osmotic agent may include a carrier moiety and a payload moiety associated with each other, optionally through a linker. In some embodiments, the permeating moiety is or includes benzothiazole.

For example, the present disclosure shows that in reconstructed 3-dimensional human skin tissue (EpiDerm)^TM) Of the applied dose, about 75% of glycine conjugated to CBT (gly-CBT) permeated the skin within 6 hours. However, only about 1/3 of the permeation amount occurred in the receptor compartment, while 2/3 remained in the skin. Furthermore, it is possible to provide a liquid crystal display device, Surprisingly, even after washing with Triton-X, methanol or dichloromethane, the majority of the amount that penetrated into the skin could not be removed. The latter two are common organic solvents used to remove molecules from the skin. These strong solvents can even extract lipids from the skin. The inability of the strong solvent to extract gly-CBT (e.g., CBT-containing entities) from the skin indicates that CBT has an unexpected retention capacity in the skin. It was also observed in porcine skin that gly-CBT (e.g., CBT-containing entities) could not be extracted from the skin. The present disclosure teaches that the ability of CBT to penetrate into and remain in the skin can be used for various dermatological and cosmetic applications. In some embodiments, the carrier moiety for use according to the present disclosure is or includes CBT or an analog thereof.

In some embodiments, such a carrier moiety (e.g., CBT or analog thereof) may be linked or otherwise associated with the payload moiety such that the payload moiety (and/or active agent component thereof) permeates into and/or is retained within the skin (e.g., to a greater extent and/or for a greater time than would be the case in comparable conditions in the absence of CBT).

In some embodiments, an osmotic agent as described herein can comprise an encapsulating component associated with an active agent, e.g., a nanoparticle, liposome, micelle, and the like. In some embodiments, such an encapsulating component may be considered a "linking moiety" to the extent that it facilitates association of the carrier moiety with the payload moiety (e.g., with the active agent). Alternatively, in some embodiments, such an encapsulating component may be considered part of the payload portion (e.g., it may be or include an encapsulating component and an active agent). In some embodiments, the encapsulating component (e.g., nanoparticle) may be made of and/or may be a biocompatible material. In some embodiments, the encapsulating component may facilitate association of the payload portion and/or active agent with the carrier portion as described herein, and/or may otherwise improve or help improve one or more characteristics (e.g., stability) of the payload portion, active agent, and/or osmotic agent. In some embodiments, the encapsulating component (e.g., nanoparticle) has a surface that can be modified with a carrier moiety (e.g., CBT).

In some embodiments, the osmotic agent is of formula (I):

Or a pharmaceutically acceptable salt thereof,

wherein

A is the payload portion;

b is a carrier moiety;

l is a linker;

and n is 1 to 100.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 5. In some embodiments, n is 10. In some embodiments, n is 20. In some embodiments, n is 50. In some embodiments, n is 1-2. In some embodiments, n is 1-5. In some embodiments, n is 1-50.

In some embodiments, the osmotic agent is of formula (I-a):

or a pharmaceutically acceptable salt thereof,

wherein

A is the payload portion;

l is a linker;

R¹independently at each occurrence-H, halogen, -CN, optionally substituted C_1-6Aliphatic, optionally substituted 5-to 10-membered heterocyclyl, optionally substituted 6-to 10-membered aryl, or optionally substituted 5-to 10-membered heteroaryl;

R²is-H, halogen, -CN, optionally substituted C_1-6Aliphatic, optionally substituted 5-to 10-membered heterocyclyl, optionally substituted 6-to 10-membered aryl, or optionally substituted 5-to 10-membered heteroaryl; and areAnd is

m is 1 to 4.

In some embodiments, the osmotic agent is of formula (I-a):

Or a pharmaceutically acceptable salt thereof,

a, L, R therein¹、R²And m is as defined herein.

In some embodiments, the osmotic agent is of formula (I-b):

or a pharmaceutically acceptable salt thereof,

wherein a is as defined herein.

In some embodiments, the osmotic agent is of formula (I-c):

or a pharmaceutically acceptable salt thereof,

wherein a is as defined herein.

In some embodiments, the osmotic agent is of formula (I-d):

or a pharmaceutically acceptable salt thereof,

wherein a is as defined herein.

In some embodiments, the osmotic agent is of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

A is the payload portion;

b is a carrier moiety;

l is a linker;

and n is 1 to 100.

Vehicle part

In some embodiments, systems provided and/or utilized according to the present disclosure can include one or more carriers and payload moieties associated with each other, optionally through a linker.

In some embodiments, the present disclosure provides the following insights: certain carrier moieties can surprisingly confer the ability of an osmotic agent as described herein to exhibit penetration into the skin to a desired degree (e.g., the fraction of the administered agent that enters the skin and/or the depth to which the administered agent penetrates — e.g., the degree to which the administered agent penetrates to a target moiety of interest) and/or retention in the skin (e.g., the time the osmotic agent is in the skin, e.g., at a target site of interest for a sustained period of time).

In those embodiments that may include multiple carrier portions, such carrier portions may be all the same in some embodiments; in other embodiments, the provided systems can include a plurality of different carrier portions.

For example, in some embodiments, a carrier moiety useful according to the present disclosure is characterized by a particular degree of lipophilicity, e.g., when associated (e.g., linked) with a particular payload moiety. In some embodiments, CBT represents a carrier moiety that can be linked to a payload moiety in a useful osmotic agent as described herein. One of skill in the art reading this disclosure will appreciate that in some embodiments, the lipophilicity of an osmotic agent including a particular payload portion can be modulated, for example, by the linkage of a plurality of hydrophobic moieties (e.g., hydrophobic carrier portions), which can be the same or different and which individually or together can be considered or constitute a carrier portion as described herein.

In some embodiments, the carrier moiety can be or include an optionally substituted benzothiazole. In some embodiments, the carrier moiety can be or include Cyanobenzothiazole (CBT). In some embodiments, the carrier moiety may be or include 2-cyano-6-hydroxybenzothiazole. In some embodiments, the carrier moiety can be or include D-fluorescein, L-fluorescein, D-aminofluorescein, or L-aminofluorescein. In some embodiments, the carrier moiety can be or include a molecule other than benzothiazole.

In some embodiments, the carrier moiety may be or include a moiety of formula (III):

wherein R is¹、R²And m is as defined herein.

In some embodiments, the carrier moiety may be or include a moiety of formula (III-a)

Wherein R is¹And m is as defined herein.

In some embodiments, the carrier moiety may be or include a moiety of formula (III-b):

wherein R is¹And m is as defined herein.

Without wishing to be bound by any particular theory, the present disclosure suggests that a carrier moiety (e.g., CBT and/or analogs thereof, or other suitable lipophilic entity) as described herein can interact with one or more extracellular matrix proteins (e.g., keratin, elastin, collagen, etc.) found in skin or mucosa with sufficient strength (e.g., which can be characterized by, for example, measuring Ka and/or Kd and/or assessing stability to an expected damaging condition such as the presence of solvents like Triton-X, methanol, and/or dichloromethane, etc.). One skilled in the art will understand upon reading this disclosure that the carrier moiety can interact with a target region, such as skin or mucosa, through hydrophobic interactions. In addition, it is also understood that in some embodiments, the carrier moiety can interact with the target region by covalent conjugation or ionic interaction.

In some embodiments, a carrier moiety as described herein can be used, for example, to retain and target actives in one or more body tissues, which can be characterized by those high levels of ECM proteins found in skin. In some embodiments, ECM proteins found in skin include, but are not limited to, keratin, elastin, or collagen. One of skill in the art reading this disclosure will appreciate that in some embodiments, the bodily tissue may comprise a mucosal membrane.

Other chemical structures of benzothiazole include, but are not limited to, European Journal of Medicinal Chemistry (European Journal of Medicinal Chemistry), 5.6.2015, volume 97, page 911-927, Current topics in Medicinal Chemistry 2017; 17(2) 208-.

Connector

In some embodiments, the skin-permeable system includes a linker that conjugates a carrier moiety and a payload (which is typically or includes an active agent). In some embodiments, the connector sub-portion is referred to as an "L". In some embodiments, the linker may be degradable under biological conditions. In some embodiments, the linker may be non-degradable under biological conditions. In some embodiments, the linker may be degraded by hydrolysis or enzymatic reaction. In some embodiments, the linker can be cleavable by application of a cleavage promoter (e.g., electrical, chemical, and/or enzymatic stimulation). In some embodiments, the linker degrades (e.g., over and/or within a specified time period such as, for example, over hours, days, weeks, or months) after systemic administration.

In some embodiments, conjugation of the carrier moiety to the payload moiety can be mediated by a chemical reaction with an amine group. In some embodiments, the linker may comprise an amine group. In some embodiments, the linker may comprise an amide group. In some embodiments, the linker may be a key.

In some embodiments, an osmotic agent as described herein may comprise an encapsulating component; in some such embodiments, association of a carrier moiety with a payload moiety as described herein can be achieved by such an encapsulation component. A variety of techniques can be used to conjugate or associate the carrier with the encapsulating component, e.g., liposomes, nanoparticles, micelles, etc.

In some embodiments, the association between the carrier moiety and the payload moiety as described herein may involve chemical conjugation; in some embodiments, the chemical conjugation may be or include click chemistry. In some embodiments, the payload portion may be or include a polypeptide; in some such embodiments, the linkage to the polypeptide may be or include conjugation to a heteroatom containing residue such as threonine, cysteine, or lysine. In some embodiments, attachment to the polypeptide can be performed by chemical conjugation to a cysteine residue. In some particular embodiments, a carrier moiety, such as CBT, may be conjugated to a cysteine moiety of a peptide or protein (e.g., by click chemistry).

In some embodiments, L is optionally substituted C_1-6An alkylene chain wherein one, two or three methylene units of L are optionally and independently replaced by-NH-, -O-, -S (O)₂-or-C (O) -substitution. A variety of techniques can be used to conjugate or associate the carrier with the active agent.

In some embodiments, L is selected from the group consisting of: -NH-, -O-, -S (O)₂and-C (O) -. In some embodiments, L is-NH-. In some embodiments, L is-O-. In some embodiments, L is-S-. In some embodiments, L is-S (O) -. In some embodiments, L is-S (O)₂-. In some embodiments, L is-C (O) NH-. In some embodiments of the present invention, the,l is-NHC (O) -. In some embodiments, L is-C (O) -.

In some embodiments, L is polyethylene glycol (PEG). In some embodiments, L may be ethylenediamine, such as polyethylene glycol diamine, and the like.

In some embodiments, L includes a portion resulting from a "click" reaction. In some embodiments, L comprises triazole. In some embodiments, L comprises imine. In some embodiments, L comprises an oxime. In some embodiments, L comprises hydrazine. In some embodiments, L comprises a moiety resulting from a nucleophilic addition. In some embodiments, L includes a portion resulting from a Michael addition (Michael addition). In some embodiments, L comprises thiomercapto (thio-ene).

In some embodiments, the payload portion or active agent may be a low molecular weight compound or small molecule; one skilled in the art will appreciate that various techniques can be used to conjugate low molecular weight compounds or small molecules to the carrier moiety.

As described herein, one of skill in the art is aware of various techniques for conjugating a carrier moiety to an encapsulating component as described herein.

Payload section

In some embodiments, systems provided and/or utilized according to the present disclosure can include one or more carriers and payload moieties associated with each other, optionally through a linker.

In some embodiments, the payload portion can be or include a therapeutic agent. In some embodiments, the therapeutic agent is or includes a polypeptide, protein, amino acid, antibody, peptidomimetic, lipid, small molecule, glycosaminoglycan, nucleic acid, or a combination thereof. In some embodiments, suitable therapeutic agents may be selected from dermatological agents, antineoplastic agents, immunological agents, neurological agents, and the like. In some embodiments, suitable dermatologically active agents may include, for example, local anesthetics, anti-inflammatory agents, antiproliferative agents, anti-infective agents (such as antiviral, antifungal, or antibacterial agents), and active agents for treating medical conditions of the skin.

Examples of suitable glycosaminoglycans include, but are not limited to, heparan sulfate, heparin, chondroitin sulfate, dermatan sulfate, and keratan sulfate. In some embodiments, the glycosaminoglycan may be in the form of glycosaminoglycan-based proteoglycans, including, for example, pluripotent proteoglycans, perlecans, phosphatidylinositolglycans, syndecans, decorin. One skilled in the art, upon reading this disclosure, will appreciate that certain payload moieties, such as glycosaminoglycan moieties, will associate with ions and water molecules to form hydrated complexes when incorporated with a carrier moiety (e.g., CBT). Administration of such embodiments may be in conjunction with the mucosa, e.g., of the eye, lips, mouth, vagina, upper respiratory tract (i.e., the nasal and nasal passages, paranasal sinuses, pharynx, and parts of the throat above the vocal folds (strips)), lungs, GI tract, urethral meatus, and anus. It will be appreciated by those skilled in the art that such embodiments will form a barrier to pathogen entry, as well as serve to recruit proteins, such as cytokines and growth factors.

In those embodiments that may include multiple payload portions, such payload portions may all be the same in some embodiments; in other embodiments, the provided system may include a plurality of different payload portions.

In some embodiments, one therapeutic agent is described in U.S. patent No. 8,791,062, which is incorporated herein by reference.

In some embodiments, suitable dermatological agents are selected from: 16-17A-epoxyprogesterone (CAS accession No. 1097-51-4), p-methoxycinnamic acid/4-methoxycinnamic acid (CAS accession No. 830-09-1), octyl methoxycinnamate (CAS accession No. 5466-77-3), methyl p-methoxycinnamate (CAS accession No. 832-01-9), 4-estrene-17 beta-OL-3-ONE (4-ESTREN-17 beta-OL-3-ONE) (CAS accession No. 62-90-8), ethyl p-methoxybenzoylacetate (CAS accession No. 2881-83-6), dihydropyrimidine (CAS accession No. 1904-98-9), Lopinavir (Lopinavir) (CAS registry number 192725-17-0), ritanserin (RITANSERIN) (CAS registry number 87051-43-2), Nilotinib (Nilotinib) (CAS registry number 641571-10-0); rocuronium bromide (CAS registry number 119302-91-9), p-nitrobenzyl-6- (1-hydroxyethyl) -1-azabicyclo (3.2.0) heptane-3, 7-dione-2-carboxylate (CAS registry number 74288-40-7), Abamectin (Abamectin) (CAS registry number 71751-41-2), Paliperidone (Paliperidone) (CAS registry number 144598-75-4), gemifloxacin (Gemifloxacin) (CAS registry number 175463-14-6), Valrubicin (Valrubicin) (CAS registry number 56124-62-0), Mizoribine (CAS registry number 50924-49-7), Solifenacin succinate (CAS registry number: 242478-38-2), and Lapatinib (CAS registry number 92-592-231277-592), Dydrogesterone (Dyhydrogesterone) (CAS registry No. 152-62-5), 2-dichloro-N- [ (1R,2S) -3-fluoro-1-hydroxy-1- (4-methylsulfonylphenyl) propan-2-yl ] acetamide (CAS registry No. 73231-34-2), Tilmicosin (Tilmicin) (CAS registry No. 108050-54-0), Efavirenz (Efavirenz) (CAS registry No. 154598-52-4), Pirarubicin (Pirarubicin) (CAS registry No. 72496-41-4), Nateglinide (Nateglinide) (registry No. 105816-04-4), Epirubicin (CAS registry No. 56420-45-2), Entecavir (Entecavir) (CAS registry No. 142217-69-4), Etoricoxib (Etoricoxib) (CAS registry number: 202409-33-4), Cilnidipine (Cilnidipine) (CAS registry number: 132203-70-4), Doxorubicin hydrochloride (Doxorubicin hydrochloride) (CAS registry number: 25316-40-9), Escitalopram (Escitalopram) (CAS registry number: 128196-01-0), Sitagliptin phosphate monohydrate (Sitagliptin phosphate monohydramate) (CAS registry number: 654671-77-9), acitretin (CAS registry number: 55079-83-9), Rizatriptan benzoate (Rizatriptan benzoate) (CAS registry number: 145202-66-0), donepeinan (Dopenem) (CAS registry number: 148016-81-3), Atracurium besylate (CAS registry number: 64228-855), nicurtaine (CAS registry number: 148016-81-3), and nicurvatamine besylate (CAS registry number: 6381-855-50) (CAS registry number: nicurvatimine registry number: 3583-3), 3, 4-Dihydroxybenzeneethanol (CAS registry number: 10597-60-1), ketanserin tartrate (KETANSERIN TARTRATE) (CAS registry number: 83846-83-7), Ozagrel (Ozagrel) (CAS registry number: 82571-53-7), Eprosartan mesylate (Eprosartan mesylate) (CAS registry number: 144143-96-4), Ranitidine hydrochloride (Ranitidine hydrochloride) (CAS registry number: 66357-35-5), 6, 7-dihydro-6-mercapto-5H-pyrazolo [ l,2-a ] [1,2,4] triazolium chloride (CAS registry number: 153851-71-9), Sulfapyridine (Sulfapyridine) (CAS registry number: 144-83-2), Teicoplanin (CAS registry number: 61036-62-2), Tacrolimus (Taolimus) (CAS registry number: 104987-11-104987), LUMIRACOXIB (CAS accession No. 220991-20-8), propenol (CAS accession No. 107-18-6), Protected meropenem (Protected meropenem) (CAS accession No. 96036-02-1), Nelarabine (Nelarabine) (CAS accession No. 121032-29-9), Pimecrolimus (Pimecrolimus) (CAS accession No. 137071-32-0), 4- [ 6-methoxy-7- (3-piperidin-1-ylpropoxy) quinazolin-4-yl ] -N- (4-propan-2-yloxyphenyl) piperazine-1-carboxamide (CAS accession No. 387867-13-2), Ritonavir (Ritonavir) (CAS accession No. 155213-67-5), Adapalene (Adapalene) (CAS accession No. 106685-40-9), Aprepitant (Aprepitant) (CAS accession No. 170729-80-3), Eplerenone (Eplerenone) (CAS accession No. 107724-20-9), Rasagiline mesylate (Rasagiline mesylate) (CAS accession No. 161735-79-1), Miltefosine (Miltefosine) (CAS accession No. 58066-85-6), Raltegravir potassium (Raltegravir potassium) (CAS accession No. 871038-72-1), Dasatinib monohydrate (Dasatinib monohydrate) (CAS accession No. 863127-77-9), oxomazine (oxommazine) (CAS accession No. 3689-50-7), Pramipexole (pramipele) (CAS accession No. 104632-26-0), PARECOXIB SODIUM (parxib sodiumline) (CAS accession No. 198470-85), Tigecycline (CAS accession No. 2207-2207), Totrozuril (Toltrazuril) (CAS registry number: 69004-03-1), Vinflunine (Vinflunine) (CAS registry number: 162652-95-1), Drospirenone (Drospirenone) (CAS registry number: 67392-87-4), Daptomycin (Daptomycin) (CAS registry number: 103060-53-3), Montelukast sodium (Montelukast sodium) (CAS registry number: 151767-02-1), Brinzolamide (Brinzolamide) (CAS registry number: 138890-62-7), Maravir (Maraviroc) (registry number: 376348-65-1), doxercerol (CAS registry number: 54573-75-0), Oxolinic acid (CAS registry number: 14698-29-4), Daunorubicin hydrochloride (Daunochlororubicin) (CAS registry number: 2356-235766), and tinidine (CAS registry number: 2353-9641) (CAS registry number: 235966-3-4), Idarubicin (Idarubicin) (CAS registry number 58957-92-9), FLUOXETINE HYDROCHLORIDE (FLUOXETINE HYDROCHLORIDE) (CAS registry number 59333-67-4), Ascomycin (Ascomycin) (CAS registry number 11011-38-4), beta-Methylvinylphosphate (MAP) (CAS registry number 90776-59-3), Amorolfine (Amorolfine) (CAS registry number 67467-83-8), Fexofenadine HYDROCHLORIDE (Fexofenadine HCl) (CAS registry number 83799-24-0), Ketoconazole (Ketoconazole) (CAS registry number 65277-42-1), 9, 10-difluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido-1 (CAS registry number 82419-35-0), Ketoconazole (CAS registry number 65277-42-1), Terbinafine hydrochloride (Terbinafine HCl) (CAS registry number: 78628-80-5), amorolfine (CAS registry number: 78613-35-1), Methoxsalen (Methoxsalen) (CAS registry number: 298-81-7), Olopatadine hydrochloride (Olopatadine HCl) (CAS registry number: 113806-05-6), Zinc Pyrithione (Zinc pyrithionone) (CAS registry number: 13463-41-7), Olopatadine hydrochloride (CAS registry number: 140462-76-6), Cyclosporine (Cyclosporine) (CAS registry number: 59865-13-3), and Botulinum (Botulinum) toxin and analogs and vaccine components thereof.

Protein, polypeptide and peptide actives

In some embodiments, proteins useful in the disclosed systems can comprise, for example, molecules such as cytokines and their receptors, as well as chimeric proteins comprising cytokines or their receptors, including, for example, tumor necrosis factors alpha and beta, their receptors, and derivatives thereof; renin; growth hormones, including human growth hormone, bovine growth hormone, methionine-human growth hormone, desphenylalanine human growth hormone (des-phenylalkane human growth hormone) and porcine growth hormone; growth hormone releasing factor (GRF); parathyroid and pituitary hormones; thyroid stimulating hormone; human pancreatic hormone releasing factor; a lipoprotein; colchicine; prolactin; corticotropin; thyroid stimulating hormone; oxytocin; a vasopressin; a somatostatin; lysergenin; pancreatin; leuprolide (leuprolide); alpha-1-antitrypsin; an insulin a chain; insulin B chain; proinsulin; follicle stimulating hormone; a calcitonin; an luteinizing hormone; luteinizing hormone-releasing hormone (LHRH); LHRH agonists and antagonists; glucagon; coagulation factors such as factor VIIIC, factor IX, tissue factor and von Willebrands factor; anticoagulant factors such as protein C; atrial natriuretic factor; a pulmonary surfactant; plasminogen activators other than tissue-type plasminogen activator (t-PA), such as urokinase; bombesin; thrombin; a hematopoietic growth factor; enkephalinase; RANTES (regulated on activation normal T-cell expressed and secreted, regulatory factors that activate normal T-cell expression and secretion); human macrophage inflammatory protein (MIP-1-alpha); serum albumin such as human serum albumin; a secondary middle renal duct inhibitory substance; a relaxin a chain; a relaxin B chain; (ii) prorelaxin; mouse gonadotropin-associated peptides; chorionic gonadotropin; gonadotropin releasing hormone; bovine growth hormone; porcine growth hormone; microbial proteins such as beta-lactamases; DNase; a statin; an activin; vascular Endothelial Growth Factor (VEGF); receptors for hormones or growth factors; an integrin; protein A or D; rheumatoid factor; neurotrophic factors such as bone-derived neurotrophic factor (BDNF), neurotrophins-3, 4, -5 or-6 (NT-3, NT-4, NT-5 or NT-6), or nerve growth factors such as NGF-beta; platelet Derived Growth Factor (PDGF); fibroblast growth factors such as acidic FGF and basic FGF; epidermal Growth Factor (EGF); transforming Growth Factors (TGF) such as TGF-alpha and TGF-beta including TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta 4, or TGF-beta 5; insulin-like growth factors-I and-II (IGF-I and IGF-II); des (1-3) -IGF-I (brain IGF-I), insulin-like growth factor binding protein; CD proteins such as CD-3, CD-4, CD-8 and CD-19; erythropoietin; an osteoinductive factor; an immunotoxin; bone Morphogenetic Protein (BMP); interferons such as interferon- α (e.g., interferon α 2A), interferon- β, interferon- γ, interferon- λ, and consensus interferon; colony Stimulating Factors (CSF), e.g., M-CSF, GM-CSF, and G-CSF; interleukins (IL), e.g., IL-1 through IL-10; superoxide dismutase; a T-cell receptor; surface membrane proteins; a decay accelerating factor; viral antigens, such as HIV-1 envelope glycoprotein gp120, a portion of gp160, or fragments thereof; a transporter protein; a homing receptor; an address element; fertility inhibitors such as prostaglandins; a fertility promoting agent; a regulatory protein; antibodies (including fragments thereof) such as immunoadhesins and chimeric proteins; precursors, derivatives, prodrugs and analogs of these compounds, and pharmaceutically acceptable salts of these compounds, or precursors, derivatives, prodrugs and analogs thereof. In some embodiments, the protein or peptide may be native or recombinant and comprise, for example, a fusion protein.

In some embodiments, the payload is or includes growth hormone. In some embodiments, the growth hormone is human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, desphenylalanine human growth hormone, and porcine growth hormone; insulin, insulin a chain, insulin B chain and proinsulin; or growth factors, such as Vascular Endothelial Growth Factor (VEGF), Nerve Growth Factor (NGF), Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Epidermal Growth Factor (EGF), Transforming Growth Factor (TGF), or insulin-like growth factors-I and-II (IGF-I and IGF-II).

In some embodiments, peptides for use in the injectable, biodegradable delivery depots disclosed herein include, but are not limited to, glucagon-like peptide-1 (GLP-1) and precursors, derivatives, prodrugs and analogs thereof.

Nucleic acids

In some embodiments, the payload portion (and/or active agent) is or includes a nucleic acid agent. In some embodiments, a nucleic acid agent useful according to the present disclosure may be or include a nucleic acid; in some embodiments, nucleic acid agents useful according to the present disclosure may be or include nucleic acid precursors, derivatives, prodrugs, analogs, and the like. In some embodiments, nucleic acid agents useful according to the present disclosure may be selected from the group consisting of: therapeutic nucleotides, nucleosides, and analogs thereof; a therapeutic oligonucleotide; and therapeutic polynucleotides.

One of ordinary skill in the art will appreciate a variety of therapeutic nucleic acid agents, many of which may be particularly useful, for example, as anti-cancer agents, antimicrobial agents, and/or antiviral agents.

In some embodiments, suitable nucleic acid agents may include, for example, ribozymes, antisense oligodeoxynucleotides, aptamers, and sirnas. In some embodiments, suitable nucleoside analogs include, but are not limited to, cytarabine (araCTP), gemcitabine (gemcitabine) (dFdCTP), and floxuridine (floxuridine) (FdUTP). In some embodiments, a suitable nucleic acid active agent is an interfering RNA, such as an shRNA, miRNA, or siRNA. In some embodiments, suitable siRNAs comprise, for example, IL-7 (interleukin-7) siRNA, IL-10 (interleukin-10) siRNA, IL-22 (interleukin-22) siRNA, IL-23 (interleukin 23) siRNA, CD86 siRNA, KRT6A (keratin 6A) siRNA, K6A N171K (keratin 6A N171K) siRNA, TNF α (tumor necrosis factor α) siRNA, TNFR1 (tumor necrosis factor receptor-1) siRNA, TACE (tumor necrosis factor (TNF) - α convertase) siRNA, RRM2 (ribonucleotide reductase subunit-2) siRNA, and VEGF (vascular endothelial growth factor) siRNA. The mRNA sequences of the human gene targets of these sirnas are known in the art. For IL-7, see, e.g., GenBank accession No.: NM-000880.3, GenBank accession No.: NM-001199886.1, GenBank accession No.: NM-001199887.1 and GenBank accession No.: NM-001199888.1; for IL-10, see, e.g., GenBank accession No.: NM-000572.2; for IL-22, see, e.g., GenBank accession No.: NM-020525.4; for IL-23, see, e.g., GenBank accession No.: NM-016584.2 and GenBank accession No.: AF 301620.1; for CD86, see, e.g., GenBank accession No.: NM-175862.4, GenBank accession No.: NM-006889.4, GenBank accession No.: NM-176892.1, GenBank accession No.: NM-001206924.1 and GenBank accession No.: NM-001206925.1; for KRT6a, see, e.g., GenBank accession No.: NM-005554.3; for TNF α, see, e.g., GenBank accession No.: NM-000594.2; for TNFR1, see, e.g., GenBank accession No.: NM-001065.3; for TACE, see, e.g., GenBank accession No.: NM-003183.4; for RRM2, see, e.g., GenBank accession No.: NM-001165931.1 and GenBank accession No.: NM-001034.3; for VEGF, see, e.g., GenBank accession No.: NM-001025366.2, GenBank accession No.: NM-001025367.2, GenBank accession No.: NM-001025368.2, GenBank accession No.: NM-001025369.2, GenBank accession No.: NM-001025370.2, NM-001033756.2, GenBank accession number: NM-001171622.1 and GenBank accession No.: NM-003376.5.

Certain exemplary therapeutic agents and/or other active agents

In some embodiments, the present disclosure provides, among other aspects, an osmotic agent including a therapeutic agent. In some embodiments, the therapeutic or active agent may be directed to one or more of the following drug targets: kringle domains, carboxypeptidases, carboxylic ester hydrolases, glycosylases, rhodopsin-like dopamine receptors, rhodopsin-like adrenoreceptors, rhodopsin-like histamine receptors, rhodopsin-like serotonin receptors, rhodopsin-like short peptide receptors, rhodopsin-like acetylcholine receptors, rhodopsin-like nucleotide-like receptors, rhodopsin-like lipid-like ligand receptors, rhodopsin-like melatonin receptors, metalloproteinases, transporter ATPases, carboxylic ester hydrolases, peroxidases, lipoxygenases, DOPA decarboxylase, A/G cyclase, methyltransferases, sulphonylurea receptors, other transporters (e.g., dopamine transporter, GABA transporter 1, noradrenaline transporter, potassium transport ATPase alpha-chain 1, sodium- (potassium) -chloride co-transporter 2, serotonin transporter, synaptamine transporter and sensitive thiazine sodium-chloride co-transporter) Electrochemical nucleoside transporters, voltage-gated ion channels, GABA receptors (Cys-loop), acetylcholine receptors (Cys-loop), NMDA receptors, 5-HT3 receptors (Cys-loop), ligand-gated ion channels Glu: kainite, AMPA Glu receptor, acid sensitive ion channel aldosterone, Ryanodine (Ryanodine) receptor, vitamin K epoxide reductase, MetGluR-like GABAB receptor, inward rectifier K + channel, NPC1L1, MetGluR-like calcium sensitive receptor, aldehyde dehydrogenase, tyrosine 3-hydroxylase, aldose reductase, xanthine dehydrogenase, ribonucleoside reductase, dihydrofolate reductase, IMP dehydrogenase, thioredoxin reductase, dioxygenase, myoinositol monophosphatase, phosphodiesterase, adenosine deaminase, peptidyl prolyl isomerase, thymidylate synthase, aminotransferase, farnesyl diphosphate synthase, protein kinase, carbonic anhydrase, tubulin, troponin, IKB kinase-beta inhibitor, amine oxidase, cyclooxygenase, cytochrome P450, thyroxine 5-deiodinase, steroid dehydrogenase, HMG-CoA reductase, steroid reductase, thyroxine, calcium phosphate, and/beta-related protein, Dihydroorotase, epoxide hydrolase, transporter atpase, transporter, glycosyltransferase, nuclear receptor NR3 receptor, nuclear receptor: NR1 receptor or topoisomerase.

In some embodiments, the therapeutic or active agent targets a rhodopsin-like GPCR, nuclear receptor, ligand-gated ion channel, voltage-gated ion channel, penicillin binding protein, myeloperoxidase-like, sodium: a neurotransmitter symporter family, a type II DNA topoisomerase, a fibronectin type III, or a cytochrome P450.

In some embodiments, the therapeutic agent is or includes an anti-cancer agent. Suitable anti-cancer agents include, but are not limited to, actinomycin D, Alemtuzumab (Alemtuzumab), Allopurinol sodium (Allopurinol sodium), Amifostine (Amifostine), Amsacrine (Amsacrine), Anastrozole (Anastrozole), Ara-CMP, asparaginase, azacytidine (Azacytadine), Bendamustine (Bendamycin), Bevacizumab (Bevacizumab), bicalutamide (Bicallutide), Bleomycin (Bleomycin) (e.g., Bleomycin A2 and B2), Bortezomib (Bortezomib), Busulfan (Busulfan), Camptothecin sodium salt (Camptothecin sodium salt), Capecitabine (Capecine), Carboplatin (Carboplatin), Carmustine (Carmustine), Cetuximab (Centumexil), Cycline (Cydramycin), azacitidine (Clotrimazine), Clarithromycin (Clotrimazine, Clarithromycin), Clarithromycin (Clotrigine), Clarithromycin A (Clotrigine), Claritosine (Clotrigine), Claritrin (Clotrigine), Claritin (Cleomycin (Clotrigine), Claritonane (Cleomycin (Clotrigine), Claritin (Cleomycin), Claritin (Cleotaxicine, Cleotaxicine (Cleotaxicine), Claritamin-D, Cleotaxine, Cleotaxicine (Cleotaxicine, Cleotaxicine (Cleotaxine, Cleotaxicine, Cleotaxine, Cleotaxicine, Cleotaxine, Cleo, Decitabine (Decitabine), Docetaxel (Docetaxel), doxorubicin, liposomal doxorubicin, epirubicin, Estramustine (Estramustine), Etoposide (Etoposide), Etoposide phosphate, Exemestane (Exemestane), floxuridine, Fludarabine (Fludarabine), Fludarabine phosphate, 5-fluorouracil, Fotemustine (Fotemustine), Fulvestrant (Fulvestrant), gemcitabine, Goserelin (Goserelin), hexamethylmelamine, urea, idarubicin, ifosfamide, Imatinib (Imatinib), Irinotecan (Irinotecan), Ixabepilone (Ixabepilone), lapatinib, Letrozole (Letrozole), leuprolide acetate, Lomustine (Lomustine), dichloromethyldiethane, Melphalan (Melphalan), 6-phatryptophane (Metxanthene), Mitoxantrone (mitomycin C), mitomycin (mitomycin C), Methotrexate (mitomycin C), Methotrexate (Mitoxantrone), Fludarabine (Mitoxantrone), Methotrexate (Mitoxantrone), flutolnaftate (Mitoxantrone), flutam (Mitoxantrone), flutamicine, Mitoxantrone, mito, Nimustine (Nimustine), Ofatumumab (Ofatumumab), Oxaliplatin (Oxaliplatin), Paclitaxel (Paclitaxel), Panitumumab (Panitumumab), Pemetrexed (pegaranase), Pemetrexed (Pemetrexed), Pentostatin (pentastatin), Pertuzumab (Pertuzumab), Picoplatin (Picoplatin), Pipobroman (Pipobroman), Plerixafor (Plerixafor), Procarbazine (Procarbazine), ranitroxer (ratrexed), Rituximab (Rituximab), streptozotocin (streptazocin), Temozolomide (Temozolomide), Teniposide (Teniposide), 6-thioguanine, Thiotepa (Thiotepa), Topotecan (Topotecan), tretinomycin (Vincristine), Vinorelbine (Vinorelbine), Vincristine (Vinorelbine), Vinorelbine (Vindesine), Vinorelbine (Vinorelbine), Vindesine (Vinorelbine), Vinorelbine (Vindesine), Vinorelbine (Vinorelbine), Vindesine (Vindesine), Vindesine (vinpocetine), vinpocetine, vinpocine (Vincristine (vinpocetine), and vinpocetine), vinpocetine, and vinpocetine, and a, in, Derivatives and prodrugs. It should be noted that two or more of the above-described compounds may be used in combination in an osmotic agent or in a composition including an osmotic agent, as described herein.

In some embodiments, the therapeutic agent may be or include an opioid or derivative thereof, and/or an opioid receptor agonist or antagonist, for example, any of naltrexone (naltrexone), naloxone (naloxone), nalbuphine (nalbuphine), fentanyl (fentanyl), sufentanil (sufentanil), oxycodone (oxycodone), or a pharmaceutically acceptable salt or derivative thereof.

In some embodiments, the therapeutic or active agent is a small molecule or low molecular weight compound, e.g., a molecule or compound having a molecular weight of less than or equal to about 1000 daltons, such as less than or equal to about 800 daltons.

In some embodiments, the therapeutic agent or active agent is or includes a label. Suitable labels include, for example, radioisotopes, fluorescers, chemiluminescent agents, chromophores, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chromophores, dyes, metal ions, magnetic particles, nanoparticles, and quantum dots.

In some embodiments, the therapeutic agent or active agent may be present in the compositions disclosed herein at any suitable concentration. Suitable concentrations may vary depending on the potency of the relevant agent, its half-life, etc. Additionally, in some embodiments, an osmotic agent composition according to the present disclosure may include one or more active agents, for example, a combination of two or more of the active agents described above.

Nanoparticles

In some embodiments, the agent is or comprises a nanoparticle. In some embodiments, the agent is encapsulated within the nanoparticle. In some embodiments, examples of materials used to make the nanoparticles include organic polymers such as polylactic-co-glycolic acid, polyanhydrides, hyaluronic acid, and inorganic materials such as gold, silica, and iron oxide. In some embodiments, the nanoparticles may also be made of lipids that form liposomes or solid lipid nanoparticles. In some embodiments, the nanoparticles may encapsulate cosmetic actives including, but not limited to, vitamins, antioxidants, colorants, fragrances, and sunscreens. In one embodiment, the size, shape or elasticity of the nanoparticles is selected so as to preferentially induce localization of the nanoparticles in the superficial skin layer.

In some embodiments, the carrier moiety (e.g., CBT) is conjugated to the nanoparticle using a linker. In some embodiments, the linker conjugating the carrier moiety to the nanoparticle may be selected from glycine, other amino acids, polyethylene glycol, succinic acid, adipic acid dihydrazide, and the like.

Cosmetic active

In some embodiments, provided osmotic agents include an active agent that is a payload or a cosmetic agent. Those skilled in the art are aware of various cosmetic agents, including, for example, those described in US 2006/0008428a1, incorporated herein. In some embodiments, the cosmetic agent may be or comprise a compound or mixture of compounds, in purified or complexed form, in particular mineral or plant based, which exhibit intrinsic activity in vitro or in vivo and which are capable of being formulated in a cosmetic product.

As understood by those skilled in the art, a composition considered to be a "cosmetic product" is any substance or formulation intended to come into contact with the various surface parts of the human body (epidermis, body hair and hair system, nails, lips and external genital organs) or the teeth and oral mucosa, the sole or primary purpose of which is to clean, perfume, modify its appearance and/or mask body odour and/or provide protection or maintain in good condition (cosmetic instructions) (76/768/EEC, revised).

In some embodiments, the payload portion or active comprised in an osmotic agent as described herein is or includes one or more cosmetic actives. Alternatively or additionally, in some embodiments, formulations of osmotic agents as described herein may comprise one or more such cosmetic actives. In some embodiments, the cosmetic active may comprise, but is not limited to, a safe and effective amount of a skin care agent selected from the group consisting of: glycosaminoglycans, amino acids, peptides and derivatives thereof, desquamation actives, vitamins and derivatives thereof, retinoids and derivatives thereof, hydroxy acids, anti-acne actives, free radical scavengers, chelators, anti-inflammatory agents, local anesthetics, moisturizers, emollients, skin conditioners, antiperspirants, antioxidants, anti-wrinkle products, surfactants, deodorants, colorants, pigments, sunscreens or other photo-protectants, tanning actives, skin lightening agents, anti-cellulite agents, probiotics/prebiotics, flavonoids, antimicrobial actives, skin healing agents, fragrances or perfumes, cannabinoids. In some embodiments, the provided systems comprise compounds identified in the OTC monograph. In some embodiments, the compounds identified in the OTC monograph include, for example, other anti-acne products, topical antifungal agents, antimicrobial products, antiperspirants, astringents, corn and callosity removal agents, dandruff products, hair growth/loss, onychomycosis products, psoriasis, eczema, rosacea, skin bleaching, skin lightening products, sunscreens, topical analgesics, verruciating agents, insecticides, pharmaceuticals, as well as other agents such as farnesol, phytantriol, allantoin, glucosamine, and any other inert or active material intended for or otherwise suitable for topical application to its skin mixture in a dermatologically acceptable carrier.

In some particular embodiments of the penetrants described herein, the CBT is conjugated directly (with or without an intermediate linker) to a cosmetic nanoparticle selected from a pigment or a sunscreen agent.

Administration of the provided System

The techniques described herein are useful for providing a system at a target site. In some embodiments, the target site is or includes (e.g., on or within) body tissue. Techniques for applying a material to an application site such that a system is provided at a target site are described herein.

For example, in some embodiments, the body tissue is or includes epithelial tissue. In some embodiments, the body tissue is or includes connective tissue. In some embodiments, the body tissue is or includes neural tissue. In some embodiments, the body tissue is or includes muscle tissue. In some embodiments, the body tissue is or includes eye tissue, skin tissue, or subcutaneous tissue. In some embodiments, the body tissue is or includes subcutaneous fat, corneal epithelium, or mucosa.

In many embodiments, the target site is a site that is reached after application to a surface, such as a tissue surface. In some embodiments, the tissue surface is a surface of a tissue (e.g., skin, eye, or certain mucous membranes) exposed on a surface of a biological body. In some embodiments, the tissue surface is a surface of internal tissue that can be accessed or exposed, for example, by performing a procedure (e.g., a medical procedure such as a surgical procedure, including, for example, an orthodontics procedure) or a procedure applied to a living organism.

In some embodiments, the present disclosure provides systems that can be applied to the skin, oral mucosa, vaginal mucosa, eye, bladder, nasal mucosa, ear canal, or anal mucosa.

As described herein, the present disclosure provides a system that can be applied to skin. In some embodiments, the provided system is topically applied (e.g., to the skin surface). In some embodiments, the provided systems are administered as a transdermal patch.

In some embodiments, the provided system is administered to the face of the subject (e.g., the entire face and/or specific parts of the subject's face, such as the lips, lower lip, upper lip, lacrimal sulcus, crow's feet, nasolabial sulcus, forehead, cheeks, or a combination thereof). In some embodiments, the provided system is applied to non-facial parts (e.g., knees, neck, chest, legs, arms, torso, buttocks, or feet). In some embodiments, the provided system is applied to a hand (e.g., the back of the hand). In some embodiments, the provided systems are applied to an earlobe.

In some embodiments, the administration site is prepared prior to administration of the provided system. In some embodiments, the application site is prepared by washing the site with warm water and soap. In some embodiments, the application site is prepared with a commercial microneedle roller. In some embodiments, the application site is prepared by tape stripping. In some embodiments, tape stripping comprises applying Scotch transparent translucent tape (Scotch semitransparent tape) to the application site. In some embodiments, tape stripping further comprises removing the previously applied scotch translucent tape from the application site. In some embodiments, tape stripping is repeated until the application site is flashed. In some embodiments, the tape stripping is repeated at least 40 times.

In some embodiments, the application site is covered after application of the provided system. In some embodiments, the application site is covered with a tegademtm type film after application of the provided system.

In some embodiments, the skin is treated with water after application of the system.

In some embodiments, the system is administered daily. In some embodiments, the system is administered at least once daily. In some embodiments, the system is administered at least twice daily. In some embodiments, the system is administered at least 1-5 times daily. In some embodiments, the system is administered at least 3-5 times daily. In some embodiments, the system is administered every 3 days. In some embodiments, the system is administered every 7 days. In some embodiments, the system is administered about every 15 days. In some embodiments, the system is administered about every 30 days. In some embodiments, the system is administered about every 60 days. In some embodiments, the system is administered about every 90 days.

In some embodiments, the provided systems are administered as or in a sustained release formulation. In some embodiments, the osmotic agent is provided as or in an emulsion or dispersion.

In some embodiments, the provided systems may be present in a particular formulation as a weight (e.g., w/w)% within a range between a lower boundary and an upper boundary (including upper and lower boundaries), the upper boundary being greater than the lower boundary, wherein the upper boundary may be about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%, and the lower boundary may be about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 1%. In some embodiments, the formulation comprises from about 0.001% w/w to about 5.00% w/w of the system. In some embodiments, the formulation comprises from about 0.01% w/w to about 5.00% w/w of the system. In some embodiments, the formulation comprises from about 0.1% w/w to about 5.00% w/w of the system. In some embodiments, the formulation comprises from about 1% w/w to about 5.00% w/w of the system. In some embodiments, the formulation comprises from about 1% w/w to about 3% w/w of the system. In some embodiments, the formulation comprises about 2% w/w of the system. In some embodiments, the formulation comprises PBS and about 2% w/w of the system.

In some embodiments, the formulation includes the provided system and cosmetic materials. In some embodiments, the formulation comprises from about 1% w/w to about 50% w/w of the system. In some embodiments, the formulation comprises from about 10% w/w to about 50% w/w of the system. In some embodiments, the formulation comprises from about 20% w/w to about 50% w/w of the system. In some embodiments, the formulation comprises from about 30% w/w to about 50% w/w of the system. In some embodiments, the formulation comprises about 40% w/w to about 50% w/w of the system. In some embodiments, the formulation comprises about 45% w/w to about 50% w/w of the system.

Various forms of the formulations may be used to administer an osmotic agent as described herein and/or deliver an associated payload portion or active agent to a patient. Pharmaceutically acceptable excipients are also well known and readily available to those of ordinary skill in the art. One skilled in the art will appreciate that the choice of excipients will generally be determined, at least in part, by the particular payload portion or active agent involved and/or the particular method used to administer the composition. Thus, one skilled in the art will appreciate that an osmotic agent as described herein may be included and/or administered in any of a variety of formulations. In some embodiments, formulations suitable for topical administration may be presented as a cream, lotion, liquid, serum, gel, paste, patch, powder, spray, or foam.

In some embodiments, the provided systems can be used to treat a disease, disorder, or condition. In some embodiments, the provided systems can be used to treat a skin disease, disorder, or condition (e.g., "skin condition"). In some embodiments, the skin condition may be selected from the group consisting of: for example, Acanthosis nigricans (Acanthosis nigricans), acne scars, Actinic keratosis (Actinic keratasis), alopecia areata, Atopic dermatitis (Atopic dermatitis), Basal cell carcinoma (Basal cell carcinoma), cellulitis, herpes labialis contact dermatitis, dandruff, diaper rash, xerosis cutis, dermatoxerasia, Dermatofibrosarcoma protruberans, pompholyx, eczema, genital herpes, genital warts, alopecia, herpes simplex infection, hidradenitis suppurativa, urticaria, hyperhidrosis, impetigo, Ichthyosis vulgaris (ichthyiosis vulgaris), keloids and other scars, keratosis pilaris, lichen planus, melanoma, liver spots, creutus cell carcinoma, nevus nigra, molluscum contagious molluscum, tinea unguium, pruritus, neurodermatitis, skin allergies (such as nickel allergy), nummula, sore, pimples, syphilis, oak poison, and oak poison, Psoriasis, psoriatic arthritis, tinea, rosacea, scabies, scalp psoriasis, scleroderma, sebaceous gland carcinoma, seborrheic dermatitis, seborrheic keratosis, shingles, skin cancer, squamous cell carcinoma, stasis dermatitis, tinea versicolor, vitiligo, warts, and wound healing.

In some embodiments, the provided systems can be used to treat a disease, disorder, or condition of a body tissue, such as a mucosa. In some embodiments, the provided systems may be used to treat diseases, disorders, or conditions associated with eye, nose, mouth, throat, and vaginal dryness. In some embodiments, the condition of the body tissue may be selected from the group consisting of anal fissure, anal fistula, bacterial vaginosis, halitosis, blurred vision, canker sores, cataracts, cervicitis, colitis, colonic polyps, achromatia, conjunctivitis, diverticulosis, dyspareunia, ocular pain, glaucoma, gum and tooth problems, hemorrhoids, Human Papilloma Virus (HPV), irritable bowel syndrome, laryngitis, vitiligo, macular degeneration, nasal and sinus polyps, perianal or perianal abscess, perianal or perianal infection, pharyngitis, post-menopausal mucosal dryness, ocular redness, sinusitis, sjogren syndrome ((r: (r) ((r))syndrome), sore throat, thrush, tonsillitis, trichomoniasis, uveitis, and yeast infections.

In some embodiments, the provided systems can be used to improve or maintain one or more cosmetic properties of skin such as pigmentation (including age spots, liver spots, vitiligo, freckles, post-inflammatory pigmentation), hair growth, hair color, scarring, dryness, shine, fine lines and wrinkles, smoothness, elasticity, elastosis, erythema, changes in nail appearance or structure, unwanted tattoos, thinning of skin, loss of skin volume due to atrophy (including atrophic scarring), purpura, damage associated with UV line exposure or chemical exposure, dandruff, scaling, perspiration, protruding pores, calluses, and other changes associated with chronological aging and photoaging.

Examples of the invention

The present examples describe, among other things, certain strategies that may be used to characterize and/or evaluate osmotic agents (and/or components and/or compositions, or combinations thereof) as described herein. Such strategies (or equivalents of such strategies as would be understood by one of skill in the art reading this disclosure) may be used to assess the suitability of an osmotic agent, component (e.g., portion), composition, or combination thereof for use in accordance with the present disclosure. Thus, in some embodiments, the present disclosure provides techniques for characterizing and/or selecting useful moieties, linkers, penetrants and/or components, compositions, and/or combinations thereof.

Example 1: skin penetration of CBT-modified molecules

CBT was conjugated with both glycine (gly-CBT) and hyaluronic acid (HA-CBT) to study skin penetration of small molecule actives functionalized with CBT and high molecular weight actives functionalized with CBT. Use of hyaluronic acid with a molecular weight of about 250kDA and use thereof¹HA-CBT was synthesized from glycine as an intermediate spacer with a H NMR measured resolution of about 10%.

Frozen pig skin was equilibrated to room temperature and then cut into pieces of about 2 x 2cm and placed into 0.9mL PBS in 6-well plates. mu.L of HA-CBT (10mg/mL in PBS), gly-CBT (1mg/mL in PBS) and PBS were gently smeared on the pig skin with a metal spatula to form a 1cm circle. After spreading the formulation, the 6-well plate was placed in a humidified incubator at 37 ℃ for 18 hours.

A small area in the center of the application area was then excised using a surgical knife and placed into OCT in a biopsy mold. The tissue was snap frozen by placing the biopsy mold directly into a methylpentane dry ice slurry. The tissue was then sectioned to 20 μm sections on a cryostat microtome. Prior to imaging, a drop of ProLong Gold was placed on each slice and covered with a coverslip. Images were taken on a zeissaxiopan 2 using a 10x objective and DAPI filter to visualize the location of the CBT.

High fluorescence of both gly-CBT and HA-CBT was observed in the stratum corneum and epidermis, and a lower signal in the dermis was observed for both molecules. These results indicate that large polymers like HA with a molecular weight of 250kDa and small hydrophilic molecules like glycine can penetrate the skin after functionalization with CBT.

Example 2: skin penetration and tissue interaction of gly-CBT

Use of a 3D human skin model (Mattek EpiDerm)^TM) The permeation and interaction of gly-CBT in human skin was evaluated. After equilibrating the skin tissue with the culture medium in 6-well plates for 1 hour at 37 ℃, the culture medium was replaced with PBS and 100 μ Ι _ of PBS and gly-CBT (1mg/mL) were each applied to the top of 4 skin tissues. After 6 hours of incubation, individual tissues from each group were snap frozen in OCT for cryosectioning and microscopy. For the remaining samples, the liquid remaining on top of the tissue insert (approximately 100 μ L) and the liquid in the receptor solution (900 μ L) were collected. The top of the tissue insert was then washed 2x with PBS and the insert was then immersed in 2mL of 1:1 PBS: MeOH solution to extract the molecules that penetrated the skin. After 2 hours of extraction at 37 ℃, the concentration of gly-CBT in the donor, acceptor and extract was measured by reading the absorbance at 326nm with a plate reader. The remaining tissue inserts were cryosectioned and imaged using fluorescence microscopy as described in example 1.

As shown in panel A of FIG. 4, only about 25% of gly-CBT applied to the surface of epidermal tissue remained after 6 hours of incubation, indicating significant penetration. Surprisingly, only about 50% of the total gly-CBT was detected after the extraction procedure and in the donor and acceptor solutions. Only about 10% of the applied gly-CBT can be extracted from epidermal tissue; however, significant fluorescence signals were observed in the tissues by microscopy (fig. 4, panels C-D).

To further investigate the penetration of gly-CBT in human skin tissue, gly-CBT and gly-aminofluorescein (gly-Luc) were applied to EpiDerm^TMAfter in the tissues, the distribution of the different chemical species was quantified using HPLC. As described above, 100. mu.L of gly-CBT and gly-Luc were applied to the top of the skin tissue. After 6 hours of incubation, the donor and acceptor solutions were collected and attempted to extract the skin penetrating chemical species with 1:1 MeOH in PBS. After the first extraction protocol, the tissue inserts were rinsed with PBS and washed by UV₂₅₄The lamp exposure was imaged in a dark room. After imaging, additional extractions were performed sequentially with 1.0% Triton X-100, acidified MeOH (0.1% TFA), and DCMAnd (6) taking. Subsequent extractions did not succeed in extracting any additional CBT species.

As shown in panels A-B of FIG. 5, < 20% of the applied gly-CBT and gly-fluorescein remained in the donor solution after 6 hours of tissue exposure. In addition and consistent with the previous study shown in FIG. 2, the overall recovery of gly-CBT and gly-Luc was < 60% (FIG. 3, panel C). After the first extraction process and washing step, the tissue inserts exposed to gly-CBT were extremely fluorescent (fig. 3, panel D). This suggests that a significant fraction of gly-CBT penetrating epidermal tissue cannot be extracted due to interaction with epidermal tissue. Surprisingly, neither surfactant (0.1% Triton X-100 solution), acidified methanol or dichloromethane extracted more CBT species, indicating a strong interaction with skin tissue.

Example 3: biocompatibility of locally applied CBT-functionalized molecules.

To assess the biocompatibility of CBT-functionalized molecules, skin irritation studies were performed using a 3D reconstructed epidermal model supplied by mantek corporation (Mattek). Skin irritation tests were performed based on the OECD TG 439 protocol. Epiderm is available from Mattek^TM(Epi-200) after the tissue inserts were removed from the agarose and incubated in 0.9mL of media in 6-well plates for 1 hour at 37 ℃. The tissue inserts were then transferred to new wells containing 0.9mL of fresh medium and incubated overnight at 37 ℃ for 18 hours. 30 μ L of PBS, HA-CBT (20mg/mL and 2mg/mL in PBS), gly-CBT (1mg/mL and 0.1mg/mL), and SDS (5 wt%) were each applied and smeared on top of 3 independent tissue inserts. After 1 hour incubation at 37 ℃, the formulation was removed and the tissue inserts were washed three times with PBS. The tissue inserts were then incubated in fresh medium at 37 ℃ for 24 hours. The medium was then exchanged with fresh medium and the inserts were incubated at 37 ℃ for a further 18 hours. Following incubation, the viability of the tissue was assessed using the MTT assay, which is discussed in detail in the protocol developed by Mattek corporation (EPI-200-SIT).

While the positive control (5% SDS) showed significant stimulation with almost 100% reduction in cell viability in skin tissue, neither gly-CBT nor HA-CBT showed any reduction in cell viability. This indicates that both CBT modified molecules are non-irritating and compatible with human skin tissue.

Example 4: the retention of HA-CBT on human skin.

To assess the retention time of HA-CBT relative to native HA, HA was labeled with an IR tag. IR-labeled HA (IR-HA) was synthesized by conjugating CF-647 amine to HA (about 50 kDa). Conjugating CBT with IR-HA to generate IR-HA-CBT, wherein the degree of substitution of CBT is 10 mol%.

The frozen human skin was thawed and the Stratum Corneum (SC) was gently washed with soap and then taped off 20 times to reduce SC thickness. The tape-peeled skin pieces were placed in a Franz diffusion cell and equilibrated with PBS for 1 hour at 37 ℃. After equilibration, the skin pieces were exposed to IR-HA (10mg/mL in PBS) or IR-HA-CBT (10mg/mL in PBS) for 5 hours in the donor compartment in a humidified oven at 37 ℃. After 5 hours, the IR-HA and IR-HA-CBT solutions were removed and the skin surface was washed three times with PBS. The skin was then exposed to PBS overnight in the donor compartment at 37 ℃. After incubation in Franz diffusion cells, skin pieces were snap frozen and sectioned on a cryostat. Slides containing frozen sections were further washed in PBS for 30 minutes at room temperature. After this last washing step, slides were fixed with 90% glycerol and imaged on a fluorescence microscope with Cy5 filter to visualize the location of the selected IR dye.

A strong IR signal was observed in the upper epidermis/SC of skin treated with IR-HA-CBT, whereas no IR signal was observed in skin treated with IR-HA (FIG. 7). Both IR-HA and IR-HA-CBT penetrated the skin because the skin was taped off to reduce the thickness of the SCs. However, after the vigorous washing steps consisting of both washing the skin overnight with PBS in Franz cells and washing the frozen sections on the slides in PBS, the skin samples retained only IR-HA-CBT, indicating that by conjugation to CBT, retention of IR-HA in human skin, specifically in the upper layers of epidermis and SC, was increased.