阅读说明：本技术 用于预防和治疗病症的组合物及方法 (Compositions and methods for preventing and treating disorders ) 是由 J·M·克里肖内 于 2018-12-14 设计创作，主要内容包括：本文提供了包含稳定的硅酮包水乳液的组合物,以及用于治疗病症的包含所述组合物的方法和试剂盒。(Provided herein are compositions comprising stable water-in-silicone emulsions, as well as methods and kits comprising the compositions for treating disorders.)

1. A composition comprising a stable water-in-silicone emulsion having a continuous silicone phase and an aqueous phase,

wherein the emulsion comprises a sterol in a concentration of about 0.1 wt% to about 4 wt% of the total weight of the composition.

2. The composition of claim 1, wherein the concentration of the sterol is from about 1 weight% to about 2 weight% of the total weight of the composition.

3. The composition of claim 1, wherein the sterol comprises cholesterol or a cholesterol derivative.

4. The composition of claim 1, wherein the silicone phase comprises silicone oil, silicone gum, or a combination thereof.

5. The composition of claim 4, wherein the silicone oil comprises polydimethylsiloxane, cyclomethicone, octylmethicone, or cyclopentasiloxane.

6. The composition of claim 4, wherein the silicone gel comprises dimethiconol.

7. The composition of claim 1, further comprising at least one co-emulsifier.

8. The composition of claim 7, wherein the co-emulsifier comprises glyceryl stearate, glyceryl monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene monolaurate, polyoxyethylene monostearate, polyoxyethylene monopalmitate, polyoxyethylene monooleate, lecithin, PEG/PPG-18/18 polydimethylsiloxane, Cetyl PEG/PPG-10/1 dimethicone, dimethicone copolyol, octyldodecanol, poly (vinyl alcohol), pluronic, poloxamer, carbomer, isopropyl myristate, or combinations thereof.

9. The composition of claim 1, wherein the aqueous phase comprises a pH buffering system.

10. The composition of claim 9, wherein the pH buffering system comprises lactic acid and its conjugate base.

11. The composition of claim 1, further comprising at least one preservative.

12. The composition of claim 12, wherein the preservative comprises sorbic acid, potassium sorbate, boric acid, sodium borate, benzoic acid, sodium benzoate, benzalkonium chloride, benzethonium chloride, EDTA, parabens, or a combination thereof.

13. The composition of claim 1, further comprising tocopherol.

14. The composition of claim 13, wherein the tocopherol comprises alpha-tocopherol, vitamin E-TPGS, or tocopherol acetate.

15. The composition of claim 1, further comprising an antioxidant.

16. The composition of claim 15, wherein the antioxidant comprises ascorbic acid, sodium ascorbate, a polyphenol, or a combination thereof.

17. The composition of claim 1, further comprising at least one fatty acid.

18. The composition of claim 17, wherein the fatty acid comprises caprylic acid, lauric acid, myristic acid, decenoic acid, lauric acid, myristoleic acid, palmitoleic acid, oleic acid, stearic acid, palmitic acid, linoleic acid, arachidonic acid, stearidonic acid, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or a combination thereof.

19. The composition of claim 1, further comprising at least one viscosity enhancing agent.

20. The composition of claim 19, wherein the viscosity enhancing agent comprises hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hyaluronic acid, sodium hyaluronate, carbomer, carbopol, poly (acrylic acid), polycarbophil, guar gum, xanthan gum, or a combination thereof.

21. The composition of claim 1, further comprising at least one bioactive agent.

22. The composition of claim 21, wherein the bioactive agent comprises glycogen.

23. The composition of claim 1, further comprising at least one active agent.

24. The composition of claim 23, wherein the active agent comprises miconazole, metronidazole, clotrimazole, estradiol, prasterone, or nonoxynol-9.

25. The composition of claim 1, wherein the composition has a pH of about 3 to about 5.

26. The composition of claim 1, wherein the osmolality of the composition is about 200 to 500 mOsm/kg.

27. The composition of claim 1, wherein the zero shear rate viscosity of the composition is from about 50kPa-s to 1000 kPa-s.

28. The composition of claim 1, wherein the composition is formulated as a personal lubricant, moisturizer, ointment, lotion, topical cream, for wound care, for skin care, for drug delivery, or ophthalmic care.

29. The composition of claim 1, wherein the composition is a vulvovaginal composition.

Technical Field

The present invention relates to compositions, methods, and kits for vulvovaginal administration or other disorders in a subject.

Background

Various compositions are needed to provide lubricity and/or to protect skin and other tissues from damage and/or infection. Such compositions may be used alone or in combination with one or more active and/or bioactive agents, wherein the composition is used as a drug delivery vehicle (e.g., as a transdermal drug delivery vehicle).

Additionally, vulvovaginal health remains an overlooked medical need, as most markets in this area are largely undifferentiated, particularly in over-the-counter medications or over-the-counter products. Thus, in all demographics from pre-to post-menopause, gynecological patients with one or more vulvovaginal conditions are often treated with prescribed products or regimens that typically have undesirable product characteristics including: (1) the duration of efficacy of a single administration is insufficient; (2) insufficient recovery from physiological stagnation; (3) undesirable side effects; and (4) unacceptable health risks.

Thus, there remains a need for a wide variety of compositions that provide lubricity, protect skin and other tissues, and/or facilitate drug delivery. In particular, for a variety of vulvovaginal health conditions, there is a need for compositions and formulations that can provide vulvovaginal symptom relief, treat the underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protect the vulvovaginal anatomy.

Disclosure of Invention

Provided herein, inter alia, are compositions, formulations, and methods that provide lubricity, protect skin, mucous membranes, and other tissues, and facilitate drug delivery. Also provided are compositions, formulations, and methods for treating, preventing, and/or reducing the severity of vulvovaginal and other conditions. Provided herein are vulvovaginal compositions designed to provide vulvovaginal symptom relief, treat an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protect the vulvovaginal anatomy in a subject. In some embodiments, the vulvovaginal composition comprises a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent. In other embodiments, the vulvovaginal composition consists of a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent. In other embodiments, the vulvovaginal composition consists essentially of a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent.

Compositions, formulations and methods for treating or protecting skin are also provided. Provided herein are dermatological compositions designed to provide treatment and protection to the skin of a subject. In some embodiments, the dermatological composition includes a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, a ceramide, and an active agent. In other embodiments, the dermatological composition consists of a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, a ceramide, and an active agent. In other embodiments, the dermatological composition consists essentially of a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, a ceramide, and an active agent.

Also provided herein is a method of preventing or treating a vaginal condition in a subject, the method comprising administering to the subject a composition comprising a stable water-in-silicone emulsion, wherein the emulsion has a sterol concentration of from about 0.1 wt% to about 4 wt% based on the total weight of the emulsion. In some embodiments, the composition is administered into the vagina, onto the vulva and/or around the vulva, or any combination thereof.

In other examples, the methods described herein are used to prevent or treat vaginal disorders, including menopause, perimenopause, postmenopause, vaginal dryness, dyspareunia, bacterial infections, viral infections, or fungal infections.

In some embodiments, the methods described herein provide a therapeutically effective dose for up to 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, or 14 days. In addition, the methods comprise administering the composition every 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, or 14 days.

Also provided herein is a method of making a water-in-silicone emulsion comprising preparing an aqueous phase comprising water, a pH buffering system, at least one active or bioactive agent, and a preservative, and separately preparing a silicone phase comprising silicone oil (silicone oil), silicone gum (silicone gum), and sterol, fatty acid, tocopherol, and preservative, and adding the aqueous phase to the silicone phase and mixing the combined phases until a water-in-silicone emulsion is formed, wherein the silicone phase comprises about 20-80% by weight of the composition and the aqueous phase comprises about 20-80% by weight of the composition, based on the total weight of the composition. In some embodiments, the method further comprises adding the aqueous phase to the silicone phase under high shear mixing (e.g., wherein the high shear mixing uses a rotor-stator homogenizer).

Also disclosed herein are methods of providing vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject, comprising administering to the subject a vulvovaginal composition comprising, consisting of, or consisting essentially of: a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent.

Also disclosed is a method for treating and protecting the skin of a subject, the method comprising administering to the subject a dermatological composition comprising, consisting of, or consisting essentially of: a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, a ceramide, and an active agent.

Also provided are kits for producing a vulvovaginal composition to provide vulvovaginal symptom relief, treat an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protect the vulvovaginal anatomy in a subject.

Kits for producing dermatological compositions for treating and protecting the skin of a subject are also provided.

Drawings

The present invention will become more fully understood from the detailed description given below when taken in conjunction with the accompanying drawings, wherein:

fig. 1A-1B illustrate exemplary stable water-in-silicone (W/O) emulsions comprising emulsifiers, cell membrane fluidity enhancers, fatty acids, preservatives, bioactive agents, pH buffering systems, antioxidants, and tocopherols. Fig. 1A shows exemplary physicochemical orientations of emulsifiers, cell membrane fluidity enhancers, and fatty acid components, where only the emulsifiers stabilized the water and silicone interface. Fig. 1B illustrates a second exemplary physicochemical orientation of the emulsifier, cell membrane fluidity-enhancing agent, and fatty acid component, wherein the emulsifier, cell membrane fluidity-enhancing agent, and fatty acid cooperatively stabilize the water and silicone interface.

Fig. 2A-2B illustrate exemplary stable water-in-silicone (W/O) emulsions comprising emulsifiers, cell membrane fluidity enhancers, fatty acids, preservatives, bioactive agents, pH buffering systems, antioxidants, tocopherols, and active agents. Fig. 2A shows exemplary physicochemical orientations of emulsifiers, cell membrane fluidity enhancers, and fatty acid components, where only the emulsifiers stabilized the water and silicone interface. Fig. 2B illustrates a second exemplary physicochemical orientation of the emulsifier, cell membrane fluidity-enhancing agent, and fatty acid component, wherein the emulsifier, cell membrane fluidity-enhancing agent, and fatty acid cooperatively stabilize the water and silicone interface.

Fig. 3A-3C show optical imaging of formulation # 8. Fig. 3A is a macroscopic optical image of formulation #8 at day 1. Fig. 3B is an optical micrograph image of formulation #8 at day 1. Fig. 3C is an optical micrograph image of formulation #8 at day 6. The scale bar is 300 microns.

Fig. 4A-4C show optical imaging of formulation # 9. Fig. 4A is a macroscopic optical image of formulation #9 at day 1. Fig. 4B is an optical micrograph image of formulation #9 at day 1. Fig. 4C is an optical micrograph image of formulation #9 at day 31. The scale bar is 100 microns.

Fig. 5A-5C show optical imaging of formulation # 10. Fig. 5A is a macroscopic optical image of formulation #10 at day 1. Fig. 5B is an optical micrograph image of formulation #10 at day 1. Fig. 5C is an optical micrograph image of formulation #10 at day 14. The scale bar is 100 microns.

Fig. 6A-6E show optical imaging of formulations #13 and # 14. Fig. 6A is a macroscopic optical image of formulation #13 at day 1. Fig. 6B is an optical micrograph image of formulation #13 at day 1. Fig. 6C is a macroscopic optical image of formulation #14 at day 1. Fig. 6C is an optical micrograph image of formulation #14 at day 1. Fig. 6E is an optical image of formulation #14 showing phase separation. The scale bar is 100 microns.

Figures 7A-7D show graphs of flow stress scan analysis of formulation # 9. Fig. 7A is a flow stress scan of formulation #9 at 25 ℃, with viscosity plotted against shear rate. Fig. 7B is a flow stress scan of formulation #9 at 25 ℃, where viscosity is plotted against stress. Fig. 7C is a flow stress scan of formulation #9 at 37 ℃, with viscosity plotted against shear rate. Fig. 7D is a flow stress scan of formulation #9 at 37 ℃, where viscosity is plotted against stress.

Fig. 8A-8B show oscillation amplitude scans of formulation # 9. Figure 8A is an oscillation amplitude scan of formulation #9 at 25 ℃. Figure 8B is an oscillation amplitude scan of formulation #9 at 37 ℃.

Fig. 9A-9B show the oscillation frequency sweep for formulation # 9. Fig. 9A is an oscillation frequency sweep of formulation #9 at 25 ℃. Fig. 9B is an oscillation frequency sweep of formulation #9 at 37 ℃.

Figure 10 is a temperature sweep of formulation #9 with shaking between 20 ℃ and 40 ℃.

Detailed Description

Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the compositions, methods, and kits disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the compositions, methods, and kits specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present invention is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention.

Moreover, in the present disclosure, similarly named components of an embodiment typically have similar properties, and thus, in a particular embodiment, each property of each similarly named component is not necessarily fully addressed.

The compositions provided herein are stable emulsions in the form of relatively viscous, lubricious liquids, lotions, ointments, or creams. The composition is stable as an emulsion for a useful period and remains stable for up to about one week after application. The compositions can be used for a variety of purposes, as described herein, including for topical, rectal, and vulvovaginal administration. In addition, the composition may or may not be used with active and/or bioactive agents. More particularly, provided herein, inter alia, are compositions comprising a water-in-silicone (W/O) emulsion, wherein the sterol concentration of the emulsion is from about 0.1 wt% to about 4 wt% of the total weight of the composition. Also provided herein are methods of preventing or treating vulvovaginal and other disorders in a subject in need thereof (e.g., for rectal use, dermatological use, sunscreen, transdermal drug delivery, or ophthalmic use), including the application of the compositions (e.g., an emulsion comprising a sterol at a concentration of about 0.1% to about 4% by weight based on the total weight of the composition) and kits including the compositions and agents. While the disclosure generally refers to compositions for treating vulvovaginal indications, it will be appreciated that this is one of many exemplary uses for the compositions disclosed herein. One skilled in the art will appreciate that the compositions have uses beyond vulvovaginal applications as described herein.

Definition of

The following definitions are included for purposes of understanding the subject matter and for interpreting the appended patent claims. The abbreviations used herein have their conventional meaning in the chemical and biological arts.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide the skilled artisan with a general definition of many of the terms used in this disclosure: cambridge scientific and technical dictionary (Walker edition, 1988); genetics vocabulary, 5 th edition, r.rieger et al (eds.), Springer Verlag (1991); and Hale & Marham, the hatper-corins biological dictionary (1991). As used herein, the following terms have the meanings assigned to them hereinafter, unless otherwise specified.

As used herein, the term "or" should be understood to include the endpoints unless specifically stated or otherwise evident from the context. As used herein, the terms "a", "an" and "the" are to be construed as either singular or plural unless specifically stated otherwise or apparent from the context.

The term "about" when used in reference to a numerical range, threshold or specific value, is used to indicate that the recited value differs from the recited value by at most 25%. Since many of the numerical values used herein are determined experimentally, those skilled in the art will appreciate that such determinations can, and often do, vary between different experiments. Due to such inherent variations, the values used herein should not be considered to be unduly limiting. The term "about" is used to encompass variations from the stated value of ± 25% or less, 20% or less, 10% or less, 5% or less, 1% or less, 0.5% or less, or 0.1% or less. About 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. All numerical values provided herein are modified by the term "about," unless the context clearly dictates otherwise.

As used herein, "administered to the subject" and similar terms refer to the process of introducing, instilling, implanting, administering, or applying the vulvovaginal composition to a subject such that target cells, tissues, mucosa, or portions of the subject's body are contacted with the composition.

As used herein, the term "administering" refers to any mode of, for example, transferring, delivering, introducing, or transporting a formulation to a subject in need of treatment for a disease or disorder. Such modes include, but are not limited to, oral, topical, intravenous, vaginal, mucosal, intraperitoneal, intramuscular, intradermal, intranasal, and subcutaneous administration.

Ranges provided herein are to be understood as shorthand for all values within the range. For example, a range of 1 to 50 should be understood to include any number, combination of numbers, or sub-range of numbers that: 1.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all intermediate fractional values between the above integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from any end point of the range are specifically contemplated. For example, nested sub-ranges of the exemplary range of 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in another direction.

As used herein, the term "analog" refers to a compound that is structurally similar to another compound but slightly different in composition (e.g., one atom is replaced with an atom of a different element, or one functional group is replaced with another functional group in the presence of a particular functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but that differs from a reference compound in structure or origin. As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

As used herein, the term "emulsion" refers to a liquefied mixture comprising at least two distinguishable substances (or "phases") that are not readily mixed and dissolved together. As used herein, "emulsion" includes a "continuous" phase (or "matrix") in which discrete droplets, bubbles, and/or particles of other phases or substances are retained. Thus, the term emulsion may refer to a foam comprising gas bubbles suspended in a liquid continuous phase, an emulsion in which droplets of a first liquid are dispersed throughout the continuous phase comprising a second liquid immiscible with the first liquid, and a continuous liquid phase dispersed throughout solid particles. As used herein, the term "emulsion" includes a continuous liquid phase distributed throughout the gas bubbles, a continuous liquid phase distributed throughout the solid particles (e.g., solid catalyst), a first liquid continuous phase distributed throughout droplets of a second liquid that is substantially insoluble in the continuous phase, and a liquid phase distributed throughout any one or combination of the solid particles, immiscible liquid droplets, and gas bubbles. Thus, depending on the nature of the materials selected for combination, the emulsion may in some cases be present as a homogeneous mixture (e.g., liquid/liquid phase), or as a heterogeneous mixture (e.g., gas/liquid, solid/liquid, or gas/solid/liquid).

As used herein, the term "stable" or "stability" refers to a water-in-silicone emulsion as described herein. Stability may refer to the ability of an emulsion to resist changes in its properties over time under appropriate storage conditions. For example, stability can generally refer to a composition that does not phase separate when stored at room temperature (e.g., between about 20 ℃ and 25 ℃) for at least 1 month, or at room temperature (e.g., between about 20 ℃ and 25 ℃) for at least 12 months in a final package. Other exemplary characteristics of stability include the stability of the final packaged product with respect to the expiration date. For example, stability may mean that the product ingredient (e.g., active or inactive ingredient) has not changed, degraded, or decomposed, that the product characteristics defined in its certificate of analysis (e.g., emulsion stability, zero shear rate viscosity) have not changed, that the product preservation system remains functional, or any combination thereof. The stability of the emulsion can be characterized using techniques described herein including, for example, light scattering, optical microscopy, freeze-thaw cycling, centrifugation, and rheology.

Further, as used herein, "stable" or "stability" refers to a composition comprising a water-in-silicone emulsion as described herein (e.g., a composition comprising an emulsion and other agents as described herein; "stable composition"). For example, the composition can include one or more carriers and/or other materials suitable for the composition to contain a plurality of active agents (e.g., active ingredients), and wherein the active agents will remain stable for an extended period of time as described herein. Additionally, the active agent according to some embodiments should be stable in the compositions described herein for a period of time.

The term "stable," as used in the context of the compositions of the present disclosure, refers to physical and chemical stability. Chemical stability refers to chemical changes to the active or inactive agent itself (e.g., degradation of the agent, oxidation of the agent). In embodiments of the present disclosure, the storage or shelf life of the composition is a measure of chemical stability. Physical stability relates to mechanical properties, physical state (e.g. crystallinity, crystal structure) and active agent (or drug) release properties.

Stability is measured after storing the compositions of the present disclosure at a temperature of about 25 ℃/60% RH to about 40 ℃/75% RH and Relative Humidity (RH) conditions. Accelerated and real-time testing of the shelf life of the composition was performed to confirm shelf life and set product expiration. In addition, the shelf life of the compositions was also tested under the expected packaging conditions.

The stability of the composition is understood to mean that the homogeneous appearance of the composition is maintained at 25 ℃ for at least 6 months without phase separation, precipitation of particles or flocculation. In other embodiments, the composition is stable at 25 ℃ for at least 9 months, at least 12 months, at least 18 months, or at least 24 months.

As used herein, the term "cream" may refer to a thick (high zero shear rate viscosity) liquid, semi-liquid, or semi-solid formulation useful for treating a disease, syndrome, or condition (i.e., a vulvovaginal disease, syndrome, or condition).

As used herein, the term "lotion" can refer to a liquid, semi-liquid, or semi-solid formulation of moderate consistency (moderate zero shear rate viscosity) that can be used to treat a disease, syndrome, or condition (i.e., a vulvovaginal disease, syndrome, or condition).

As used herein, the term "ointment" may refer to a high viscosity liquid or semi-liquid formulation useful for treating a disease, syndrome, or condition (i.e., a vulvovaginal disease, syndrome, or condition).

As used herein, "liquid" is a dosage form consisting of a composition in its liquid state. The liquid is pourable; it will flow at room temperature and conform to its container. The liquid exhibits newtonian or pseudoplastic flow behavior. In some embodiments, a "semi-liquid" or "semi-solid" as used herein may have the properties of both a liquid and another formulation (i.e., a dispersion, a suspension, an emulsion, a lotion cream, etc.).

As used herein, the term "moisturization" refers to an improvement in the hydration of a surface such that the water binding capacity of the surface is increased. The term "moisturization" or derivatives thereof refers to the conversion or increase in the water content of the surface of an object.

As used herein, "zero shear rate viscosity" refers to the resistance to flow of a fluid or semi-solid when the shear rate is close to zero.

In the above description and in the claims, phrases such as "at least one" or "one or more" may appear to precede a list of elements or features. The term "and/or" may also be present in a list of two or more elements or features. Such phrases are intended to mean any one of the listed elements or features alone, or in combination with any of the other described elements or features, unless implicitly or explicitly contradicted by context in which it is used. For example, the phrases "at least one of a and B", "one or more of a and B", and "a and/or B" each mean "a alone, B alone, or a and B together". Similar explanations apply to lists containing three or more items. For example, the phrases "at least one of A, B and C", "one or more of A, B and C", and "A, B and/or C" are each intended to mean "a alone, B alone, C alone, a and B together, a and C together, B and C together, or a and B and C together". Additionally, use of the term "based on" in the foregoing and in the claims is intended to mean "based, at least in part, on" such that unrecited features or elements are also permitted.

"ameliorating" means reducing, inhibiting, attenuating, reducing, arresting or stabilizing the development or progression of a disease or disorder, such as a pseudo-allergic-type reaction.

The terms "subject," "patient," "individual," and the like, as used herein, are not intended to be limiting and may be generally interchangeable. Individuals described as "subjects," "patients," "individuals," etc., do not necessarily have a given disease, but may simply seek medical advice. The terms "subject", "patient", "individual" and the like as used herein include all members of the kingdom animalia that may be afflicted with the disease. In certain aspects, the subject is a mammal, and in certain aspects, the subject is a human.

When the term "surrounding" is used with reference to the site of administration of the vulvovaginal composition, it should be understood by those skilled in the art to mean administration to the anatomical region of interest within the limits of conventional practice procedures. For example, administration "around" an anatomical site of interest refers to a site that is not directly within or on the site, but is sufficiently close to the site to provide a physiologically or therapeutically relevant effect thereon. One of ordinary skill in the art can readily determine the maximum distance from a given anatomical site that will be sufficient to provide a physiological or therapeutically relevant effect using a vulvovaginal composition according to the present disclosure.

"pharmaceutically acceptable" refers to those properties and substances that are acceptable to the patient from a pharmacological/toxicological standpoint, and acceptable to the manufacturing pharmaceutical chemist from a physical/chemical standpoint in terms of composition, formulation, stability, patient acceptance and bioavailability.

"pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids in the administration of an active agent to a subject, or aids in absorption by a subject, or improves the stability or other properties of an active agent, and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Unless indicated to the contrary, the terms "active agent", "active ingredient", "therapeutically active agent", "therapeutic agent", "biologically active agent" and the like are used synonymously. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, ringer's lactate, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (e.g., ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, pigments, and the like. These preparations can be sterilized and, if desired, mixed with adjuvants which do not deleteriously react with the compounds of the invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and/or aromatic substances, etc. One skilled in the art will recognize that other pharmaceutical excipients may be used in the present invention.

As used herein, the terms "active agent", "active ingredient", "therapeutically active agent", "therapeutic agent", "biologically active agent" refer to "having biological activity", e.g., biochemical, pharmacological or therapeutic activity. In some embodiments, the biological activity is to provide symptomatic relief, treat an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protect the vulvovaginal anatomy in a subject. In certain embodiments, the biological activity is an effect on enhancing skin function and/or on skin homeostasis. In other examples, the biological activity is an enhancement of the rectal system and anatomical structures. In other examples, the biological activity is enhancement of ophthalmic systems and anatomical structures. Also, as provided, the biological activity is for treating or preventing sun damage (e.g., sun cream).

In certain embodiments, the biological activity is, but is not limited to, analgesia, antifungal, antiviral, anti-infective, anti-inflammatory, anti-tumor, immunostimulatory, immunosuppressive, immunomodulatory, endocrine regulating, cell viability enhancing, cell membrane fluidization, antioxidant, oxygen carrier, contraception, cell recruitment, cell attachment, angiogenesis, wound healing activity, host stem or progenitor cell mobilization, cell proliferation, stimulation of cell migration to the site of injury, improvement of cell and tissue fibrosis, or any combination thereof.

A "therapeutically effective dose" refers to an amount of a composition as described herein that is effective to achieve a particular physiological, biological, or therapeutic result, such as, but not limited to, the physiological, biological, or therapeutic results disclosed, described, or exemplified herein. Such physiological, biological, or therapeutic results include, but are not limited to, restoring pH, providing lubrication, promoting healthy flora, or eliminating infection (e.g., restoring pH to the vagina, providing lubrication to the vagina, promoting healthy flora, eliminating infection, or providing contraceptive measures). The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the subject. Such results may include, but are not limited to, providing symptomatic relief, treating the underlying pathophysiology or prophylactically protecting the vagina, as determined by any method suitable in the art.

The term "treatment" refers to any success or sign of success in: alleviating or ameliorating the infection, pathology, or condition, including any objective or subjective parameter, such as diminishing, eliminating, alleviating a symptom, or making the patient more tolerant to the infection, pathology, or condition, slowing the disease process, making the condition less debilitating, or improving the physical or mental well-being of the subject. Treatment may be assessed by objective or subjective parameters including the results of physical examination.

As used herein, "prophylactically protect" refers to treating a disorder (e.g., a vulvar or vaginal disorder) in a prophylactic manner.

As used herein, "incorporated" means that the emulsifier, cell membrane fluidity enhancer, fatty acid, preservative, and at least one of a bioactive agent, pH buffering system, viscosity enhancer, antioxidant, tocopherol, ceramide, active agent, or any combination thereof, is at least partially covered, contained, dispersed, distributed, encapsulated, or embedded with the water and silicone emulsion. Depending on the type of ingredient, excipient, or agent, the ingredient, excipient, or agent may be in the aqueous phase, silicone phase, or both.

It is contemplated that each embodiment disclosed herein may be applicable to each and every other disclosed embodiment. Accordingly, all combinations of the various elements described herein are within the scope of the invention.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All published foreign patents and patent applications cited herein are incorporated herein by reference. The Genbank and NCBI submissions indicated by the accession numbers cited herein are incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated by reference. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Composition comprising a metal oxide and a metal oxide

The present disclosure provides compositions comprising a water-in-silicone (W/O) emulsion containing a cell membrane fluidity enhancer. In some embodiments, the concentration of the cell membrane fluidity-enhancing agent is from about 0.1% to about 4% by weight of the total weight of the composition.

In some embodiments, the compositions disclosed herein are stable water and silicone emulsions, including but not limited to creams, lotions, ointments, moisturizers, or personal lubricants.

Suitable water and silicone emulsions include, but are not limited to, water-in-silicone (W/O), silicone-in-water (O/W), or water-in-silicone-in-water (W/O/W). In some embodiments, the water and silicone emulsion is a W/O emulsion. In a preferred example, a suitable emulsion is a water-in-silicone (W/O) emulsion. For example, without intending to be limiting, the W/O emulsion may have an aqueous phase comprising up to 50 wt% (inclusive) water and a silicone phase comprising 20 wt% to 95 wt% (inclusive) silicone.

In some examples, the water-in-silicone emulsion comprises a silicone phase, wherein the silicone phase comprises a silicone oil, a silicone wax, a silicone gum, or any combination thereof.

When producing a water-in-silicone emulsion, a variety of silicone oils, silicone gums, or silicone waxes may be selected from those known in the art. For the purposes of this disclosure, suitable silicone oils include, but are not limited to, polydimethylsiloxane, cyclomethicone, octylmethicone, cyclopentasiloxane, cyclohexasiloxane, or any combination thereof. For the purposes of this disclosure, suitable silicone gums include, but are not limited to, dimethiconol. For purposes of this disclosure, suitable silicone waxes include, but are not limited to, stearyl dimethicone.

In some embodiments, the dispersant phase (e.g., the phase used to disperse the small particles or droplets) may be stabilized to produce a stable emulsion. Exemplary agents for stabilizing to produce a stable emulsion include, but are not limited to, emulsifiers and co-emulsifiers. Suitable emulsifying and co-emulsifying agents for stabilizing the resulting emulsion (e.g., liquid-liquid droplets) include, but are not limited to, sterols, sterol derivatives, cholesterol derivatives, glyceryl stearate, glyceryl monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene monolaurate, polyoxyethylene monostearate, polyoxyethylene monopalmitate, polyoxyethylene monooleate, lecithin, PEG/PPG-18/18 dimethicone, cetyl PEG/PPG-10/1 dimethicone, dimethicone copolyol, octyldodecanol, poly (vinyl alcohol), pluronic, poloxamer, carbomer, isopropyl myristate, or any combination thereof.

In some examples, the compositions described herein can comprise one or more (e.g., at least one) cell membrane fluidity-enhancing agent(s) to achieve (e.g., promote) increased cell membrane fluidity, increased cell permeation, increased absorption of a desired ingredient, excipient, or agent, increased lubrication and moisturization, or any combination thereof. Suitable cell membrane fluidity enhancers include, but are not limited to, sterols (e.g., steroidal alcohols). Sterols are a subclass of steroids, with a hydroxyl group at the 3-position of the a ring. They are amphiphilic lipids synthesized from acetyl-coa. The chemical structure of sterols is shown below:

one or more cell membrane fluidity-enhancing agents may be incorporated into the emulsion. In some embodiments, the one or more cell membrane fluidity-enhancing agents are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more cell membrane fluidity-enhancing agents are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more cell membrane fluidity-enhancing agents are incorporated into both the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 0.1% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 0.25% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 0.5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 1% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 1.5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 2% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to constitute up to 2.5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 3% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to constitute up to 3.5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to comprise up to 4% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to constitute up to 4.5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to constitute up to 5% by weight (inclusive) of the composition. In some embodiments, the cell membrane fluidity-enhancing agent can be formulated to constitute up to 5.5% by weight (inclusive) of the composition.

Throughout the present disclosure, the phrase "cell membrane fluidity-enhancing agent" may refer to more than one cell membrane fluidity-enhancing agent, provided that more than one such agent is present in the composition. For example, when only one cell membrane fluidity-enhancing agent is incorporated in the emulsion, reference to "50% by weight of the cell membrane fluidity-enhancing agent" means that 50% of a single cell membrane fluidity-enhancing agent is present. When more than one cell membrane fluidity-enhancing agent is incorporated in the emulsion, the phrase "50% by weight of the cell membrane fluidity-enhancing agent" means that 50% of the total supplement (supplement) of the cell membrane fluidity-enhancing agent is incorporated into the emulsion. Thus, if the composition comprises 1mg of a first cell membrane fluidity-enhancing agent and 1mg of a second cell membrane fluidity-enhancing agent, "50% by weight of the cell membrane fluidity-enhancing agent" can mean that 50% of a total supplement of 2mg of the cell membrane fluidity-enhancing agent is incorporated into the emulsion.

The term "sterol" as used herein may refer to natural or synthetic plant or animal sterols. Exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof. Other sterols include diosgenin, stigmastanol, tigogenin, alpha-sitosterol, beta-sitosterol, stigmasterol, ergosterol, campesterol, oleic acid, soyasapogenol (e.g., soyasapogenol A or soyasapogenol B), protosapogenin, and protopanaxadiol. In some embodiments, the sterol is cholesterol. When the sterol is cholesterol, its physicochemical and biochemical properties make it uniquely and simultaneously useful as a cell membrane fluidity enhancer, as an emulsifier that plays a key role in stabilizing the water-in-silicone droplet interface, and as a bioactive agent.

In other examples, the compositions described herein can comprise one or more (e.g., at least one) fatty acids. Fatty acids are carboxylic acids with long aliphatic chains, which are saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of even number of carbon atoms, for example 4 to 28 carbon atoms. In some embodiments, the fatty acid may promote cellular interactions with the preparation. Suitable fatty acids include, but are not limited to, caprylic acid, lauric acid, myristic acid, decenoic acid, lauric acid, myristoleic acid, palmitoleic acid, oleic acid, stearic acid, palmitic acid, linoleic acid, arachidonic acid, stearidonic acid, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or any combination thereof.

The one or more fatty acids may be incorporated into the emulsion. In some embodiments, the one or more fatty acids are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more fatty acids are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more fatty acids are incorporated into both the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the fatty acid may be formulated up to 0.1% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 0.25% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 0.5% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated to comprise up to 1% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 1.5% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated to comprise up to 2% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 2.5% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated to comprise up to 3% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 4% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 5% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 6% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 8% by weight (inclusive) of the composition. In some embodiments, the fatty acid may be formulated up to 10% by weight (inclusive) of the composition.

Throughout the present disclosure, the phrase "fatty acid" may refer to more than one fatty acid, provided that more than one such agent is present in the composition. For example, when only one fatty acid is incorporated in the emulsion, reference to "50% by weight fatty acid" means that 50% of that single fatty acid is present. When more than one fatty acid is incorporated in the emulsion, the phrase "50% by weight fatty acid" refers to 50% of the total supplement of fatty acids being incorporated into the emulsion. Thus, if the composition comprises 1mg of the first fatty acid and 1mg of the second fatty acid, "50 wt% fatty acids" may mean that 50% of the total supplement of 2mg fatty acids is incorporated into the emulsion.

In other examples, the phrase "fatty acid" may refer to more than one fatty acid derivative, provided that more than one such agent is present in the composition. Suitable fatty acid derivatives include, but are not limited to, caprylic acid derivatives, lauric acid derivatives, myristic acid derivatives, decenoic acid derivatives, lauric acid derivatives, myristoleic acid derivatives, palmitoleic acid derivatives, oleic acid derivatives, stearic acid derivatives, palmitic acid derivatives, linoleic acid derivatives, arachidonic acid derivatives, stearidonic acid derivatives, or any combination thereof.

In some embodiments, the disclosed compositions may comprise one or more preservatives. Preservatives, for example, can be used to control the stability and shelf life of the formulation, wherein stability and shelf life are assessed by methods known to those skilled in the art. Suitable preservatives include, but are not limited to, sorbic acid, potassium sorbate, boric acid, sodium borate, benzoic acid, sodium benzoate, benzalkonium chloride, benzethonium chloride, EDTA, parabens, or any combination thereof.

The one or more preservatives may be incorporated into a composition comprising an emulsion. In some embodiments, the one or more preservatives are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more preservatives are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more preservatives are incorporated into both the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the preservative may be formulated to comprise up to 0.01% by weight (inclusive) of the emulsion. In some embodiments, preservatives can be formulated in amounts up to 0.025 wt% (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 0.05% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 0.1% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 0.2% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 0.5% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 1% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 2% by weight (inclusive) of the composition. In some embodiments, the preservative may be formulated to comprise up to 4% by weight (inclusive) of the composition.

Throughout the present disclosure, the phrase "preservative" may refer to more than one preservative, provided that more than one such agent is present in the composition. For example, when only one preservative is incorporated in the emulsion, reference to "50% by weight of the preservative" means that 50% of the single preservative is present. When more than one preservative is incorporated in the emulsion, the phrase "50% by weight of the preservative" means that 50% of the total supplement of preservatives is incorporated into the emulsion. Thus, if the composition comprises 1mg of the first preservative and 1mg of the second preservative, "50% by weight of preservatives" may mean that 50% of the total supplement of 2mg of preservatives is incorporated into the emulsion.

The disclosed compositions may comprise a bioactive agent. In some embodiments, the bioactive agent can affect the biochemistry or cellular physiology of a desired condition (e.g., vulvar or vaginal anatomy). Suitable bioactive agents include, but are not limited to, glycogen, cholesterol, lactic acid, lactate, tocopherol, or any combination thereof. Additional bioactive agents are described in detail below.

Throughout the present disclosure, the phrase "bioactive agent" may refer to more than one bioactive agent, provided that more than one such agent is present in the composition. For example, one or more bioactive agents may be incorporated into the emulsion. In some embodiments, the one or more bioactive agents are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more bioactive agents are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more bioactive agents are incorporated into both the aqueous phase and the silicone phase of the emulsion.

In some examples, the bioactive agent can be used in an amount of about 0.01 wt% to about 100 wt%, based on the total weight of the composition. In other examples, the active agent can be used in an amount of about 0.01% to about 90%, about 0.01% to about 80%, about 0.01% to about 70%, about 0.01% to about 60%, about 0.01% to about 50%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 1%, or about 0.01% to about 0.1% by weight of the composition.

In some embodiments, the disclosed compositions may comprise one or more pH buffering systems. For example, a pH buffering system may be capable of restoring physiological pH (e.g., the pH of the vagina). Suitable pH buffering systems include, but are not limited to, lactic acid and lactate. In some embodiments, the pH buffering system is lactic acid and sodium lactate. In other embodiments, the pH buffering system is lactic acid and calcium lactate. In addition, the composition (e.g., vulvovaginal composition) can have a pH of 3.8, and the pH buffering system can have a buffering capacity in the range of 3.5-4.2.

In some examples, the present disclosure includes compositions (e.g., emulsions) having a pH buffering system comprising one or more pH adjusting agents. The pH adjusting agent may be, for example, sodium hydroxide, hydrochloric acid, citric acid, malic acid, tartaric acid, acetic acid, phosphoric acid, maleic acid, glycine, sodium lactate, lactic acid, sodium citrate, ascorbic acid, sodium acetate, acetic acid, sodium bicarbonate, sodium carbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphate, tris (hydroxymethyl) aminomethane, histidine hydrochloride, or any combination thereof.

Compounds useful as pH adjusters include, but are not limited to, boric acid, sodium borate, sodium phosphate (including mono, di, tri basic phosphates and mixtures thereof). Any other physiologically relevant buffer can be used to stabilize the pH level of the composition by conferring an approved physiological pH value to the drug. Since the buffers are merely exemplary, and such buffers are well known in the art, one skilled in the art will be able to select suitable buffers for use in the compositions of the present disclosure.

In some examples, the pH of the formulation is from about 2 to about 9. In other examples, the pH is in the range of about 3 to 9, or about 4 to 9, or about 5 to 9, or about 6 to 9, or about 7 to 9, or about 8 to 9. In other examples, the pH is in the range of about 3 to 8, or about 4 to 8, or about 5 to 8, or about 6 to 8, or about 7 to 8. In other examples, the pH is in the range of about 3 to 7, or about 4 to 7, or about 5 to 7, or about 6 to 7. In other examples, the pH is in the range of about 3 to 6, or about 4 to 6, or about 5 to 6.

Also as described herein, the disclosed compositions may include one or more viscosity enhancing agents, for example, to achieve desired mechanical properties. In some examples, the mechanical properties can be measured by rheological methods known to those skilled in the art. Suitable viscosity enhancing agents include, but are not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hyaluronic acid, sodium hyaluronate, carbomer, carbopol, poly (acrylic acid), polycarbophil, guar gum, xanthan gum, or any combination thereof.

In some embodiments, the zero shear rate viscosity of the stable water-in-silicone emulsion may be between 100Pa-s and 1000 kPa-s. To determine the zero shear rate viscosity of the emulsion, suitable characterization methods include, but are not limited to, rheology and viscosity methods.

Throughout the present disclosure, the phrase "viscosity enhancing agent" may refer to more than one viscosity enhancing agent, provided that more than one such agent is present in the composition. For example, one or more viscosity enhancing agents may be incorporated into the emulsion. In some embodiments, the one or more viscosity enhancing agents are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more viscosity enhancing agents are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more viscosity enhancing agents are incorporated into both the aqueous phase and the silicone phase of the emulsion.

The disclosed compositions may include one or more antioxidants to enhance formulation stability, affect cellular physiology, or any combination thereof. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium ascorbate, polyphenols, or any combination thereof.

Throughout the present disclosure, the phrase "antioxidant" may refer to more than one antioxidant, provided that more than one such agent is present in the composition. For example, one or more antioxidants can be incorporated into the emulsion. In some embodiments, the one or more antioxidants are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more antioxidants are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more antioxidants are incorporated into both the aqueous phase and the silicone phase of the emulsion.

The disclosed compositions may comprise one or more tocopherols to affect cell physiology, lubrication, or any combination thereof. Suitable tocopherols include, but are not limited to, alpha-tocopherol, vitamin E-TPGS, tocopherol acetate, or any combination thereof. Tocopherols (e.g., vitamin E) can provide lubricity, antioxidant properties, or any combination thereof.

Throughout the present disclosure, the phrase "tocopherol" may refer to more than one tocopherol, provided that more than one such agent is present in the composition. For example, one or more tocopherols may be incorporated into the emulsion. In some embodiments, the one or more tocopherols are incorporated into the aqueous phase of an emulsion. In other embodiments, the one or more tocopherols are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more tocopherols are incorporated into both the aqueous phase and the silicone phase of the emulsion.

The disclosed compositions may comprise one or more active agents to provide symptomatic relief, treat an underlying pathophysiology or infection, or prophylactically protect a subject's anatomy (e.g., vagina). Suitable classes of active agents include, but are not limited to, antifungal agents, antibiotics, spermicidal agents, estrogens, estrogen derivatives, progesterone derivatives, estrogen precursors, steroids, anti-inflammatory agents, antiviral/antiretroviral agents (e.g., CCR5 antagonists, Nucleoside Reverse Transcriptase Inhibitors) (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease Inhibitors (PIs), fusion inhibitors, integrase inhibitors, post-attachment inhibitors, pharmacokinetic enhancers), or any combination thereof. Suitable active agents include, but are not limited to, miconazole, metronidazole, clotrimazole, estradiol, prasterone, nonoxynol-9, or any combination thereof. In some embodiments, the active agent is miconazole. In some embodiments, the active agent is metronidazole. In some embodiments, the active agent is clotrimazole. In some embodiments, the active agent is estradiol. In some embodiments, the active agent is prasterone. In some embodiments, the active agent is nonoxynol-9.

The disclosed compositions may comprise one or more active agents to treat or protect the skin of a subject. Suitable classes of active agents include, but are not limited to, antibiotics, antimicrobials, antifungals, disinfectants, local anesthetics, analgesics, anti-inflammatory agents, immunosuppressive agents, steroids, corticosteroids, calcineurin inhibitors, PDE4 inhibitors, salicylic acid, retinoic acid, antihistamines, benzoyl peroxide, nanocrystalline silver, or any combination thereof.

Exemplary antibiotics include, but are not limited to, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanic acid and levofloxacin. Other antibiotics include micacein, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin (B), geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cephradine, cefapirin, cephalothin, cephalexin, cefaclor, cefoxitin, cefotetan, cefamandole, roxithromycin, telithromycin, spiramycin, fidaxomicin, furazolidone, furadar (B), rizamide, bosizuli (Posizoli), lefludizide, tedizole, ampicillin, azlocillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin G, penicillin V, piperacillin, penicillin G, temocillin, ticarcillin, ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gamifloxacin, levofloxacin, norfloxacin, ofloxacin, trovafloxacin, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, calicheamicin, cyclopropylamine pyrazinamide, rifampin, rifabutin, rifapentin, streptomycin, metronidazole and mupirocin.

Exemplary antimicrobial agents include, but are not limited to, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanic acid, and levofloxacin.

Exemplary antifungal agents include, but are not limited to, miconazole, clotrimazole, amphotericin B, ketoconazole, fluconazole, isaconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and flucytosine.

Exemplary disinfectants include ethanol, sodium hypochlorite, chlorhexidine, hexachlorophene, povidone iodine, sodium hypochlorite, benzethonium chloride, triclosan, sodium chloride oxide, benzalkonium chloride and silver nitrate.

Exemplary local anesthetics include amethocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, tetracaine, bendinecarin, chloroprocaine, cinchocaine (INN), ***e, cyclomethiocaine, dibucaine, deparaffin, dicaine, ***e, etidocaine, hexylcaine, fomocaine, tropicaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, m-butoxycaine, nitaracaine, o-caine, otacaine (eticaine), oxybuprocaine, p-ethoxycaine, phenanthrocaine, perocaine, perlidocaine, pramoxine, prilocaine, procaine, procainamide, proparacaine, pyrrole caine, quinicaine (INN), ropivacaine, trimecaine, tetracaine, tropicaine and tolaracaine.

Exemplary analgesics include codeine, fentanyl, hydrocodone (Hysingla, Zohyd, hydrocodone/acetaminophen (Lorcet, Lortab, Norco, Vicodin), hydromorphone (dilaudd, Exalgo), meperidine (Demerol), methadone (Dolophine, Methhadose), morphine (Kadian, MS Contin, Morphabond), oxycodone (OxyContin, Oxaydo), oxycodone and acetaminophen (Percocet, Roxicet) and oxycodone and naloxone.

Exemplary anti-inflammatory agents include celecoxib (Celebrex), diclofenac (Cambia, Cataflam, Voltaren-XR, Zipsor, zorvelex), difluorac (Dolobid), etodolac (Lodine), ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen (active ketoprofen, ketorolac, nabumetone naproxen (Aleve, Anaprox, naperan, naproxen), oxaprozin (Daypro), piroxicam (Feldene), salsalate, sulindac, and tolmetin.

Exemplary immunosuppressive agents include corticosteroids (e.g., prednisone (Delosone, Orasone), budesonide (Entocort EC), prednisolone and (Millipred)), Janus kinase inhibitors (e.g., tofacitinib (Xeljanz)), calcineurin inhibitors, such as cyclosporine (Neoral, Sandimun, SangCya) and tacrolimus (AstagrafL, Envarsus XR, Prograf), mTOR inhibitors (e.g., sirolimus (Rapamone) and everolimus (Afinitor, Zorres), IMDH inhibitors, such as azathioprin (Azan, Imuran), leflunomide (Arava) and phenolate (CellCept, Myforic), biologicals, such as, e (Orencia), adalimumab (adalimumab), Humulin (Kineret), Cixacitabine (Cixacitab), Rituzumab (Rituzumab), Eisenia (Tyrosigliomab (Rituzumab), Eisentexib (Rentux (Rituzumab), secukinumab (Cosentyx), tositumumab (actemma), ustekumab (stellara), vedolizumab (Entyvio) and monoclonal antibodies, such as basiliximab (simulent), daclizumab (Zinbryta) and molobuzumab (Orthoclone OKT 3).

Exemplary calcineurin inhibitors include astagraf XL, cyclosporine ophthalmic, Elidel, Envarsus XR, Gengraf, Hecoria, Neoral, pimecrolimus, pleconus (Prograf), protetil (Protopic), ritonas (Restasis), sandimmine (Sandimmune), tacrolimus, and tacrolimus ointment.

Exemplary phosphodiesterase 4(PDE4) inhibitors include aldibendane, aminophylline, anhydroaminophylline, dapsone, apremilast, arotheophylline, Atizoram, phenyalanine, bemaline hydrochloride, bemoradan, palafenamic prefrom (Benafentrine), bravadipine (Bucladesene), Buflomedil (Buflomedil), bufeliron (Buquineran), CC-1088, carbafuran (Carbazeran), katrinast (Catalast), cilomilst (Cilomilast), Cilostamide (Cilosamide), Cilostazol (Cilostazol), siphylline (Cipamfylline), Crisabolole, Daxalipram, Denbufylline (Dinbufylline), dimafylline (Dimafylline), theophylline (Dinopaline), theophylline (Dirofylline), theophylline (Deltayline), doxyline (Fluoroline), etoposine (Fluoroline (Etaflorine), etorphine (Fluoroline (Etaflorine), Etaflorine (Fluoroline), furalatezine (Furafylline), fenamidone (imazadan), fenamidone hydrochloride, amrinone lactate, isobutyltheophylline, Lirimilast, lisofepotamine, lomiphylline, medoxolone, medoxine, mefenofylline, milrinone lactate, mopiprone, nanrinone, nestheophylline, nifolizone, ogelist (ogemeilast), ogelist sodium, olprinone, oxogrelate, choline, papaverine hydrochloride, papaverine sulfate, paroxetine, pellicone hydrochloride, pentiteine, pentoxifylline, hexetidine, petylline, pirimidyl, meperidine, pimelandine, pimozolone, propiophenone, propiverine, hydroxypropylmafelinine, ziprinone, quintillodone, quintiazeine, teflufenacetone, tezomib, troxacillin, trospit, trospide, trospilate, vesnarinone and zadavvilin.

The disclosed compositions may comprise one or more active agents to provide symptom relief or to treat the underlying pathophysiology, or to protect the anatomy of the subject (e.g., rectum). Suitable classes of active agents include, but are not limited to, vasoconstrictors, anti-inflammatory agents, steroids, local anesthetics, alpha-adrenergic receptor agonists, botulinum toxin a, calcium channel inhibitors, nitrates, or any combination thereof.

One or more active agents may be incorporated into the emulsion. In some embodiments, the one or more active agents are incorporated into the aqueous phase of the emulsion. In other embodiments, the one or more active agents are incorporated into the silicone phase of the emulsion. In other embodiments, the one or more active agents are incorporated into both the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the active agent may be formulated to be present in amounts typical for such formulations. For example, the formulation may be formulated to comprise up to 0.01% by weight (inclusive) of the composition. In some embodiments, the active agent can be formulated to comprise up to 0.025 wt% (inclusive) of the composition. In some embodiments, the active agent may be formulated up to 0.05% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 0.1% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 0.2% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 0.5% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 1% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 2% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 4% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 6% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 8% by weight (inclusive) of the composition. In some embodiments, the active agent may be formulated to comprise up to 10% by weight (inclusive) of the composition.

Throughout the present disclosure, the phrase "active agent" may refer to more than one active agent, provided that more than one such agent is present in the composition. For example, when only one active agent is incorporated in the emulsion, reference to "50% active agent by weight" means that 50% of the single active agent is present. When more than one active agent is incorporated into the emulsion, the phrase "50% active agent by weight" refers to 50% of the total supplement of active agent being incorporated into the emulsion. Thus, if the composition comprises 1mg of the first active agent and 1mg of the second active agent, "50% by weight of active agent" may mean that 50% of the total supplement of 2mg of active agent is incorporated into the emulsion.

The compositions of the present invention may contain a safe and effective amount of conditioning agents such as humectants, emollients, moisturizers and skin conditioning agents. A wide variety of these materials may be used and may be present at levels of from about 0.01% to about 80%, more preferably from about 0.1% to about 25%, still more preferably from about 0.5% to about 10% of the composition. The exact level (%) of moisturizer, emollient, humectant and conditioner to be used in the composition will depend on the moisturizer, emollient, humectant and conditioner used, as the efficacy of such formulations vary widely.

Moisturizers are ingredients that help maintain the moisture level of the skin. Wetting agents include, for example, polyols, water-soluble alkoxylated nonionic polymers, and mixtures thereof. Polyols useful in the present invention include the above-described polyhydric alcohols and glycerol, hexylene glycol, ethoxylated glucose, 1, 2-hexanediol, dipropylene glycol, trehalose, diglycerol, maltitol, maltose, glucose, fructose, sodium chondroitin sulfate, sodium hyaluronate, sodium adenosine phosphate, sodium lactate, pyrrolidone carbonate, glucosamine, cyclodextrin, and mixtures thereof. Water-soluble alkoxylated nonionic polymers useful herein include polyethylene glycols and polypropylene glycols having a molecular weight of up to about 1000, such as those having the CTFA names PEG-200, PEG-400, PEG-600, PEG-1000, and mixtures thereof. Other humectants include acetyl arginine, algae extract, aloe barbadensis leaf extract, 2, 3-butylene glycol, chitosan lauroyl glycinate, diglycerin malate, diglycerin, diethylene glycol guanidine succinate, erythritol, fructose, glucose, glycerin, honey, hydrolyzed protein, hydroxypropyl trimethyl ammonium hyaluronate, inositol, lactitol, maltitol, maltose, mannitol, mannose, methoxypolyethylene glycol, myristoyl butyl guanidine acetate, polyglycerol sorbitol, pyrrolidone Potassium Carboxylate (PCA), propylene glycol, butylene glycol, sodium Pyrrolidone Carboxylate (PCA), sorbitol, sucrose, dextran sulfate (i.e., of any molecular weight), natural moisturizing factor and/or urea.

Skin conditioning agents may include, but are not limited to, guanidine, urea, glycolic acid, glycolate salts (e.g., ammonium and quaternary alkylammonium), salicylic acid, lactic acid, lactate salts (e.g., ammonium and quaternary alkylammonium), various forms of aloe vera (e.g., aloe vera gel), polyhydric alcohols (e.g., sorbitol, mannitol, xylitol, erythritol, hexanetriol, butanetriol, propylene glycol, butylene glycol, hexylene glycol, and the like, polyethylene glycols, propoxylated glycerin, saccharides (e.g., raffinose), starches, sugar and starch derivatives (e.g., alkoxylated glucose, fructose, glucosamine), C1-C30 mono-and polyesters of sugars and related materials, hyaluronic acid, lacylamide monoethanolamine, acetamidomethamine, panthenol, dexfenteol, allantoin, and mixtures thereof. Cholesterol esters, beeswax, petrolatum and mineral oil.

The emulsifier may be configured to be administered and/or applied to a subject. Suitable methods of administration include, but are not limited to, being introduced into the vulvovaginal anatomy, rectal anatomy, skin, or eye of the subject, instilled therein, implanted therein, applied thereto, or applied thereto. For example, in some aspects, the lotion is configured to be applied into the vagina of a subject. In other aspects, the emulsion is configured to be applied on and around the vulva of a subject.

The anatomical and physiological interaction, physiological clearance, diffusion, or any combination thereof can result in the release of at least one of a cell membrane fluidity enhancer, a fatty acid and a bioactive agent, a pH buffering system, an antioxidant, a tocopherol, a ceramide, an active agent, or any combination thereof, from the stable water-in-silicone emulsion, thereby providing a therapeutically effective dose to the subject.

In some embodiments, the emulsified formulation provides a therapeutically effective dose of up to 2 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 4 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 8 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 12 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose of up to 18 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 24 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 48 hours from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 3 days from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 5 days from a single dose. In some embodiments, the emulsified formulation provides a therapeutically effective dose from a single dose for up to 7 days. In some embodiments, the emulsified formulation provides a therapeutically effective dose for up to 14 days from a single dose.

In some embodiments, the composition may be administered as needed, e.g., once daily, from two to five times daily, up to two or up to three times daily, or up to eight times daily. In some embodiments, the composition is administered three times daily, twice daily, once daily, fourteen days (four times daily, three times daily or twice daily, or once daily) and 7 days non-daily over a 3 week period, up to five or seven days (four times daily, three times daily or twice daily, or once daily) and 14-16 days non-daily, or once every two days, or once weekly, or once every two weeks, or once every three weeks over a 3 week period.

In other examples, the composition is administered once a week, or once every two weeks, or once every 3 weeks, or once every 4 weeks for at least 1 week, in some embodiments 1 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, or 2 to 12 weeks, 2 to 16 weeks, or longer (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 36, 48 or more weeks).

Pharmaceutically acceptable ingredients, excipients, or agents may also be included in the compositions described herein. In some aspects, the pharmaceutically acceptable agent can stabilize the composition, facilitate administration to the vulvovaginal anatomy (e.g., vulva, vagina, or both), rectal anatomy, skin, or eye of the subject, increase its ability to provide symptomatic relief, treat an underlying pathophysiology or infection, or prophylactically protect the vagina of the subject, or adapt the composition for therapeutic use in the subject. Thus, the described compositions may further comprise pharmaceutically acceptable excipients as known to those skilled in the relevant art. Considering that some of the vaginal, rectal, dermatological, or ophthalmological compositions described comprise an active agent, also disclosed herein are pharmaceutical compositions having a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, a ceramide, and an active agent, as provided herein. The pharmaceutical composition can be administered to a subject to provide symptomatic relief, treat an underlying pathophysiology or infection or prophylactically protect the vagina of the subject.

The present disclosure also provides methods comprising combination therapies for treating or preventing the diseases and disorders described herein. As used herein, "combination therapy" or "combination therapy" includes administration of a composition described herein, for example, a composition comprising a stable water-in-silicone emulsion having a continuous silicone phase and an aqueous phase, wherein the emulsion comprises a sterol at a concentration of about 0.1% to about 4% by weight of the total weight of the composition, and at least one additional agent as disclosed herein as part of a particular treatment regimen, thereby providing a beneficial effect from the combined action of these therapeutic compositions.

In some embodiments, the at least one additional agent in the combination therapy may be a therapeutic agent or a non-therapeutic agent. The beneficial effects of the combination include, but are not limited to, the pharmacokinetic or pharmacodynamic co-action resulting from the combination of the therapeutic compound and the disclosed composition. The beneficial effects of the combination may also involve a reduction in toxicity, side effects, or adverse events associated with the other agent in the combination. "combination therapy" can, but is not generally intended to encompass the administration of two or more of these therapeutic compounds as part of a single monotherapy regimen that results, by chance and at will, in the combination of the present disclosure.

In the context of combination therapy, administration of a composition described herein may be simultaneous or sequential with administration of one or more additional agents. In another aspect, the administration of the different components of the combination therapy may be performed at different frequencies. The administration of the one or more additional agents can be performed prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, the first 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a compound of the disclosure.

As described herein, the one or more additional agents can be formulated for co-administration with the compositions of the present disclosure in a single dosage form. The one or more additional agents may be administered separately from a dosage form comprising a composition of the present disclosure. When the additional agent is administered separately from the composition of the disclosure, it may be administered by the same or a different route of administration as the composition of the disclosure.

Preferably, administration of a composition of the present disclosure in combination with one or more additional agents provides a synergistic response in a subject having a disorder, disease, or condition of the present disclosure. In this context, the term "synergistic" means that the efficacy of the combination is more effective than the additive effects of either monotherapy alone. The synergistic effect of the combination therapy according to the present disclosure may allow for the administration of at least one agent in the combination using lower doses and/or lower frequency as compared to the dose and/or frequency outside the combination. The synergy may be manifested by avoiding or reducing adverse or unwanted side effects associated with either therapy used alone in combination.

"combination therapy" also includes administration of a composition of the present disclosure in further combination with non-drug therapy (e.g., surgery or radiation therapy). Where combination therapy also includes non-drug treatment, the non-drug treatment may be carried out at any suitable time, provided that a beneficial effect is obtained from the combined action of the therapeutic compound and the non-drug treatment.

Physical and chemical Properties of Water-in-Silicone emulsions

Droplet size

In some examples, the emulsions described herein comprise droplets (or "particles"). The median diameter of the liquid-droplets comprising the emulsified formulation may be up to 250 microns. For example, the droplets may have a median diameter of about 10 to about 250 microns, about 50 to 250 microns, about 100 to 250 microns, about 150 to 250 microns, or about 200 to 250 microns. In some examples, the droplets/particles have a diameter of about 10 to about 100,000 nanometers (100 μm). For example, the droplets/particles may be about 10, 50, 100, 200, 300, 400, 500, 1000, 10,000, or 100,000 nanometers in diameter. In some embodiments, the droplets/particles may be delivered to a subject using a device or apparatus.

Droplet size can be analyzed by methods known in the art. Suitable methods of droplet size analysis include, but are not limited to, optical microscopy, dynamic light scattering and laser diffraction.

Preparation method

Also provided herein are methods of making compositions comprising water-in-oil emulsions. In some examples, the emulsion may be prepared using techniques including, but not limited to, rotor-stator emulsification, static mixing, or high shear mixing.

In some embodiments, the composition is emulsified to form a stable emulsion having a desired droplet size. High shear devices that may be used include, but are not limited to, IKA Ultra-Turrax dispersers, IKA Dispax-Reactor DR and DRs (Dispax-Reactor shear mixer includes DR3-6 with a three stage rotor/stator combination, and the tip speed of the rotor/stator generator can be varied by controlling the variable frequency drive of the electric motor), Silverson mixers (two stage mixer, which incorporates a rotor/stator design and has large capacity pumping characteristics similar to a centrifugal pump), Silverson's in-line shear mixer (rotor-stator emulsification), jet mixer (venturi/cavitation shear mixer), Sonic's Ultrasonolator (ultrasonic emulsification process), microfluidizer shear mixer (high pressure homogenizing shear mixer) provided by Microfluidics, Ultra-Sonic mixer, and any other available high shear mixer.

In other embodiments, the composition is emulsified using a static mixer to form a stable emulsion. A static mixer is a precision-designed device for continuously mixing fluid materials without moving components.

Compositions in general

As described herein, certain aspects of the present invention relate to the use of the compositions for the preparation of cosmetics, personal care products, feminine care products, hygiene products, dermatological products, ophthalmic products, pharmaceutical formulations, or medicaments for maintaining healthy skin, rejuvenating skin, repairing damaged skin including but not limited to skin after cosmetic and dermatological surgery, wound healing, treating atrophy of any human tissue including vulvovaginal atrophy and/or other conditions, disorders and diseases of human skin and mucous membranes associated with changes in extracellular matrix components.

This is achieved by topically applying the composition of the present invention to the skin or mucosa of a person in need of such treatment. In certain limited cases, this may be achieved by topical administration of the compositions of the present invention in a human in need of such treatment.

Certain aspects of the invention also relate to the use of such compositions for treatment or prevention in dermatological applications, as well as for enhancing wound healing, reducing atrophy of any human tissue including vulvar atrophy, and improving other conditions, disorders, and diseases of human skin and mucosa. These methods generally involve topically applying the composition to the affected skin or affected anatomy in an amount and frequency most suitable for the purpose, when desired. Methods of preventing, delaying onset, or treating skin or mucosal membrane conditions, disorders, and diseases are also contemplated.

One skilled in the art will further recognize that administration of any of the compositions and/or formulations of the present invention will treat, alleviate or ameliorate human skin and mucous membranes, such as wounded skin after cosmetic and dermatological surgery, conditions, disorders and diseases of damaged skin, atrophy of skin and mucous membranes due to other causes than aging (e.g., emotional stress, use of oral contraceptives, use of aromatase inhibitors for surgery, etc.), and other conditions and/or disorders and diseases of human skin and mucous membranes.

Vulvovaginal compositions

Vulvar and Vaginal Atrophy (VVA) caused by loss of estrogen stimulation on the vaginal and vulvar tissues is a common medical condition in peri-and post-menopausal women. VVAs are often uncomfortable and can be manifested by vaginal dryness, lack of lubrication, astringency, burning, irritation, inflammation, atrophic vaginitis, dyspareunia (pain during intercourse) and general pain. VVA occurs most frequently after menopause, but it may also develop during breastfeeding due to treatment of breast cancer, or when estrogen production declines in women at any other time. In addition, recent evidence suggests that women taking oral contraceptives (which may lead to reduced production of certain sex hormones, such as testosterone), may also experience vulvovaginal atrophy. VVA occurs in most postmenopausal women at some point during their life. In the united states, it is estimated that 6400 million post-menopausal women, up to 3200 million women, may suffer from VVA symptoms.

Some areas lack existing over-the-counter treatments (e.g., non-hormonal, over-the-counter (OTC) creams, moisturizers, and lubricants), for example, they are unable to restore anatomical and physiological stasis; they often contain poorly tolerated ingredients in the vaginal canal; they are generally not isotonic; they are far less than Hormone Replacement Therapy (HRT) in terms of symptom relief and potential pathological treatment.

The pathophysiology of VVA is such that the decrease in estrogen levels associated with perimenopause leads to (1) thinning of superficial and stratified squamous epithelial cells lining the vaginal mucosa, and (2) reduction in glycogenesis of squamous epithelium, leading to reduction in desquamated glycogenic cells. Glycogen is an important biomolecule that can maintain vaginal health. The beneficial group of lactobacilli in the vaginal mucosa converts glycogen to lactic acid, which is essential for maintaining a healthy low vaginal pH. In the absence of glycogen, vaginal pH rises, leading to a decrease in lactobacilli and the possibility of excessive proliferation of harmful bacteria that can lead to infection and inflammation. In addition, a decrease in estrogen levels results in decreased vulvovaginal blood flow, decreased mucus production, and decreased vaginal lubrication. Accordingly, provided herein are compositions and methods that address these needs. Vaginal compositions (e.g., lubricants, moisturizers, creams) provided herein are non-hormonal, isotonic, long lasting, capable of slowing VVA progression (e.g., by restoring pH balance, providing meaningful lubrication, and providing symptom relief-vaginal dryness-single application for at least 24 hours), and contain only well tolerated, Generally Regarded As Safe (GRAS) ingredients compatible with lotions and lactobacilli.

Provided herein are compositions, such as vulvovaginal compositions. In some embodiments, the vulvovaginal composition is specifically formulated without the need for active agents for treatment of certain indications. Alternatively, the present disclosure also provides a vulvovaginal composition formulated to enable incorporation of an active agent. In both cases, the formulation approach is specifically chosen to control 1) formulation stability, 2) mechanical properties, and 3) therapeutically relevant incorporation of the desired ingredient, excipient, or agent.

The disclosed vulvovaginal compositions can be administered by application. For example, the vulvovaginal composition can be applied into the vagina using applicators known to those skilled in the art. Additionally, the vulvovaginal composition can be applied to the vulva by methods known to those skilled in the art. In some embodiments, the vulvovaginal composition can be administered into the vagina. In some aspects, the vulvovaginal composition can be applied in the vagina. In other embodiments, the vulvovaginal composition can be administered onto or around the vulva. In some aspects, the vulvovaginal composition can be applied to or around the vulva. In other embodiments, the vulvovaginal composition can be administered on or around vaginal superficial cells. In some aspects, the vulvovaginal composition can be applied on or around vaginal superficial cells. In other embodiments, the vulvovaginal composition can be administered on or around vaginal squamous epithelial cells. In some aspects, the vulvovaginal composition can be applied to or around vaginal squamous epithelial cells.

The disclosed vulvovaginal compositions can be used to provide vaginal symptom relief, treat underlying pathophysiology or infection of the vaginal anatomy, or prophylactically protect the vagina of a subject, for example, by administering the compositions into the vagina. The disclosed vulvovaginal compositions can be used to provide vulvar symptom relief, treat the underlying pathophysiology or infection of the vulvar anatomy, or prophylactically protect the vulva in a subject, for example, by administering the compositions to the vulva.

In some embodiments, the vulvovaginal composition may be used as a Sexually Transmitted Infection (STI) and/or Sexually Transmitted Disease (STD) prophylactic treatment, personal lubricant, vaginal moisturizer, topical hormone replacement therapy, or as a contraceptive, for preventing or treating bacterial vaginosis, vulvovaginal atrophy, yeast infections.

Additionally, the disclosed compositions can be used to provide vulvovaginal symptom relief, treat an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protect the vulvovaginal anatomy in a subject. The need for treatment or prevention may arise from a variety of conditions, including but not limited to, menopause, premenopause, postmenopause, decreased estrogen concentrations, atrophic vaginitis, vulvar and vaginal atrophy, bacterial vaginosis, vaginal dryness, vaginal itching, vaginal irritation, dyspareunia, bacterial infections, yeast infections, urinary tract infections, need for vaginal lubrication and moisturization, need for sexual intercourse, need for contraceptive prevention, or any combination thereof.

In some examples, the disclosed vulvovaginal compositions can include a bioactive agent. Examples of contemplated bioactive agents include, but are not limited to, glycogen, lactic acid, cholesterol, or any combination thereof.

In some examples, the disclosed vulvovaginal compositions can comprise an active agent. Examples of contemplated active agents include, but are not limited to, antifungal agents, antibiotics, spermicidal agents, estrogens, estrogen derivatives, progestins, progesterone derivatives, estrogen precursors, steroids, anti-inflammatory agents, antiviral/antiretroviral agents (e.g., CCR5 antagonists, Nucleoside Reverse Transcriptase Inhibitors (NRTI), as described herein), non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease Inhibitors (PI) (e.g., atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (virapt), ritonavir (Norvir), saquinavir (invitase), tipranavir (aptus), atazanavir/cobicistat (Evotaz), and darunavir/cobicistat (Prezcobix)), fusion inhibitors (e.g., T-20 (enrvirdine, fuzeon)), integrase inhibitors (e.g., raltegravir, dolutegravir, and caboteravir (cabotegravir)), post-attachment inhibitors, and pharmacokinetic enhancers.

In some embodiments, the active agent of the vulvovaginal composition can include a steroidal anti-inflammatory agent. Exemplary steroidal anti-inflammatory bioactive agents include, but are not limited to, corticosteroids such as prasterone, hydrocortisone (hydrocortisone), triamcinolone hydroxylase (hydroxytrimcinolone), alpha-methyl dexamethasone (alpha-methylidexamethosone), dexamethasone phosphate (dexamethosone-phosphate), beclomethasone dipropionate (beclomethasone dipropionate), clobetasol valerate (clobetasol valetate), desonide (desonide), desoximes (desoxymethasone), desoxycorticosterone acetate (desoxycorticosterone), dexamethasone (desoximone), dichloropine (difloronone), diflunisone diacetate (diflupredacerate), diflunisone valerate (diflupredone), fluocinolone diflucortolone acetate (fluocinolone acetonide), fluocinolone acetonide (fluocinolone acetonide), fluocinolone acetonide (fluocinolone acetonide), fluocinolone acetonide (fluocinolone acetonide, fluocino, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodioxolone (cortidoxone), fluocinonide, fludrocortisone (flucyclortisone), diflorosone diacetate, fludaradronolone acetonide, medroxsone (medrysone), amcinafel, amcinonide, prednisolone acetonide, betamethasone (betamethasone) and the balance of esters thereof, prednisone (chlororednisolone), prednisone acetate (chlororednisolone), clocortilone, clemolone, dichloroprednisone (diflorrissone), difluoroprednisolone (triamcinolone), triamcinolone acetonide (triamcinolone acetonide, triamcinolone aceton, triamcinolone (triamcinolone), and mixtures thereof.

In other embodiments, the active agent comprises a second class of anti-inflammatory agents useful in the compositions, and includes a non-steroidal anti-inflammatory agent. The various compounds included in this group are well known to those skilled in the art.

In one embodiment, the additional agent is an antiviral agent. Non-limiting examples of antiviral agents that may be used in combination with the compositions described herein include acetyl mannan (Acemannan); acyclovir; acyclovir sodium; adefovir dipivoxil; alovudine; avulsdito (Alvircept Sudotox); amantadine hydrochloride; (ii) alafenadine; (ii) an oretone; avastine mesylate; alfvudine; cidofovir depsiphylline; cytarabine hydrochloride; delavirdine mesylate; de-acyclovir; digoxin; dioxazar; etidocidine; cyclopentene; a cyclohexoxime; famciclovir; famotidine hydrochloride; non-capecitabine; (ii) fexuridine; phosphate (Fosarilate); foscarnet sodium; sodium phosphonate; ganciclovir; sodium ganciclovir; isouridine; glyoxal; lamivudine; (ii) lobucavir; mometatin hydrochloride; metixazone (Methisazone); nevirapine; penciclovir; (ii) nelfinavir; ribavirin; rimantadine hydrochloride; saquinavir mesylate; sumatridine hydrochloride; solivudine; vistomuron; stavudine; tiolone hydrochloride; a trifluoropyridine; valacyclovir hydrochloride; (ii) Vidalabin; vidarabine phospho-ate (vidarabine phospho-phosphate); sodium vidarabine phosphate; viroxime (Viroxime); zalcitabine; zidovudine; and neat viroxime (Zinviroxime). Combinations of antiviral agents are also contemplated in the compositions described herein.

In some embodiments, the vulvovaginal composition comprises one or more active and/or bioactive agents. In some embodiments, the vulvovaginal composition comprises two active agents, e.g., estradiol and prasterone. In another example, the vulvovaginal composition includes an active agent and a bioactive agent, such as estradiol and glycogen, respectively.

In some embodiments, the vulvovaginal composition comprises an active agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.001%, from about 0.001% to about 60%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 60 wt%, from about 0.1 wt% to about 70 wt%, and any range therebetween.

In some embodiments, the vulvovaginal composition comprises a bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 70%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes a vulvovaginal composition comprising a cell membrane fluidity-enhancing agent (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, the pH of the vulvovaginal composition comprising a cell membrane fluidity-enhancing agent (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 3 to about 4.5. In other embodiments, the pH is about 3.8.

In some examples, the osmolarity (osmolarity) of the vulvovaginal composition including a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, plant sterols, or any combination thereof) is about 280 to about 380 mOsm/kg.

The vulvovaginal composition should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As described herein, viscosity can generally refer to the vulvovaginal composition having a zero shear rate viscosity of about 50kPa-s to about 1000kPa-s at 25 ℃. In some examples, the composition has a desired zero shear rate viscosity (e.g., about 200kPas at 25 ℃) for at least 12 months.

In some examples, a vulvovaginal composition comprising a cell membrane fluidity-enhancing agent (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, plant sterols, or any combination thereof) has a zero shear rate viscosity of about 50kPa-s to about 1000kPa-s at 25 ℃.

In some examples, a vulvovaginal composition including a cell membrane fluidity-enhancing agent (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

Vulvovaginal method

Also provided herein are methods of providing vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject, comprising administering to the subject any of the compositions disclosed herein. In some embodiments, a method for providing vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject may include administering to the subject a vulvovaginal composition comprising a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent. In other embodiments, a method for providing a vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject may comprise administering to the subject a vulvovaginal composition consisting of: a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent. In other embodiments, a method for providing vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject may comprise administering to the subject a vulvovaginal composition consisting essentially of: a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent.

Dermatological composition

Also provided herein are dermatological compositions. The dermatological compositions described herein are useful as skin protectants or moisturizers. In other examples, the dermatological composition may be used to treat or prevent eczema, psoriasis, psoriatic plaques, dry skin, cracked skin, diaper rash, urticaria, ivy rash (poison ivy), skin pain, post-herpetic neuralgia, burns, wound healing, skin infections, dermatitis, atopic dermatitis, acne, impetigo, melanoma, rosacea, dry cracked skin, dry cracked lips, or skin wrinkles. In some embodiments, the dermatological composition may be formulated as a cosmetic, a skin lotion, a skin moisturizer, or a skin cream.

In some examples, the disclosed dermatological compositions may include a bioactive agent. Examples of contemplated bioactive agents include, but are not limited to, hyaluronic acid, cholesterol, or any combination thereof.

In some examples, the disclosed dermatological compositions may include an active agent. Exemplary active agents contemplated include, but are not limited to, antibiotics, antimicrobials, antifungals, disinfectants, local anesthetics, analgesics, anti-inflammatory agents, immunosuppressive agents, steroids, corticosteroids, calcineurin inhibitors, PDE4 inhibitors, salicylic acid, retinoic acid, antihistamines, benzoyl peroxide, and nanocrystalline silver.

Exemplary antibiotics include, but are not limited to, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanic acid and levofloxacin. Other antibiotics include micacein, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin (B), geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cephradine, cefapirin, cephalothin, cephalexin, cefaclor, cefoxitin, cefotetan, cefamandole, roxithromycin, telithromycin, spiramycin, fidaxomicin, furazolidone, furadane (B), rizonamide, boscalide, reduzolve, tediramate, tedizolid, penicillin, alocillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, penicillin G, temocillin, ticarcillin, ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gamifloxacin, levofloxacin, norfloxacin, ofloxacin, trovafloxacin, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, calicheamicin, cyclopropylamine pyrazinamide, rifampin, rifabutin, rifapentin, streptomycin, metronidazole and mupirocin.

Exemplary antimicrobial agents include, but are not limited to, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate, and levofloxacin.

Exemplary antifungal agents include, but are not limited to, miconazole, clotrimazole, amphotericin B, ketoconazole, fluconazole, ivaconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and flucytosine.

Exemplary disinfecting agents include ethanol, sodium hypochlorite, chlorhexidine, hexachlorophene, povidone iodine, sodium hypochlorite, benzethonium chloride, triclosan, sodium oxychlorosene (sodium), benzalkonium chloride, and silver nitrate.

Exemplary local anesthetics include amethocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, tetracaine, bendinecarin, chloroprocaine, cinchocaine (INN), ***e, cyclomethiocaine, dibucaine, deparaffin, dicaine, ***e, etidocaine, hexylcaine, fomocaine, tropicaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, m-butoxycaine, nitaracaine, o-caine, otacaine (eticaine), oxybuprocaine, p-ethoxycaine, phenanthrocaine, perocaine, perlidocaine, pramoxine, prilocaine, procaine, procainamide, proparacaine, pyrrole caine, quinicaine (INN), ropivacaine, trimecaine, tetracaine, tropicaine and tolaracaine.

Exemplary analgesics include codeine, fentanyl, hydrocodone (hysynla, Zohydro, hydrocodone/acetaminophen (loret, Lortab, Norco, Vicodin), hydromorphone (dilaudd, Exalgo), meperidine (Demerol), methadone (Dolophine, Methadose), morphine (Kadian, MS control, morphobond), oxycodone (oxycontrol, Oxaydo), oxycodone and acetaminophen (Percocet, Roxicet) as well as oxycodone and naloxone.

Exemplary anti-inflammatory agents include celecoxib (Celebrex), diclofenac (Cambia, Cataflam, Voltaren-XR, Zipsor, zorvelex), difluorac (Dolobid), etodolac (Lodine), ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen (active ketoprofen, ketorolac, nabumetone naproxen (Aleve, Anaprox, naperan, naproxen), oxaprozin (Daypro), piroxicam (Feldene), salsalate, sulindac, and tolmetin.

Exemplary immunosuppressive agents include corticosteroids (e.g., prednisone (Delosone, Orasone), budesonide (Entocort EC), prednisolone and (Millipred)), Janus kinase inhibitors (e.g., tofacitinib (Xeljanz)), calcineurin inhibitors, such as cyclosporine (Neoral, Sandimun, SangCya) and tacrolimus (AstagrafL, Envarsus XR, Prograf), mTOR inhibitors (e.g., sirolimus (Rapamone) and everolimus (Afinitor, Zorres), IMDH inhibitors, such as azathioprin (Azan, Imuran), leflunomide (Arava) and phenolate (CellCept, Myforic), biologicals, such as, e (Orencia), adalimumab (adalimumab), Humulin (Kineret), Cixacitabine (Cixacitab), Rituzumab (Rituzumab), Eisenia (Tyrosigliomab (Rituzumab), Eisentexib (Rentux (Rituzumab), secukinumab (Cosentyx), tositumumab (actemma), ustekumab (stellara), vedolizumab (Entyvio) and monoclonal antibodies, such as basiliximab (simulent), daclizumab (Zinbryta) and molobuzumab (Orthoclone OKT 3).

Exemplary calcineurin inhibitors include astagraf XL, cyclosporine ophthalmic, Elidel, Envarsus XR, Gengraf, Hecoria, Neoral, pimecrolimus, pleconus (Prograf), protetil (Protopic), ritonas (Restasis), sandimmine (Sandimmune), tacrolimus, and tacrolimus ointment.

Exemplary phosphodiesterase 4(PDE4) inhibitors include aldibendane, aminophylline, anhydroaminophylline, dapsone, apremilast, arotheophylline, Atizoram, phenyalanine, bemaline hydrochloride, bemoradan, palafenamic prefrom (Benafentrine), bravadipine (Bucladesene), Buflomedil (Buflomedil), bufeliron (Buquineran), CC-1088, carbafuran (Carbazeran), katrinast (Catalast), cilomilst (Cilomilast), Cilostamide (Cilosamide), Cilostazol (Cilostazol), siphylline (Cipamfylline), Crisabolole, Daxalipram, Denbufylline (Dinbufylline), dimafylline (Dimafylline), theophylline (Dinopaline), theophylline (Dirofylline), theophylline (Deltayline), doxyline (Fluoroline), etoposine (Fluoroline (Etaflorine), etorphine (Fluoroline (Etaflorine), Etaflorine (Fluoroline), furalatezine (Furafylline), fenamidone (imazadan), fenamidone hydrochloride, amrinone lactate, isobutyltheophylline, Lirimilast, lisofepotamine, lomiphylline, medoxolone, medoxine, mefenofylline, milrinone lactate, mopiprone, nanrinone, nestheophylline, nifolizone, ogelist (ogemeilast), ogelist sodium, olprinone, oxogrelate, choline, papaverine hydrochloride, papaverine sulfate, paroxetine, pellicone hydrochloride, pentiteine, pentoxifylline, hexetidine, petylline, pirimidyl, meperidine, pimelandine, pimozolone, propiophenone, propiverine, hydroxypropylmafelinine, ziprinone, quintillodone, quintiazeine, teflufenacetone, tezomib, troxacillin, trospit, trospide, trospilate, vesnarinone and zadavvilin.

In some embodiments, the dermatological composition comprises one or more active and/or bioactive agents. In some embodiments, the dermatological composition comprises two active agents, such as lidocaine and clindamycin. In another example, the dermatological composition comprises an active agent and a bioactive agent, such as retinol and hyaluronic acid, respectively.

In some embodiments, the dermatological composition comprises an active agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.001%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 60%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the dermatological composition comprises a bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 60%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes a dermatological composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, the pH of the dermatological composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 4.5 to about 6.5. In other embodiments, the pH is about 5.5.

In some examples, the osmolality of the dermatological composition including a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 200 to about 500 mOsm/kg.

The dermatological composition should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As described herein, viscosity may generally refer to the dermatological composition having a zero shear rate viscosity of from about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, a dermatological composition comprising a cell membrane fluidity-enhancing agent (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has a zero shear rate viscosity of about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, a dermatological composition including a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

As described herein, an exemplary dermatological composition comprises a ceramide.

Dermatological method

Also provided herein are methods for providing dermatological symptom relief, treating an underlying pathophysiology or infection, or prophylactically protecting a subject, comprising administering to the subject any of the compositions disclosed herein.

In some embodiments, the method for dermatological use comprises treating or preventing a condition including, but not limited to: eczema, psoriasis, psoriatic plaques, dry skin, cracked skin, diaper rash, urticaria, ivy rash, skin pain, post herpetic neuralgia, burns, wound protection and/or healing, skin infections, dermatitis, atopic dermatitis, acne, impetigo, melanoma, rosacea, dry cracked skin, dry cracked lips or skin wrinkles. In other exemplary embodiments, the dermatological use of the disclosed compositions requires that the compositions be capable of being formulated as a cosmetic, skin lotion, skin moisturizer, skin cream, or skin protectant.

Rectal compositions

Also provided herein are rectal compositions. For example, the compositions may be used to treat or prevent hemorrhoids or anal fissures.

In some examples, the disclosed rectal compositions may include an active agent. Exemplary agents contemplated include, but are not limited to, vasoconstrictors, anti-inflammatory agents, steroids, local anesthetics, alpha-adrenergic receptor agonists, botulinum toxin a, calcium channel inhibitors, and nitrates.

In some embodiments, the rectal composition comprises one or more active agents. In some embodiments, the rectal composition comprises two active agents, e.g., lidocaine and hydrocortisone.

In some embodiments, the rectal composition comprises an active agent in an amount from about 0.0001% to about 90% by weight, from about 0.0001% to about 1% by weight, from about 0.0001% to about 10% by weight, from about 0.0001% to about 20% by weight, from about 0.0001% to about 30% by weight, from about 0.0001% to about 40% by weight, from about 0.0001% to about 50% by weight, from about 0.0001% to about 60% by weight, from about 0.0001% to about 70% by weight, from about 0.0001% to about 80% by weight, from about 0.001% to about 90% by weight, from about 0.001% to about 1% by weight, from about 0.001% to about 10% by weight, from about 0.001% to about 20% by weight, from about 0.001% to about 30% by weight, from about 0.001% to about 40% by weight, from about 0.001% to about 0.70% by weight, from about 0.001% to about 50% by weight, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 60 wt%, from about 0.1 wt% to about 70 wt%, and any range therebetween.

In some embodiments, the rectal composition comprises the bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 60%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes rectal compositions comprising a cell membrane fluidity enhancer (e.g., sterols, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, the pH of a rectal composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 7 to about 8. In other embodiments, the pH is about 7.4.

In some examples, the osmolality of the rectal composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 200 to about 500 mOsm/kg.

Rectal compositions should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As used herein, viscosity may generally refer to the rectal composition having a zero shear rate viscosity at 25 ℃ of from about 50kPa-s to about 1000 kPa-s.

In some examples, a rectal composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has a zero shear rate viscosity of about 50kPa-s to about 1000kPa-s at 25 ℃.

In some examples, rectal compositions that include a cell membrane fluidity enhancer (e.g., sterols, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) have rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

Rectal method

Also provided herein are methods of providing rectal symptom relief or treating an underlying pathophysiology or infection in a subject comprising administering to the subject any of the compositions disclosed herein.

In some embodiments, the methods for rectal use include treating conditions including, but not limited to, hemorrhoids or anal fissures.

Sunscreen cream composition

Sunscreen compositions are also provided herein. For example, the composition can be used to treat or prevent sun damage (e.g., damage caused by ultraviolet radiation). By using the compositions described herein, modulation of skin darkening due to exposure to ultraviolet light can be achieved. Useful sunblocks include, for example, zinc oxide and titanium dioxide. Ultraviolet light is a major cause of skin darkening.

In some embodiments, sunscreen compositions may include an active agent. Exemplary active agents (e.g., ultraviolet absorbers) in sunscreen compositions described herein include, but are not limited to, zinc oxide, titanium dioxide, oxybenzone, avobenzone, octyl salicylate, octocrylene (octocrylene), methyl salicyl cinnamate, and p-aminobenzoic acid (e.g., PABA).

In some embodiments, sunscreen compositions include one or more active agents capable of absorbing ultraviolet radiation. In some embodiments, sunscreen compositions include two active agents, such as zinc oxide and oxybenzone.

In some embodiments, the sunscreen cream composition comprises an active agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 50%, from about 0.001% to about 70%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 60 wt%, from about 0.1 wt% to about 70 wt%, and any range therebetween.

In some embodiments, the sunscreen composition comprises a bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.001%, from about 0.001% to about 60%, from about 0.001% to about 70%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes sunscreen compositions comprising a cell membrane fluidity enhancer (e.g., sterols, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, sunscreen compositions comprising a cell membrane fluidity enhancer (e.g., sterols, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) have a pH of about 4.5 to about 6.5. In other embodiments, the pH is about 5.5.

In some examples, a sunscreen composition including a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has an osmolarity of about 200 to about 500 mOsm/kg.

Sunscreen compositions should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As used herein, viscosity may generally refer to the sunscreen composition having a zero shear rate viscosity at 25 ℃ of from about 100Pa-s to about 1000 kPa-s.

In some examples, sunscreen compositions comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) have a zero shear rate viscosity of from about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, sunscreen compositions that include a cell membrane fluidity enhancer (e.g., sterols, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) have rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

Sun protection method

Also provided herein are methods of prophylactically protecting a subject from ultraviolet light, comprising administering to the subject any of the compositions disclosed herein.

In some embodiments, the method for sunscreen use comprises treating or preventing a disorder comprising UV damage (e.g., sun damage) in a subject. For the purposes described herein, the compositions may be used to protect or treat against UVA and/or UVB exposure.

Transdermal drug delivery compositions

Also provided herein are transdermal drug delivery compositions. Transdermal drug delivery works well for highly effective drugs (e.g., oral doses of less than 10mg) for the treatment of sub-chronic and chronic indications. Transdermal drug delivery provides an ideal route of administration because it avoids first-pass (first-pass), hepatic circulation, and clearance. For example, the composition can be used to treat or prevent pain, diabetes, a neurological disease or disorder, hormone deficiency, or nausea.

In some examples, the disclosed transdermal drug delivery compositions can comprise a bioactive agent. Examples of contemplated bioactive agents include, but are not limited to, serine proteases, chemical penetration enhancers, cholesterol, or any combination thereof.

In some examples, the disclosed transdermal drug delivery compositions can comprise an active agent. Exemplary active agents contemplated include, but are not limited to, analgesics, local anesthetics, hormones, steroids, sulfonylureas, α -glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase 4(DDP-4) inhibitors, insulin, selective sodium glucose transporter 2(SGLT-2) inhibitors, antidepressants, anticonvulsants, antipsychotics, antiparkinson and antiemetics.

In some embodiments, the transdermal drug delivery composition comprises one or more active and/or bioactive agents. In some embodiments, the transdermal drug delivery composition comprises two active agents, e.g., estrogen and progesterone. In another example, the transdermal drug delivery composition includes an active agent and a biologically active agent, such as testosterone and serine protease, respectively.

In some embodiments, the transdermal drug delivery composition comprises an active agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the transdermal drug delivery composition comprises a bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes transdermal drug delivery compositions comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, the transdermal drug delivery composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has a pH of from about 4.5 to about 6.5. In other embodiments, the pH is about 5.5.

In some examples, the osmolality of a transdermal drug delivery composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 200 to about 500 mOsm/kg.

The transdermal drug delivery composition should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As used herein, viscosity may generally refer to the transdermal drug delivery composition having a zero shear rate viscosity at 25 ℃ of from about 100Pa-s to about 1000 kPa-s.

In some examples, a transdermal drug delivery composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has a zero shear rate viscosity of from about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, a transdermal drug delivery composition including a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

Transdermal method

Also provided herein are methods for providing a transdermal drug delivery system comprising administering to a subject any of the compositions disclosed herein.

In some embodiments, the method for transdermal drug delivery systems comprises treating or preventing conditions including, but not limited to, pain, diabetes, neurological disorders or diseases, hormone deficiency, or nausea.

Ophthalmic composition

Ophthalmic compositions are also provided herein. The ophthalmic compositions described herein are useful for treating or preventing ocular surface disorders, ophthalmic diseases, ophthalmic disorders, and the like, including, but not limited to, dry eye, hordeolum, epithelial defects, retinal detachment, conjunctivitis (e.g., viral, bacterial, or allergic conjunctivitis), superior limbal keratoconjunctivitis, keratoconjunctivitis sicca, neurotrophic keratopathy, sjogren's syndrome, Ocular Cicatricial Pemphigus (OCP), pharmaceutical conjunctivitis, corneal ulcers and erosions, and macular degeneration. In addition, the ophthalmic composition may be used before or after ophthalmic surgery, including, for example, retinal surgery, penetrating corneal transplantation and refractive surgery, laser-assisted in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK) or photorefractive keratomileusis (PRK).

As used herein, the term "ophthalmic composition" refers to a composition intended to be applied to the eye or its associated or surrounding tissue, such as the eyelid or cornea. The term also includes compositions intended to treat disorders of the eye itself or tissues surrounding the eye. The ophthalmic composition may be applied topically or by other techniques known to those skilled in the art, such as injection into the eye. Examples of suitable topical administration to the eye include administration in eye drops and spray formulations. Another suitable route of topical administration is by subconjunctival injection. The composition may also be provided to the eye periocularly or retroorbitally.

In some examples, the disclosed ophthalmic compositions can comprise an active agent. Exemplary active agents contemplated include, but are not limited to, antibiotics, antimicrobials, antivirals, disinfectants, local anesthetics, antihistamines, vasoconstrictors, analgesics, anti-inflammatory agents, immunosuppressants, immunostimulants, immunomodulators, steroids and corticosteroids.

In some embodiments, the ophthalmic composition comprises one or more active agents. For example, ophthalmic compositions include a vasoconstrictor and an antihistamine, such as naphazoline and phenylethylamine.

In some embodiments, the ophthalmic composition comprises an active agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.001%, from about 0.001% to about 50%, from about 0.001% to about 70%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 60 wt%, from about 0.1 wt% to about 70 wt%, and any range therebetween.

In some embodiments, the ophthalmic composition comprises a bioactive agent in an amount from about 0.0001% to about 90%, from about 0.0001% to about 1%, from about 0.0001% to about 10%, from about 0.0001% to about 20%, from about 0.0001% to about 30%, from about 0.0001% to about 40%, from about 0.0001% to about 50%, from about 0.0001% to about 60%, from about 0.0001% to about 70%, from about 0.0001% to about 80%, from about 0.001% to about 90%, from about 0.001% to about 1%, from about 0.001% to about 10%, from about 0.001% to about 20%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 0.60%, from about 0.001% to about 70%, from about 0.001% to about 30%, from about 0.001% to about 40%, from about 0.001% to about 60%, from about 0.001 wt% to about 80 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 80 wt%, from about 0.1 wt% to about 90 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 0.1 wt%, and any range therebetween.

In some embodiments, the present disclosure includes ophthalmic compositions comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) and a preservative. Examples of preservatives include antimicrobial preservatives, such as benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, benzoic acid, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, thiolates, acetates and phenylmercuric borates, polymyxin B sulfate, methylparaben and propylparaben, quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodium propionate and sodium perborate or any combination thereof.

In some embodiments, preservatives can be used in any suitable amount. For example, preservatives can be used in amounts of about 0.001 wt% to 1.0 wt%, based on the total weight of the composition.

In some embodiments, the pH of an ophthalmic composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) is from about 7 to about 7.4 (e.g., a neutral pH or a physiological pH). In other embodiments, the pH is about 7.

In some examples, an ophthalmic composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has an osmolarity of about 200 to about 500 mOsm/kg.

Ophthalmic compositions should have a zero shear rate viscosity that resists changes over time and/or temperature. The terms "viscosity," "zero shear rate viscosity," and the like are used herein in a generic and customary sense to refer to a measure of the resistance of a material to deformation (e.g., liquid behavior) when a force (e.g., shear or tensile stress) is applied. The viscosity of the emulsion may also depend on temperature, as well as other effects such as shear rate, average droplet size, and droplet size distribution. As described herein, viscosity may generally refer to the ophthalmic composition having a zero shear rate viscosity of about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, an ophthalmic composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has a zero shear rate viscosity of about 100Pa-s to about 1000kPa-s at 25 ℃.

In some examples, an ophthalmic composition comprising a cell membrane fluidity enhancer (e.g., a sterol, wherein exemplary sterols include cholesterol, cholesterol derivatives, phytosterols, or any combination thereof) has rheological properties that change negligibly at temperatures between 25 ℃ and 37 ℃.

Ophthalmic methods

Also provided herein are methods for providing ophthalmic symptom relief, treating an underlying pathophysiology or infection, or prophylactically protecting a subject, the method comprising administering to the subject any of the compositions disclosed herein. In some embodiments, methods for ophthalmic use include treating or preventing conditions including, but not limited to, ocular surface disorders, ophthalmic diseases, ophthalmic disorders, and the like, including, but not limited to, dry eye, hordeolum, epithelial defects, retinal detachment, conjunctivitis (e.g., viral conjunctivitis, bacterial conjunctivitis, or allergic conjunctivitis), superior limbal keratoconjunctivitis, keratoconjunctivitis sicca, neurotrophic keratopathy, sjogren's syndrome, Ocular Cicatricial Pemphigus (OCP), pharmaceutical conjunctivitis, corneal ulcers and erosions, and macular degeneration. In addition, the ophthalmic composition may be used before or after ophthalmic surgery, including, for example, retinal surgery, penetrating corneal transplantation and refractive surgery, laser-assisted in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK) or photorefractive keratomileusis (PRK). In other exemplary embodiments, ophthalmic use of the disclosed compositions requires that the compositions can be formulated as solutions, suspensions, semisolids, emulsions, semiliquids, ointments, creams, or controlled/sustained release vehicles. For example, the composition may be in the form of a contact lens solution, an eye drop, an eye ointment, and the like.

In some embodiments, the method of treating an ophthalmic disorder comprises treating: dry eye associated with or caused by the treatment of inflammation of the ocular surface, lacrimal gland, or conjunctiva; dry eye associated with any disease process that alters tear composition; dry eye associated with increased eye surface, as is the case with thyroid disease when the eye is protruding anteriorly; and/or dry eye associated with cosmetic surgery, for example, if the eyelids are opened too widely during surgery.

In some embodiments, a method of treating an ophthalmic disorder comprises alleviating a symptom comprising: eye stinging or burning; have a sand or gravel feel as if something is in the eyes; excessive tears after a very dry eye period; ocular outflow dope; eye pain and redness; symptoms of blurred vision; heavy eyelids; the user cannot cry when the user is nervous; contact lenses are uncomfortable; reduced tolerance for reading, working on a computer, or any activity requiring sustained visual attention; and/or eye fatigue.

Further applications

The compositions as described herein may also be formulated for a variety of industrial applications, including but not limited to providing lubrication, protection, or moisturization to surfaces to which they are applied.

For example, the compositions of the present invention are useful in applications such as automotive and motor sports; a rowing application; agricultural applications; garage/workshop applications; hobby and handicraft applications; and many applications in the fields of home and garden applications. For example, the composition may be used to provide a protective coating on a metal object to prevent rust; providing lubrication to the contacting metal parts; cleaning and lubricating moving parts; lubricating and infiltrating the adhered object; cleaning and lubricating tools, saws and blades; repairing or polishing the surface (after physico-chemical modification of the surface). Exemplary surfaces include wood, porcelain, enamel, tile, stainless steel, fiberglass, chrome, and rubber.

Reagent kit

Also provided herein are kits for use in a composition for symptom relief, treatment of an underlying pathophysiology or infection of an anatomical structure associated with a disorder, or prophylactic protection of an anatomical structure in a subject. In some embodiments, the kit comprises a stable water-in-silicone emulsion and a cell membrane fluidity enhancer. In other embodiments, the kit further comprises an emulsifier, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancing agent, an antioxidant, a tocopherol, a ceramide, or an active agent, and instructions for producing the composition. The instructions may describe the steps and reagents for producing the composition by emulsification. Such steps and reagents may be in accordance with the steps and reagents disclosed herein for emulsification.

In some embodiments, provided herein are kits for producing a vulvovaginal composition for providing vulvovaginal symptom relief, treating an underlying pathophysiology or infection of the vulvovaginal anatomy, or prophylactically protecting the vulvovaginal anatomy in a subject; the kit comprises, consists of or consists essentially of: a stable water-in-silicone emulsion, an emulsifier, a cell membrane fluidity enhancer, a fatty acid, a preservative, and at least one of a bioactive agent, a pH buffering system, a viscosity enhancer, an antioxidant, a tocopherol, and an active agent, and instructions for producing a vulvovaginal composition. The instructions may describe steps and reagents for producing the vulvovaginal composition by emulsification. Such steps and reagents may be in accordance with the steps and reagents disclosed herein for emulsification.

Also provided herein are dermatological kits comprising the compositions described herein. The dermatological kits provided herein are useful for treating or preventing conditions including, but not limited to: eczema, psoriasis, psoriatic plaques, dry skin, cracked skin, diaper rash, urticaria, ivy rash, skin pain, post herpetic neuralgia, burns, wound healing, skin infections, dermatitis, atopic dermatitis, acne, impetigo, melanoma, rosacea, cracked skin, cracked lips, or skin wrinkles. In other exemplary embodiments, the dermatological kits of the disclosed compositions allow the compositions of the kits to be formulated as cosmetics, skin lotions, skin moisturizers, skin creams, or skin protectants.

In other examples, provided herein are rectal kits comprising the compositions described herein. The rectal kits provided herein are useful for treating or preventing conditions including, but not limited to, hemorrhoids or anal fissures.

In other examples, provided herein are sunscreen kits comprising the compositions described herein. The sunscreen kits provided herein are useful for treating or preventing disorders including, but not limited to, ultraviolet light damage (e.g., sun damage).

In other examples, provided herein are transdermal drug delivery system kits comprising the compositions described herein. The transdermal drug delivery system kits provided herein are useful for treating or preventing conditions including, but not limited to: pain, diabetes, neurological disorders or diseases, hormone deficiency or nausea.

In other examples, provided herein are ophthalmic kits comprising the compositions described herein. The ophthalmic kits provided herein are useful for treating or preventing conditions including, but not limited to, ocular surface diseases, ophthalmic disorders, and the like.