HK1236423A1 - Silicone-based biophotonic compositions and uses thereof - Google Patents

Description

Silicone-based biophotonic compositions and uses thereof

Reference to related applications

This application claims the benefit of U.S. provisional application No. 62/009,870, filed 6, 9, 2014, the disclosure of which is incorporated by reference herein in its entirety.

Background

Recently, phototherapy (phototherapeutic) has been considered to be widely used in the medical and cosmetic fields, including for surgery, therapy and diagnosis. For example, phototherapy has been developed for the treatment of cancers and tumors with reduced invasiveness, as an antimicrobial treatment to disinfect target sites, to promote wound healing, and for facial skin rejuvenation (rejuvenation).

Photodynamic therapy (photodynamic therapy) is a type of phototherapy that involves applying a photosensitizer to target tissue and then exposing the target tissue to a light source after a specified period of time during which the photosensitizer is absorbed by the target tissue. However, such therapies are often associated with undesirable side effects, including systemic or local toxicity to the patient or damage to non-target tissues. In addition, the efficacy of such prior therapies is generally low, for example, due to poor selectivity of the photosensitizer for administration into the target tissue.

Silicone (Silicone) is an alkyl siloxane or organo siloxane based compound and includes Polydimethylsiloxane (PDMS), which has been considered biocompatible and has been successfully used in medical applications in the last sixty years (Curtis et al, Biomaterials Science 2)^ndEdition, 2004). PDMS-based compositions are widely used in personal care and topical skin applications because they are non-irritating, non-sensitizing, and conform to the strict standards set forth by the U.S. and european regulatory agencies.

It is therefore an object of the present invention to provide new and improved silicone-based compositions useful in phototherapy and methods of use thereof.

Disclosure of Invention

The present invention provides silicone-based biophotonic compositions and methods useful for phototherapy. In particular, the biophotonic compositions of the present disclosure include a silicone matrix and at least one chromophore, wherein the at least one chromophore can absorb and emit light from within the biophotonic composition, and which can be used for cosmetic or medical treatment of human or animal tissue.

In one aspect, the present invention provides a silicone-based biophotonic composition comprising a silicone phase and a surfactant phase, wherein the surfactant phase comprises at least one chromophore dissolved in a surfactant. In some embodiments, the surfactant phase is emulsified in the silicone phase. In certain embodiments, the silicone phase is a continuous phase. In some embodiments, the surfactant is a block copolymer. The block copolymer may comprise at least one hydrophobic block and at least one hydrophilic block. In some embodiments, the surfactant is thermally gellable.

In certain embodiments of any of the foregoing or following, the surfactant comprises at least one sequence of polyethylene glycol-polypropylene glycol ((PEG) - (PPG)). In another embodiment, the surfactant is a triblock copolymer of formula (PEG) - (PPG) - (PEG) or a poloxamer (poloxamer). In yet another embodiment, the surfactant is Pluronic F127.

In certain embodiments of any of the foregoing or following, the surfactant comprises at least one sequence of polyethylene glycol-polylactic acid ((PEG) - (PLA)). In some embodiments, the surfactant comprises at least one sequence of polyethylene glycol-poly (lactic-c-glycolic acid) ((PEG) - (PLGA)). In some embodiments, the surfactant comprises at least one sequence of polyethylene glycol-polycaprolactone ((PEG) - (PCL)). In another embodiment, the surfactant is a triblock copolymer or poloxamer of the formula A-B-A or B-A-B, wherein A is PEG and B is PLA or PLGA or PCL.

In certain embodiments of any of the foregoing or following, the silicone phase comprises silicone. In certain embodiments, the silicone may be a silicone elastomer. In certain embodiments, the silicone comprises polydimethylsiloxane. In certain embodiments, the silicone comprises184. In certain embodiments, the silicone comprises184 and527, respectively. In another embodiment, the silicone comprises about 15 percent184 and about 85%527, respectively. In some embodiments of the present invention, the substrate is,184 and527, achieves a silicone-based biophotonic composition in the form of an elastic and adhesive film, which may be well suited for skin applications. In particular, elasticity may allow for easier handling of silicone-based biophotonic membranes, and tackiness (stickiness) may allow the membrane to stay in place during the course of treatment as may be achieved in the present invention.

In certain embodiments of any of the foregoing or following, the silicone-based biophotonic composition comprises 80 wt% of a silicone phase and about 20 wt% of a surfactant phase. In some embodiments, the silicone-based biophotonic composition comprises about 60/40 wt%, or about 65/55 wt%, or about 70/30 wt%, or about 75/25 wt%, or about 80/20 wt%, or about 85/15 wt%, or about 90/10 wt% of the silicone phase/surfactant phase wt% of the composition.

In certain embodiments of any of the above or below, at least one chromophore is water soluble and dissolved in the surfactant phase. The at least one chromophore may be a fluorophore. In some embodiments, the chromophore can absorb and/or emit light. In some embodiments, the light absorbed and/or emitted by the chromophore is in the visible range of the electromagnetic spectrum. In some embodiments, the light absorbed and/or emitted by the chromophore is in the range of about 400nm to about 750 nm. In certain embodiments, the chromophore can emit light from about 500nm to about 700 nm. In some embodiments, the chromophore or fluorophore is a xanthene dye. Xanthene dyes may be selected from Eosin (Eosin) Y, Eosin B, Erythrosine (Erythrosine) B, Fluorescein (fluoroescein), Rose Bengal (Rose Bengal) and phloxine (Phloxin) B.

In certain embodiments of any of the foregoing or following, the surfactant phase of the silicone-based biophotonic composition further comprises a stabilizer. In further embodiments, the stabilizing agent comprises gelatin, hydroxyethyl cellulose ether (HEC), carboxymethyl cellulose (CMC), or any other thickening agent.

In certain embodiments of any of the above or below, the silicone-based biophotonic composition is at least substantially translucent. The silicone-based biophotonic composition may be transparent. In some embodiments, the silicone-based biophotonic composition has a translucency of at least about 40%, about 50%, about 60%, about 70%, or about 80% in the visible range. Preferably, the light transmission through the composition is measured in the absence of the at least one chromophore.

In certain embodiments, the composition is in the form of a film. In other embodiments, the composition is in the form of a spreadable gel.

In certain embodiments of any of the foregoing or following, the surfactant phase further comprises an oxidizing agent. The oxidizing agent may include peroxides such as hydrogen peroxide, urea peroxide, and benzoyl peroxide, or any other oxidizing agent that can modulate the light absorption and/or emission properties of at least one chromophore or can oxidize or degrade the chromophore. For example, in certain embodiments where a single use composition is desired, the surfactant phase may include a peroxide to ensure degradation of the at least one chromophore over a single treatment time.

In certain embodiments of any of the above or below, the silicone-based biophotonic composition (e.g., in the form of a silicone-based biophotonic film) has a thickness of about 0.1mm to about 50mm, about 0.5mm to about 20mm, or about 1mm to about 10mm, or about 1mm to about 5 mm. In some embodiments, the biophotonic composition is in the form of a gel that is applied at a thickness of about 0.1mm to about 50mm, about 0.5mm to about 20mm, or about 1mm to about 10mm, or about 1mm to about 5 mm.

In certain embodiments of any of the above or below, the silicone-based composition (e.g., in the form of a silicone-based biophotonic membrane) has a removable coating for covering one or both sides of the membrane. The removable coating may be peelable. The removable cover may comprise a sheet or film material, such as paper or foil. In certain embodiments, the removable cover is opaque and protects the membrane from irradiation until the treatment time. The cover may be partially removable. In certain embodiments, such as after a treatment time, the coating may be reapplied to the membrane surface so as to protect the membrane from further irradiation between treatments.

In certain embodiments of any of the foregoing or following, the surfactant phase is uniformly distributed within the silicone phase and is nano-and/or micro-sized. It can be considered to be microemulsified. The surfactant phase cannot be detected visibly by the eye. In other words, the film appears as one phase as seen by the eye.

The silicone-based biophotonic compositions of any aspect or embodiment of the present invention may be used for cosmetic or medical treatment of tissue. In some embodiments, the cosmetic treatment is skin rejuvenation and conditioning, and the medical treatment is wound healing, periodontal treatment, or acne treatment, or treatment of other skin disorders (including eczema, psoriasis, or dermatitis). In some aspects, the silicone-based biophotonic membranes are used to modulate inflammation, to modulate collagen synthesis, or to promote angiogenesis.

The present invention also provides a method for biophotonic therapy comprising applying the silicone-based biophotonic composition of the present invention to a target tissue and irradiating the composition with light.

In one aspect, the present invention provides a method for biophotonic treatment of a skin disorder, wherein the method comprises placing the silicone-based biophotonic composition of the present invention on or over a target skin tissue, and illuminating the silicone-based biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of at least one chromophore. In some embodiments, the biophotonic composition emits fluorescence at a wavelength and intensity that promotes healing of the skin condition. The skin disease is selected from eczema, psoriasis or dermatitis.

In another aspect, the present invention provides a method for biophotonic treatment of acne, comprising: placing the silicone-based biophotonic composition of the present disclosure on or over a target skin tissue; and irradiating the composition with light having a wavelength that overlaps with an absorption spectrum of at least one chromophore. In some embodiments, the biophotonic composition emits fluorescence at a wavelength and intensity to treat acne.

In another aspect, the present invention provides a method for promoting wound healing, comprising: the silicone-based biophotonic composition of the present disclosure is placed on or over a wound and the silicone-based biophotonic composition is illuminated with light having a wavelength that overlaps with an absorption spectrum of the at least one chromophore. In some embodiments, the biophotonic composition emits fluorescence at a wavelength and intensity that promotes wound healing.

In another aspect, the present invention provides a method for biophotonic tissue repair, comprising: placing the silicone-based biophotonic composition of the present disclosure on or over a target tissue; and illuminating the silicone-based biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of at least one chromophore. In some embodiments, the biophotonic composition emits fluorescence at a wavelength and intensity that promotes tissue repair.

In another aspect, the present invention provides a method of promoting skin rejuvenation, comprising: placing the silicone-based biophotonic composition of the present disclosure on or over a target skin tissue; and illuminating the silicone-based biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of at least one chromophore. In some embodiments, the biophotonic composition emits fluorescence at a wavelength and intensity that promotes skin rejuvenation. Promoting skin turnover may include promoting collagen synthesis.

In another aspect, the present invention provides a method for preventing or treating scar formation, comprising: placing the silicone-based biophotonic composition of the present disclosure on or over a tissue scar; and illuminating the silicone-based biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of at least one chromophore. In some embodiments, the silicone-based biophotonic composition emits fluorescence at a wavelength and intensity that reduces or prevents scar formation.

In certain embodiments, the silicone-based biophotonic composition remains in place after irradiation. In certain embodiments, the silicone-based biophotonic composition is re-irradiated. In some embodiments, the chromophore is at least partially photobleached during or after irradiation. In certain embodiments, the silicone-based biophotonic composition is irradiated until the chromophore is at least partially photobleached.

In certain embodiments of any of the foregoing or following, the light has a peak wavelength between about 400nm and about 750 nm. The light may have a peak wavelength between about 400nm and about 500 nm.

In certain embodiments of any of the foregoing or following, the light is from a direct light source, such as a lamp. The lamp may be an LED lamp. In certain embodiments, the light is from an ambient light source.

In certain embodiments of any of the foregoing or following, the silicone-based biophotonic composition is irradiated with a direct light source for about 1 minute to greater than 75 minutes, about 1 minute to about 60 minutes, about 1 minute to about 55 minutes, about 1 minute to about 50 minutes, about 1 minute to about 45 minutes, about 1 minute to about 40 minutes, about 1 minute to about 35 minutes, about 1 minute to about 30 minutes, about 1 minute to about 25 minutes, about 1 minute to about 20 minutes, about 1 minute to about 15 minutes, about 1 minute to about 10 minutes, or about 1 minute to about 5 minutes.

In another aspect, the present invention provides the use of the above composition: for use in tissue repair; for wound healing; for preventing or treating scars; for skin rejuvenation; for the treatment of skin disorders such as acne, eczema, psoriasis or dermatitis; for modulating inflammation; or for modulating collagen synthesis.

Drawings

Other aspects and advantages of the invention will become better understood with reference to the following description, in which:

fig. 1 shows the light emission spectra during 0-5 minutes of irradiation of one embodiment of the present invention comprising a silicone-based biophotonic composition in the form of a film.

Fig. 2 shows the light emission spectra of the film of fig. 1 during 5-10 minutes of irradiation.

Fig. 3 shows the light emission spectrum of the film of fig. 1 during 10-15 minutes of irradiation.

Figure 4, panels a and B show photo bleaching of the film of figure 1 over a specified period of time.

Fig. 5 shows a graph indicating the dermal thickness reduction of scars in a dermal fibrosis mouse-human skin graft model after treatment with a silicone-based biophotonic composition of the present specification.

Fig. 6 shows a graph of improved collagen remodeling measured with Collagen Orientation Index (COI) in a skin fibrotic mouse-human skin graft model after treatment with a silicone-based biophotonic composition.

Detailed Description

(1) Overview

The present invention provides silicone-based biophotonic compositions and uses thereof. Biophotonic therapies using these compositions will combine the beneficial effects of topical silicone compositions with photobiostimulation caused by the fluorescence generated by the chromophore upon irradiation of the composition. Furthermore, in certain embodiments, phototherapy using the silicone-based biophotonic membranes of the present invention will, for example, rejuvenate the skin, promote wound healing, prevent or treat scarring or treat skin disorders (such as acne, eczema, psoriasis) and treat periodontitis by, for example, promoting collagen synthesis.

(2) Definition of

Before proceeding with the further detailed description of the present invention, it is to be understood that this invention is not limited to particular compositions or process steps, as these may vary. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" as used herein in the context of a given value or range means that the value or range is within 20%, preferably within 10% and more preferably within 5% of the value or range given.

As used herein, "and/or" means that each feature or component specifically disclosed for two specified features or components, both of which may be present concurrently or separately. For example, "A and/or B" means that three cases (i) A, (ii) B and (iii) A and B are disclosed, each case independently in the present invention.

"biophotonic" refers to the generation, manipulation, detection, and application of photons in a biologically relevant context. In other words, biophotonic compositions exert their physiological effects primarily due to the generation and manipulation of photons.

By "topical application" or "topical use" is meant application to a body surface, such as the skin, mucosa, vagina, oral cavity, internal surgical wound site, and the like.

"emulsion" is understood to mean a temporary or permanent dispersion of one liquid phase in a second liquid phase. Typically, one of the phases is an aqueous solution and the other is a water-immiscible liquid. The water-immiscible liquid is generally referred to as the continuous phase. In the present invention, the continuous phase comprises silicone and is referred to as the silicone phase. Further, in the present invention, the aqueous phase contains a surfactant and is referred to as a surfactant phase.

In the present invention, the terms "chromophore" and "photoactivator" are used interchangeably. Chromophores are compounds that absorb light when exposed to light. Chromophores are readily photoexcited and then transfer their energy to other molecules or emit it as light (fluorescence).

"photobleaching" refers to the photochemical destruction of chromophores. The chromophore may be fully or partially photobleached.

The term "actinic light" refers to light energy emitted by a particular light source (e.g., a lamp, LED, or laser) and capable of being absorbed by a substance (e.g., a chromophore or photoactivator). The terms "actinic light" and "light" are used interchangeably herein. In a preferred embodiment, the actinic light is visible light.

"skin rejuvenation" refers to the process of reducing, eliminating, delaying or reversing one or more signs of skin aging or generally improving the condition of the skin. For example, skin rejuvenation may include increasing the brightness of the skin, reducing pore size, reducing fine lines or wrinkles, improving thinning and transparency of the skin, improving firmness, improving skin laxity (such as laxity caused by bone loss), improving skin dryness (which may be itchy), reducing or reversing freckles, reducing or preventing the appearance of age spots, spider veins, rough and leathery skin, fine wrinkles that disappear when stretched, reducing lax skin, or improving spot skin quality. According to the present invention, one or more of the conditions described above may be improved or one or more of the signs of aging may be reduced, eliminated, delayed or even reversed by certain embodiments of the compositions, methods and uses of the present invention.

"wound" refers to any tissue injury, including, for example, acute, subacute, delayed-healing or difficult-to-heal wounds, as well as chronic wounds. Examples of wounds may include open wounds and closed wounds. Wounds include, for example, amputations, burns, incisions, resections, injuries, lacerations, abrasions, puncture or penetrating wounds, surgical wounds, amputations, contusions, hematomas, pressure wounds, ulcers (such as pressure ulcers, diabetic ulcers, venous or arterial ulcers), scar formation, and wounds resulting from periodontitis (periodontal inflammation).

The features and advantages of the present subject matter will become more apparent with reference to the following detailed description of selected embodiments thereof, taken in conjunction with the accompanying drawings. As will be realized, the disclosed and claimed subject matter is capable of modifications in various respects, all without departing from the scope of the appended claims. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive, with the full scope of the subject matter being indicated in the claims.

(3) Silicone-based biophotonic compositions

The present invention broadly provides silicone-based biophotonic compositions and methods of using silicone-based biophotonic compositions. Silicone-based biophotonic compositions are broadly activatable by light (e.g., photons) of a particular wavelength. A silicone-based biophotonic composition according to various embodiments of the present disclosure includes a silicone phase and a surfactant phase, wherein at least one chromophore is dissolved in the surfactant phase. In some embodiments, the surfactant phase is emulsified in the silicone phase. Chromophores in silicone-based biophotonic compositions can be activated by light. This activation accelerates the dispersion of light energy, results in the light itself having a therapeutic effect and/or has a photochemical activation effect on other agents contained in the composition (e.g., accelerates the decomposition process of peroxides (oxidizing agents or oxidizing agents) when present in or in contact with the composition, which results in the formation of oxygen radicals, such as singlet oxygen). This can lead to decomposition of the chromophore and, in some embodiments, ensure that the silicone-based biophotonic composition (e.g., in the form of a film) is for a single use.

The chromophore is excited when it absorbs photons of a certain wavelength. This is an unstable state and the molecule will try to return to the ground state, releasing excess energy. For some chromophores, it is desirable to emit excess energy in the form of light when it returns to the ground state. This process is called fluorescence emission. As the conversion process loses energy, the peak wavelength of the emitted fluorescence is shifted towards longer wavelengths compared to the absorption wavelength. This phenomenon is called Stokes' shift. In a suitable environment (e.g., in a biophotonic composition), much of this energy is transferred to other components of the biophotonic composition or directly to the treatment site.

Without being bound by theory, it is believed that the light-activated chromophore emits fluorescence having therapeutic properties because of its femtosecond, picosecond, or nanosecond emission properties that are recognized by biological cells and tissues, resulting in beneficial biological modulation. Furthermore, in general, the emitted fluorescence has a longer wavelength and therefore penetrates deeper into the tissue than the activation light. Irradiating the tissue with such a wide range of wavelengths, including in certain embodiments activating light through the composition, has different and complementary effects on cells and tissue. In other words, chromophores are used in the silicone-based biophotonic compositions of the present invention in order to produce a therapeutic effect on tissue. This is a completely different application of these photoactivators, as opposed to the use of chromophores as simple colorants or as catalysts for photo-polymerization.

The silicone-based biophotonic compositions of the present invention may have topical applications, such as masks or wound dressings. In some embodiments, the silicone-based biophotonic composition is tacky. The tacky nature of these silicone-based biophotonic compositions may provide ease of removal from the treatment site and thus ease of use. Additionally or alternatively, the silicone-based biophotonic compositions of the present disclosure have functional and structural properties, and these properties may also be used to define and describe the compositions. The individual components of the silicone-based biophotonic compositions of the present invention, including the chromophore, the surfactant, the silicone, and other optional ingredients, are described in detail below.

(a)Chromophores

Suitable chromophores can be fluorescent compounds (or stains) (also referred to as "fluorescent dyes" or "fluorophores"). Other dye sets or dyes (biological and histological dyes, food colorants, carotenoids and other dyes) may also be used. Suitable photoactivators may be those Generally Regarded As Safe (GRAS). Advantageously, photoactivators that are not well tolerated by the skin or other tissue may be included in the biophotonic compositions of the present invention, such as in certain embodiments, the photoactivators are encapsulated in the surfactant phase of an emulsion in a silicone continuous phase.

In certain embodiments, the chromophore is a chromophore that undergoes partial or complete photobleaching upon application of light. In some embodiments, the chromophore absorbs at a wavelength in the visible spectral range, such as at a wavelength of about 380-800nm, 380-700nm, 400-800nm, or 380-600 nm. In other embodiments, the chromophore absorbs at a wavelength of about 200-800nm, 200-700nm, 200-600nm, or 200-500 nm. In one embodiment, the chromophore absorbs at a wavelength of about 200 nm to about 600 nm. In some embodiments, the chromophore absorbs light at a wavelength of about 200-300nm, 250-350nm, 300-400nm, 350-450nm, 400-500nm, 450-650nm, 600-700nm, 650-750nm, or 700-800 nm.

It will be appreciated by those skilled in the art that the optical properties of a particular chromophore may vary depending on the surrounding medium of the chromophore. Thus, as used herein, the absorption and/or emission wavelengths (or spectra) of a particular chromophore corresponds to the wavelengths (or spectra) measured in the biophotonic compositions of the present invention.

The silicone-based biophotonic compositions disclosed herein may include at least one additional chromophore or a second chromophore. The combination chromophore can increase light absorption by combining dye molecules and enhance the selectivity of absorption and photo-biological modulation. This creates a number of possibilities for creating new mixtures of photosensitive and/or selective chromophores. Thus, in certain embodiments, the silicone-based biophotonic compositions of the present disclosure comprise more than one chromophore, and energy transfer between the chromophores can occur when illuminated with light. This process, known as resonance energy transfer, is a widely prevalent photophysical process by which an excited "donor" chromophore (also referred to herein as the first chromophore) transfers its excitation energy to an "acceptor" chromophore (also referred to herein as the second chromophore). The efficiency and directionality of resonance energy transfer depends on the spectral characteristics of the donor and acceptor chromophores. In particular, the energy flow between chromophores depends on the spectral overlap reflecting the relative position and shape of the absorption and emission spectra. More specifically, for energy transfer to occur, the emission spectrum of the donor chromophore must overlap with the absorption spectrum of the acceptor chromophore.

Energy transfer is manifested by a reduction or quenching of the donor emission and a reduction in the excited state lifetime (also accompanied by an increase in the intensity of the acceptor emission). To enhance the energy transfer efficiency, the donor chromophore should have good ability to absorb and emit photons. In addition, the more overlap between the emission spectrum of the donor chromophore and the absorption spectrum of the acceptor chromophore, the better the donor chromophore can transfer energy to the acceptor chromophore.

Thus, in embodiments comprising a mixture of chromophores, the first chromophore has an emission spectrum that overlaps at least about 80%, 50%, 40%, 30%, 20%, or 10% of the absorption spectrum of the second chromophore. In one embodiment, the emission spectrum of the first chromophore overlaps at least about 20% with the absorption spectrum of the second chromophore. In some embodiments, the first chromophore has an emission spectrum that overlaps at least 1-10%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 50-60%, 55-65%, 60-70%, or 70-80% of the absorption spectrum of the second chromophore.

As used herein,% spectral overlap refers to the percentage of overlap of the emission wavelength range of the donor chromophore with the absorption wavelength range of the acceptor chromophore measured at one-quarter full width maximum (FWQM) of the spectrum. In some embodiments, the second chromophore absorbs at a wavelength in the visible spectral range. In some embodiments, the second chromophore has a relatively longer absorption wavelength than the absorption wavelength of the first chromophore, with the wavelength being in the range of about 50-250nm, 25-150nm, or 10-100 nm.

The chromophore may be present in an amount of about 0.001-40% per weight of the composition or surfactant phase. In certain embodiments, the at least one chromophore is present in an amount of about 0.001-3%, 0.001-0.01%, 0.005-0.1%, 0.1-0.5%, 0.5-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%, 10-15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40% per weight of the silicone-based biophotonic composition or surfactant phase.

When present, the second chromophore may be present in an amount of about 0.001-40% per weight of the silicone-based biophotonic composition or surfactant phase. In certain embodiments, the second chromophore is present in an amount of about 0.001-3%, 0.001-0.01%, 0.005-0.1%, 0.1-0.5%, 0.5-2%, 1-5%, 2.5-7.5%, 5% -10%, 7.5-12.5%, 10-15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40% per weight of the silicone-based biophotonic composition or surfactant phase. In certain embodiments, the total weight/weight of the chromophore or combination of chromophores may be an amount of about 0.005-1%, 0.05-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%, 10-15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40.001% per weight of the silicone-based biophotonic composition or surfactant phase.

The concentration of chromophore used may be selected based on the desired intensity and duration of biophotonic activity from the silicone-based biophotonic composition, and based on the desired medical or cosmetic effect. For example, some dyes, such as xanthene dyes, reach "saturation concentrations" after which further increases in concentration do not provide significantly higher emitted fluorescence. Further increasing the concentration of the chromophore above the saturation concentration may reduce the amount of activating light that passes through the matrix. Thus, if more fluorescence is required than the activating light for a certain application, a high concentration of chromophore can be used. However, if a balance is required between the emitted fluorescence and the activating light, a concentration near or below the saturation concentration may be selected.

Suitable chromophores that can be used in the silicone-based biophotonic compositions of the present invention include, but are not limited to, the following:

chlorophyll dyes

Exemplary chlorophyll dyes include, but are not limited to, chlorophyll a; chlorophyll b; chlorophyllin; bacteriochlorophyll a; bacteriochlorophyll b; bacteriochlorophyll c; bacteriochlorophyll d; a primary chlorophyll; a primary chlorophyll a; amphiphilic chlorophyll derivative 1; and amphiphilic chlorophyll derivative 2.

Xanthene derivative

Exemplary xanthene dyes include, but are not limited to, eosin B; eosin B (4',5' -dibromo-2 ',7' -dinitro-fluorescein dianion); eosin Y; eosin Y (2',4',5',7' -tetrabromo-fluorescein dianion); eosin (2',4',5',7' -tetrabromo-fluorescein dianion); eosin (2',4',5',7' -tetrabromo-fluorescein dianion) methyl ester; eosin (2',4',5',7' -tetrabromo-fluorescein monovalent anion) p-isopropylbenzyl ester; eosin derivatives (2',7' -dibromo-fluorescein dianion); eosin derivatives (4',5' -dibromo-fluorescein dianion); eosin derivatives (2',7' -dichloro-fluorescein dianion); eosin derivatives (4',5' -dichloro-fluorescein dianion); eosin derivatives (2',7' -diiodo-fluorescein dianion); eosin derivatives (4',5' -diiodo-fluorescein dianion); eosin derivatives (tribromofluorescein dianion); eosin derivatives (2',4',5',7' -tetrachloro-fluorescein dianion); eosin; eosin dihexadecylpyridinium chloride ion pair; erythrosin B (2',4',5',7' -tetraiodo-fluorescein dianion); erythrosine; erythrosine dianion; erythrosine B; fluorescein; a fluorescein dianion; fluorescent pink B (2',4',5',7' -tetrabromo-3, 4,5, 6-tetrachloro-fluorescein dianion); fluorescent pink B (tetrachloro-tetrabromo-fluorescein); fluorescent pink B; rose bengal (3,4,5, 6-tetrachloro-2 ',4',5',7' -tetraiodofluorescein dianion); pyronin G, pyronin J, pyronin Y; rhodamine dyes, such as rhodamine including 4, 5-dibromo-rhodamine methyl ester; 4, 5-dibromo-rhodamine n-butyl ester; rhodamine 101 methyl ester; rhodamine 123; rhodamine 6G; rhodamine 6G hexyl ester; tetrabromo-rhodamine 123; and tetramethyl-rhodamine ethyl ester.

Methylene blue dye

Exemplary methylene blue derivatives include, but are not limited to, 1-methyl methylene blue; 1, 9-dimethylmethylene blue; methylene blue; methylene violet; bromomethylene violet; 4-iodomethylene violet; 1, 9-dimethyl-3-dimethyl-amino-7-diethyl-amino-phenothiazine; and 1, 9-dimethyl-3-diethylamino-7-dibutyl-amino-phenothiazine.

Azo dyes

Exemplary azo (or disazo-) dyes include, but are not limited to, methyl violet, neutral red, para-red (pigment red 1), amaranth (azorubin S), acid red (azorubin, food red 3, acid red 14), allura red AC (FD & C40), tartrazine (FD & C yellow 5), orange G (acid orange 10), ponceau 4R (food red 7), methyl red (acid red 2), and ammonium diuranate-ammonium rhodanate.

In some aspects of the invention, the one or more chromophores of the silicone-based biophotonic composition can be independently selected from any of the following chromophores: acid black 1, Acid blue 22, Acid blue 93, Acid magenta (Acid fuchsin), Acid green 1, Acid green 5, Acid magenta, Acid orange 10, Acid red 26, Acid red 29, Acid red 44, Acid red 51, Acid red 66, Acid red 87, Acid red 91, Acid red 92, Acid red 94, Acid red 101, Acid red 103, Acid magenta (Acid roseine), Acid magenta (Acid rubin), Acid violet 19, Acid yellow 1, Acid yellow 9, Acid yellow 23, Acid yellow 24, Acid yellow 36, Acid yellow 73, Acid yellow S, orange, acridine yellow, alcian blue, alcian yellow, caneosin, alizarin blue 2RC, alizarin carmine, alizarin cyanine BBS, alizarin red S, alizarin magenta, aining aluline, amido black 10B, aminoblack (amowarz), aniline blue WS, SWR, anthranol blue B, azo red G, azo red, Azodiazo (Azoicdiazo)5, azodiazo 48, azure A, azure B, azure C, basic blue 8, basic blue 9, basic blue 12, basic blue 15, basic blue 17, basic blue 20, basic blue 26, basic Brown 1, basic fuchsin, basic Green 4, basic orange 14, basic Red 2, basic Red 5, basic Red 9, basic Violet 2, basic Violet 3, basic Violet 4, basic Violet 10, basic Violet 14, basic yellow 1, basic yellow 2, Bibriscarlet, Bismith Brown Y, Brilliant scarlet 6R, Callerian Red, carmine, carminic acid, azure blue B, Chinese blue, Worcehong, Coelestine blue, chrome Violet CG, chrome Variant 2R, Chromoxane cyanine R, Congo corinth, Congo Red, Cotton blue, Cotton Red, Crocein, scarlet, crocein Red, crocetin 6R, Crystal Chunhong 6R, Crystal Violet B, Crystal Green, Crystal blue B, Diamond Red, direct Variosa blue 14, direct Red 58, direct Violet blue, direct Red, Direct red 28, direct red 80, direct yellow 7, eosin B, blue eosin, eosin Y, yellow eosin, Eosinol, illipe red B, chrome cyanine R, erythrosine B, ethyl eosin, ethyl green, ethyl violet, Evans blue, fast blue B, fast green FCF, fast red B, fast yellow, fluorescein, food green 3, pyrogallophthalein, Galamin blue, betacyanin, gentian violet, hematoxylin oxide, hematoxylin violet, sunlight fast magenta BBL, methyl blue, hematoxylin violet, Hoffman violet, royal red, indocyanine green, Alisin blue 1, Alisin yellow 1, magenta, carmine, kermesic acid, heliotropin, shellac, Lacquercus, Rough violet, Richard green, Lissamine green SF, Luxol blue, Caragave blue, II, fuchsin, magenta, eosin green, chester yellow, chester green, eosin B, eos, Merbromin, mercuric oxide, acid m-amine yellow, methylene blue a, methylene blue B, methylene blue C, methylene blue, methyl green, methyl violet 2B, methyl violet 10B, mordant blue 3, mordant blue 10, mordant blue 14, mordant blue 23, mordant blue 32, mordant blue 45, mordant red 3, mordant red 11, mordant violet 25, mordant violet 39, naphthol blue black, naphthol green B, naphthol yellow S, natural black 1, natural green 3 (chlorophyll), natural red 3, natural red 4, natural red 8, natural red 16, natural red 25, natural red 28, natural yellow 6, NBT, natural red, neofuchsin, nija blue 3B, night blue, nitro BT, nitro blue tetrazolium, karyon red, lig G, orcein red, parafuchsin, fluorescent pink B, picric acid, ponceau 2R, livin red 6R, livid red B, ponceau B, xylidine B, ponceau 2R, mordant red B, mordant, Ponceau S, primrose, purpurin, pyronin B, phycocyanin, phycoerythrin, Phycoerythrocyanin (PEC), phthalocyanine, pyronin G, pyronin Y, quinine, rhodamine B, rosaniline, rose bengal, safranin O, scarlet R, shellac, champagne F3B, morrochromene cyanine R, soluble blue, genistein soluble eosin, sulfur S, Swiss blue, tartrazine, sulfur S, thioflavin T, thionin, toluidine blue, toluidine red, Kishina G, acridine yellow, trypan blue, fluorescein sodium, Victoria blue 4R, Victoria blue B, Victoria green B, vitamin B, water soluble blue I, water soluble eosin, xylidine red or yellow eosin.

In certain embodiments, the silicone-based biophotonic compositions of the present invention include any of the chromophores listed above, or combinations thereof, to provide a synergistic biophotonic effect at the site of administration.

Without being limited to any particular theory, the synergistic effect of the chromophore combination means that the biophotonic effect is greater than the sum of their respective effects. Advantageously, this may translate into increased reactivity, faster speed or improved treatment times of the biophotonic composition. Furthermore, no changes in treatment conditions, such as time of exposure to light, power of light source used and wavelength of light used, are required to achieve the same or better treatment results. In other words, the same or better treatment can be achieved using a synergistic combination of chromophores without necessarily requiring prolonged exposure to the light source, increased power to the light source, or the use of light sources of different wavelengths.

In some embodiments, the composition includes eosin Y as a first chromophore and one or more of rose bengal, fluorescein, erythrosine, phloxine B, chlorophyll as a second chromophore. It is believed that these combinations have a synergistic effect in that they can transfer energy from one chromophore to another chromophore when they are activated, in part, by overlapping or proximity to their absorption and emission spectra. This transferred energy is then emitted as fluorescence and/or results in the production of reactive oxygen species. This absorbed and re-emitted light is believed to be transmitted throughout the composition, and also into the treatment site.

In other embodiments, the silicone-based biophotonic composition may include, for example, the following synergistic combinations: eosin Y and fluorescein; fluorescein and rose bengal; erythrosin with eosin Y, rose bengal or fluorescein; phloxine B is associated with one or more of eosin Y, rose bengal, fluorescein, and erythrosine.

By the synergistic effect of the chromophore combination in the silicone-based biophotonic composition, chromophores that are not normally activated by activating light (such as blue light from an LED) can be activated by energy transfer from the chromophores activated by the activating light. In this way, photoactivated chromophores of different nature can be utilized and tailored according to the desired cosmetic or medical treatment.

For example, rose bengal may produce higher singlet oxygen when it is activated in the presence of molecular oxygen. However, the quantum yield of rose bengal is low in terms of emission of fluorescence. The peak absorption of rose bengal is around 540nm and therefore it can be activated with green light. Eosin Y has a high quantum yield and can be activated with blue light. The combination of rose bengal and eosin Y results in a composition that emits therapeutically useful fluorescence and produces singlet oxygen when activated by blue light. In this case, blue light photoactivates eosin Y, which transfers some of its energy to rose bengal and emits some of the energy as fluorescence.

In some embodiments, the one or more chromophores are selected such that upon photo-activation they emit fluorescence in one or more of the green, yellow, orange, red, and infrared portions of the electromagnetic spectrum, e.g., with a peak wavelength in the range of about 490nm to about 800 nm. In some embodiments, the emitted fluorescence has from 0.005 to about 10mW/cm²About 0.5 to about 5mW/cm²The power density of (a).

(b)Surfactant phase

The silicone-based biophotonic compositions of the present invention comprise a surfactant phase. The surfactant may be present in an amount of at least 5%, 10%, 15%, 20%, 25% or 30% of the total composition. In certain embodiments, the surfactant phase comprises a block copolymer. The term "block copolymer" as used herein refers to a copolymer consisting of 2 or more blocks (or segments) of different homopolymers. The term homopolymer refers to a polymer composed of a single monomer. Many variations of block copolymers are possible, including simple diblock polymers having an A-B structure and triblock polymers having an A-B-A, B-A-B or A-B-C structure, and more complex block copolymers are known. In addition, unless otherwise specified herein, the number and type of repetition of the monomers or repeating units constituting the block copolymer are not particularly limited. For example, when the monomer repeating unit is represented by "a" and "b", it means that the copolymer includes not only having (a)_m(b)_nAnd comprising the composition (a)_m(b)_nAnd composition (a)_l(b)_m(a)_nAnd the like.In the above formula, l, m and n represent the number of repeating units and are positive numbers.

In certain embodiments of any of the foregoing or following, the block copolymer is biocompatible. The polymers are "biocompatible" in that the polymers and their degradation products are substantially non-toxic to cells or organisms, including non-carcinogenic and non-immunogenic, and are cleared or otherwise degraded in biological systems such as organisms (patients) without substantial toxic effects.

In certain embodiments, the block copolymer of the surfactant phase is from a group of triblock copolymers known as poloxamers. Poloxamers are A-B-A block copolymers in which the A segment is a hydrophilic polyethylene glycol (PEG) homopolymer and the B segment is a hydrophobic polypropylene glycol (PPG) homopolymer. PEG is also known as polyethylene oxide (PEO) or Polyethylene Oxide (POE), depending on its molecular weight. In addition, PPG is also known as polypropylene oxide (PPO), depending on its molecular weight. Poloxamers are commercially available from BASF corporation. Poloxamers produce reverse phase hot gelatin compositions, i.e. having the following properties: its viscosity increases with increasing temperature up to the point where the viscosity decreases again. Depending on the relative size of the blocks, the copolymer may be solid, liquid or paste. In certain embodiments of the invention, the poloxamer is a poloxamerF127 (also known as poloxamer 407). In some embodiments of the silicone-based biophotonic compositions, the amount of the total composition may be included in the range of 1 to 40 wt.%F127. In some embodiments of the silicone-based biophotonic compositions, 1-5 wt.%, 2.5-7.5 wt.%, 5-10 wt.%, 7.5-12.5 wt.%, 10-15 wt.%, 12.5-17.5 wt.%, 15-20 wt.%, 20-25 wt.%, 25-30 wt.%, 30-35 wt.%, 35-40 wt.% of pluronic may be included. In some embodiments of the present invention, the substrate is,f127 is present in an amount of 2-8 wt% of the total composition of the silicone based biophotonic composition.

In certain embodiments of the present invention, the surfactant phase comprises a block copolymer comprising at least a-B units, wherein a is PEG and B is polylactic acid (PLA) or polyglycolic acid (PGA) or poly (lactic-co-glycolic acid) PLGA) or Polycaprolactone (PCL) or Polydioxanone (PDO).

Since the PEG block provides hydrophilicity to the polymer, increasing the length of the PEG block or the total amount of PEG in the polymer will tend to make the polymer more hydrophilic. Depending on the amount and ratio of the other components of the polymer, the desired overall hydrophilicity, and the nature and chemical functionality of any chromophore that may be included in the polymer formulation, one skilled in the art can readily adjust the length (or MW) of the PEG block and/or the total amount of PEG incorporated into the polymer in order to obtain a polymer having the desired physical and chemical properties.

The total amount of PEG in the polymer may be about 80 wt% or less, 75 wt% or less, 70 wt% or less, 65 wt% or less, about 60 wt% or less, about 55 wt% or less, or about 50 wt% or less. In particular embodiments, the total amount of PEG is about 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, or about 70 wt%. Unless otherwise specified, a weight percent of a particular component of a polymer means that the total weight of the polymer consists of the specified percentage of monomers of that component. For example, 65 wt.% PEG means that 65 wt.% of the polymer is made up of PEG monomers that are linked into blocks of different lengths that are distributed along the length of the polymer, including in a random distribution.

The total amount of PPG or PLA or PLGA or PCL or PDO present in the block copolymer may be about 50 wt% or less, about 45 wt% or less, about 40 wt% or less, about 35 wt% or less, about 30 wt% or less, about 25 wt% or less, or about 20 wt% or less.

The surfactant phase may also include thickeners or stabilizers such as gelatin and/or modified celluloses such as hydroxyethyl cellulose (HEC) and carboxymethyl Cellulose (CMD), and/or polysaccharides such as xanthan gum, guar gum and/or starch and/or any other thickener. In certain embodiments of the invention, the stabilizing or thickening agent may comprise gelatin. For example, the surfactant phase may comprise about 0-5 wt%, about 5-25 wt%, about 0-15 wt%, or about 10-20 wt% gelatin.

The surfactants and/or stabilizers may be selected according to their effect on the optical transparency of the biophotonic film. The silicone-based biophotonic composition should be capable of transmitting (transmit) sufficient light to activate at least one chromophore, and in embodiments where fluorescence is emitted by the activated chromophore, the surfactant phase should also be capable of transmitting the emitted fluorescence to the tissue.

(c)Silicone phase

The silicone-based biophotonic compositions of the present invention comprise a continuous phase of silicone. Silicones are synthetic polymers containing chains composed of (-Si-O-) repeating units, in which two organic groups are attached directly to the Si atom. In certain embodiments, the silicone is Polydimethylsiloxane (PDMS) fluid (Me)₂SiO)_nOr a PDMS based gel or a PDMS based elastomer.

Non-limiting examples of PDMS polymers include those sold under the trademark Sylgard, and specifically Sylgard 182, Sylgard184, Sylgard 186, and Sylgard 527.

In certain embodiments, the silicone phase of the silicone-based biophotonic composition can be prepared by using commercially available kits such as184 silicone elastomer kit. The kit consists ofTwo-part liquid components, namely a binder (part a) and a curing agent or catalyst (part B), both parts being based on polydimethylsiloxane. When mixed at a ratio of 10(A)/1(B), the mixture cures into a flexible and transparent elastomer.

Sylgard184 is a silicone elastomer comprising polydimethylsiloxane and organically modified silica gel. Sylgard184 was prepared by combining the base (part a) and curing agent (part B). The binder contains about > 60% by weight dimethylvinyl terminated dimethylsilane, about 30 to 60% by weight dimethylvinylated and trimethylated silica gel and about 1 to 5% by weight tetrakis (trimethylsiloxy) silane. The curing agent contains about 40 to 70 weight percent dimethyl, methylhydrogen siloxane, about 15 to 40 weight percent dimethylvinyl terminated dimethyl siloxane, about 10 to 30 weight percent dimethylvinylated and trimethylated silica gel and about 1 to 5 weight percent tetramethyltetravinylcyclotetrasiloxane.

In another embodiment, the silicone phase of the silicone-based biophotonic composition may be formed by using527 Silicone gel kit preparation, which allows for the preparation of a soft and viscous gel when the two parts A and B are mixed in 1(A)/1 (B). The A and B parts of Sylgard contain about 85 to 100 weight percent dimethylvinyl terminated dimethylsiloxane and about 1 to 5 weight percent dimethyl, methylhydrogensiloxane.

In other embodiments, silicone-based biophotonic compositions, such as silicone-based biophotonic films having tunable flexibility, may be prepared in a manner that provides a desired tunable flexibility. One method of producing the tunable silicone-based biophotonic membranes of the present invention is by combining different proportions of commercially available PDMS such as184 and527. in some implementationsIn the scheme, the silicone phase contains silicone phase in an amount of 5-100 wt%184. In some embodiments of the present invention, the substrate is,184 is present in an amount of about 5-10 wt.%, 10-15 wt.%, 15-20 wt.%, 20-25 wt.%, 25-30 wt.%, 30-35 wt.%, 35-40 wt.%, 40-45 wt.%, 45-50 wt.%, 50-55 wt.%, 55-60 wt.%, 60-65 wt.%, 65-70 wt.%, 70-75 wt.%, 75-80 wt.%, 80-85 wt.%, 85-90 wt.%, 90-95 wt.%, or 95-100 wt.% of the silicone phase. In certain embodiments of the present invention, the silicone phase comprises527. In certain other embodiments of the present invention,527 is present in an amount of about 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100% by weight of the silicone phase.

In one embodiment, the silicone phase of the silicone-based biophotonic composition is a mixture using 15% Sylgard184 and 85% Sylgard 527.

(d)Oxidizing and antimicrobial agents

According to certain embodiments, the silicone-based biophotonic compositions of the present invention or the surfactant phase of these silicone-based biophotonic compositions may optionally comprise one or more additional components, such as oxygen-rich compounds as a source of oxygen radicals. Oxygen-rich compounds include, but are not limited to, peroxides such as hydrogen peroxide, benzoyl peroxide, and urea peroxide. Peroxide compounds are peroxy-containing (R-O-R) oxidizing agents which are chain structures containing two oxygen atoms, each oxygen atom being linked to another oxygen atom and a group or an element. When the silicone-based biophotonic compositions of the present invention are irradiated with light, the chromophore is excited to a higher energy state. When the electrons of the chromophores return to a lower energy state, they emit photons with a lower energy level, causing the emission of light with a longer wavelength (stokes shift). Some of this energy may be transferred to the oxidant and may result in the formation of oxygen radicals such as singlet oxygen. These oxygen radicals can contribute to degradation of the chromophore.

Hydrogen peroxide (H)₂O₂) Is a powerful oxidant and decomposes into water and oxygen without forming any persistent toxic residual compounds. Suitable concentrations of hydrogen peroxide that may be used in the silicone-based biophotonic composition range from about 0.1% to about 3%, about 0.1 to 1.5%, about 0.1% to about 1%, less than about 1%.

Carbamide peroxide (also known as urea peroxide, carbamide peroxide, percarbamide) is soluble in water and contains about 35% hydrogen peroxide. Suitable concentration ranges for carbamide peroxide that can be used in the silicone-based biophotonic compositions of the present invention are less than about 0.25%, or less than about 0.3%, 0.001 to 0.25%, or about 0.3% to about 5%. Carbamide peroxide decomposes in a slow-release manner to urea and hydrogen peroxide, which can be accelerated by heat or photochemical reactions.

Benzoyl peroxide consists of two benzoyl groups attached to a peroxy group (carboxylic acid H in benzoic acid is removed). Suitable concentrations of benzoyl peroxide that can be used in the silicone-based biophotonic composition range from about 2.5% to about 5%.

Antimicrobial agents kill microorganisms or inhibit their growth or accumulation, and may optionally be included in the silicone-based biophotonic compositions of the present invention. Suitable antimicrobial agents for use in the methods and compositions of the present invention include, but are not limited to, hydrogen peroxide, urea peroxide, benzoyl peroxide, phenolic and chlorinated phenolic compounds, resorcinol and its derivatives, bisphenol compounds, benzoates (parabens), halocarbanilides, polymeric antimicrobial agents, thiazolines, trichloromethylthioimides, natural antimicrobial agents (also known as "natural essential oils"), metal salts, and broad spectrum antibiotics.

Specific phenolic and chlorophenol-type antimicrobial agents that can be used in the present invention include, but are not limited to: phenol; 2-methylphenol; 3-methylphenol; 4-methylphenol; 4-ethylphenol; 2, 4-dimethylphenol; 2, 5-dimethylphenol; 3, 4-dimethylphenol; 2, 6-dimethylphenol; 4-n-propylphenol; 4-n-butylphenol; 4-n-pentylphenol; 4-tert-amylphenol; 4-n-hexylphenol; 4-n-heptylphenol; mono-and poly-alkyl and aromatic halophenols; p-chlorophenol; methyl p-chlorophenol; ethyl p-chlorophenol; n-propyl p-chlorophenol; n-butyl p-chlorophenol; n-pentyl-p-chlorophenol; sec-pentyl p-chlorophenol; n-hexyl p-chlorophenol; cyclohexyl p-chlorophenol; n-heptyl p-chlorophenol; n-octyl p-chlorophenol; o-chlorophenol; methyl o-chlorophenol; ethyl o-chlorophenol; n-propyl o-chlorophenol; n-butyl o-chlorophenol; n-pentyl o-chlorophenol; tert-amyl o-chlorophenol; n-hexyl ortho-chlorophenol; n-heptyl ortho-chlorophenol; o-benzyl p-chlorophenol; o-benzyl-m-methyl-p-chlorophenol; o-benzyl-m, m-dimethyl-p-chlorophenol; o-phenylethyl p-chlorophenol; o-phenylethyl-m-methyl-p-chlorophenol; 3-methyl-p-chlorophenol; 3, 5-dimethyl-p-chlorophenol; 6-ethyl-3-methyl-p-chlorophenol, 6-n-propyl-3-methyl-p-chlorophenol; 6-isopropyl-3-methyl-p-chlorophenol; 2-ethyl-3, 5-dimethyl-p-chlorophenol; 6-sec-butyl-3-methyl-p-chlorophenol; 2-isopropyl-3, 5-dimethyl-p-chlorophenol; 6-diethylmethyl-3-methyl-p-chlorophenol; 6-isopropyl-2-ethyl-3-methyl-p-chlorophenol; 2-sec-pentyl-3, 5-dimethyl-p-chlorophenol; 2-diethylmethyl-3, 5-dimethyl-p-chlorophenol; 6-sec-octyl-3-methyl-p-chlorophenol; p-chloro-m-cresol p-bromophenol; methyl p-bromophenol; ethyl p-bromophenol; n-propyl p-bromophenol; n-butyl p-bromophenol; n-pentyl p-bromophenol; sec-pentyl p-bromophenol; n-hexyl p-bromophenol; cyclohexyl p-bromophenol; o-bromophenol; tert-amyl o-bromophenol; n-hexyl o-bromophenol; n-propyl-m, m-dimethyl o-bromophenol; 2-phenylphenol; 4-chloro-2-methylphenol; 4-chloro-3-methylphenol; 4-chloro-3, 5-dimethylphenol; 2, 4-dichloro-3, 5-dimethylphenol; 3,4,5, 6-tetrabromo-2-methylphenol; 5-methyl-2-pentylphenol; 4-isopropyl-3-methylphenol; para-chloro-meta xylenol (PCMX); chlorothymol; phenoxyethanol; phenoxy isopropanol; and 5-chloro-2-hydroxydiphenylmethane.

Resorcinol and its derivatives are also useful as antimicrobial agents. Specific resorcinol derivatives include, but are not limited to: methyl resorcinol; ethyl resorcinol; n-propyl resorcinol; n-butyl resorcinol; n-amyl resorcinol; n-hexylresorcinol; n-heptyl resorcinol; n-octyl resorcinol; n-nonyl resorcinol; phenyl resorcinol; benzyl resorcinol; phenethyl resorcinol; phenylpropylresorcinol; p-chlorobenzyl resorcinol; 5-chloro-2, 4-dihydroxydiphenylmethane; 4' -chloro-2, 4-dihydroxydiphenylmethane; 5-bromo-2, 4-dihydroxydiphenylmethane; and 4' -bromo-2, 4-dihydroxydiphenylmethane.

Specific bisphenol antimicrobial agents that may be used in the present invention include, but are not limited to: 2,2' -methylenebis- (4-chlorophenol); 2,4,4 '-trichloro-2' -hydroxy-diphenyl ether, Ciba Geigy, Florham Park, n.jA product for sale; 2,2' -methylenebis- (3,4, 6-trichlorophenol); 2,2' -methylenebis- (4-chloro-6-bromophenol); bis- (2-hydroxy-3, 5-dichloro-p-hexyl) sulfide; and bis- (2-hydroxy-5-chlorophenylmethyl) sulfide.

Specific benzoates (parabens) that may be used in the present invention include, but are not limited to: methyl paraben; propyl p-hydroxybenzoate; butyl p-hydroxybenzoate; ethyl p-hydroxybenzoate; isopropyl p-hydroxybenzoate; isobutyl p-hydroxybenzoate; benzyl paraben; sodium methyl paraben; and sodium propyl p-hydroxybenzoate.

Specific halocarbanilides useful in the present invention include, but are not limited to: 3,4,4' -trichlorocarbanilides, such as 3- (4-chlorophenyl) -1- (3, 4-dichlorophenyl) urea, Ciba-Geigy, Florham Park, N.J. under the trade nameA product for sale; 3-trifluoromethyl-4, 4' -dichlorocarbanilide; and 3,3', 4-trichlorocarbanilide.

Specific polymeric antimicrobial agents that may be used in the present invention include, but are not limited to: polyhexamethylene biguanide hydrochloride; and poly (iminoiminoiminocarbonyliminohexamethylenehydrochloride) under the trade name ofIB is sold.

Specific thiazolines that may be used in the present invention include, but are not limited to: under the trade name ofA product for sale; and 2-n-octyl-4-isothiazolin-3-one, trade nameIT-3000 DIDP.

Specific trichloromethylthioimides which may be used in the present invention include, but are not limited to: n- (trichloromethylthio) phthalimide, trade nameSelling; and N-trichloromethylthio-4-cyclohexene-1, 2-dicarboximide, trade nameAnd (5) selling.

Specific natural antimicrobial agents that may be used in the present invention include, but are not limited to, oils of the following: anise; lemon; citrus; rosemary; wintergreen; thyme; lavender; clove; hop; tea trees; 1, citronella; wheat; barley; herba Cymbopogonis Citrari; cedar leaf; fir; cinnamon; inula flower (fleagrass); geranium wilfordii; sandalwood; violet; blueberry; eucalyptus; verbena; mint; benzoin gum; basil; fennel; fir tree; impatiens balsamina L; menthol; oregano (ocea origanin); coptisine; carrageen (carratensis); berberidaceae (berberidaceae); ratanhiae root (Ratanhiae longa); and turmeric. Also included in the class of natural antimicrobial agents are key chemical components found in vegetable oils that can provide antimicrobial benefits. These chemicals include, but are not limited to: anethole; catechol; camphene; thymol; eugenol; eucalyptol; ferulic acid; farnesol; hinokitiol; an oxalophenone; a limonene; menthol; methyl salicylate; carvacrol; terpineol; verbenone; berberine; ratanhiae root (ratanhiae) extract; eugenol oxide; citronellac acid; turmeric; nerolidol; and geraniol.

Specific metal salts that can be used in the present invention include, but are not limited to, salts of metals of groups 3a-5a, 3b-7b and 8 of the periodic Table of the elements. Specific examples of the metal salt include, but are not limited to, salts of the following metals: aluminum; zirconium; zinc; silver; gold; copper; lanthanum; tin; mercury; bismuth; selenium; strontium; scandium; yttrium; cerium; praseodymium; neodymium; promethium; samarium; europium; gadolinium; terbium; dysprosium; holmium; erbium; thallium; ytterbium; distilling; and mixtures thereof. An example of a metal ion-based antimicrobial agent is HealthShield Technology, manufactured by Wakefield, Mass., under the trade nameAn antimicrobial agent is marketed.

Specific broad spectrum antimicrobial agents that may be used in the present invention include, but are not limited to, those referenced in other antimicrobial classes of the present invention.

Other antimicrobial agents that may be used in the methods of the present invention include, but are not limited to: pyrithione species (pyrithiones), in particular pyrithione-including zinc complexes, such as are known under the trade nameA product for sale; dimethyldimethyldimethyldimethyldimethylol hydantoin (dimethyldimethyldimethylol hydantoin) under the trade name dimethylol hydantoinA product for sale; methylchloroisothiazolinone/methylisothiazolinone, tradename KathonA product for sale; sodium sulfite; sodium bisulfite; imidazolidinyl ureas under the trade name GermallA product for sale; diazolidinyl ureas under the trade name GermallA product for sale; benzyl alcohol v 2-bromo-2-nitropropane-1, 3-diol, tradenameA product for sale; formalin or formaldehyde; iodopropenylbutyl carbamate (Iodopropenylbutyl carbamate) available under the trade name PolyphaseSelling; chloroacetamide; methylamine (methanamine); methylbromicronitrile glutaronitrile (1, 2-dibromo-2, 4-dicyanobutane), trade nameSelling; glutaraldehyde; 5-bromo-5-nitro-1, 3-dioxane, trade nameSelling; phenyl ethyl alcohol; o-phenylphenol/sodium o-phenylphenol hydroxymethyl glycine sodium salt under the trade name SuttocideSelling; polymethoxybicyloxazolidines, under the name NuoseptSelling; dimethyl siloxane; thimerosal; dichlorobenzyl alcohol; captan; chlorepnenesin; a bischlorophenol; chlorobutanol; lauric acid glyceride; halogenated diphenyl ethers; 2,4,4 '-trichloro-2' -hydroxy-diphenyl ether, trade nameSold and available from Ciba-Geigy, Florham Park, n.j.; and 2,2 '-dihydroxy-5, 5' -dibromo-diphenyl ether.

(4) Optical properties of silicone-based biophotonic compositions

In certain embodiments, the silicone-based biophotonic compositions of the present invention are substantially transparent or translucent. The% light transmittance of the silicone-based biophotonic composition may be measured in the wavelength range of 250nm to 800nm using, for example, a Perkin-Elmer Lambda 9500 series UV-visible spectrophotometer. In some embodiments, the light transmittance in the visible range is measured and the data averaged. In some other embodiments, the light transmittance of the silicone-based biophotonic composition is measured with the chromophore omitted. Since the light transmittance is dependent on the thickness, the thickness of each sample was measured using a caliper before the samples were loaded into the spectrophotometer. The transmittance data can be normalized according to the following equation

Wherein, t₁Actual thickness of the sample, t₂Normalized thickness is measured as light transmittance. In the art, the light transmittance measurement is typically normalized to 1 cm.

In some embodiments, the silicone-based biophotonic composition has a light transmittance of greater than about 20%, 30%, 40%, 50%, 60%, 70%, or 75% in the visible range. In some embodiments, the light transmittance in the visible range is more than 40%, 41%, 42%, 43%, 44%, or 45%. In some embodiments, the silicone-based biophotonic composition has a light transmittance of about 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, or 95-100%.

(5) Forms of silicone-based biophotonic compositions

The silicone-based biophotonic compositions of the present invention may be in the form of a silicone-based biophotonic film comprising at least one chromophore.

The silicone-based biophotonic membranes of the present invention may be deformable. They may be elastic or inelastic (i.e., flexible or rigid). For example, silicone-based biophotonic films can be in a peelable form ("peelable"), making them simple and quick to use. In certain embodiments, the peel form has a tear strength and/or tensile strength greater than its adhesive strength. This may contribute to the operability of silicone-based biophotonic membranes. One skilled in the art will recognize that properties of the peeled silicone-based biophotonic film, such as tack, flexibility, elasticity, tensile strength, and tear strength, can be determined and/or adjusted by methods known in the art, such as by selecting appropriate PDMS-based compositions and adjusting their relative ratios.

The silicone-based biophotonic composition may be provided in a preformed shape. In certain embodiments, the preformed shape is (including but not limited to) a film, mask, patch, dressing, or bandage. In certain embodiments, the preformed shape may be customized for an individual user by modifying the dimensions. In some embodiments, holes are provided at the perimeter of the preformed shape to facilitate trimming. In some embodiments, preforming may be accomplished manually or by mechanical means (such as 3-D printing). If 3-D printing is used, the size of the area to be treated can be imaged, such as a wound or face, and then the 3-D printer is configured, constructed or formed with an adhesive silicone-based biophotonic composition that matches the size and shape of the imaged treatment area.

The silicone-based biophotonic compositions of the present disclosure may be configured to have a shape and/or size suitable for a desired site of a subject's body. For example, the silicone-based biophotonic composition may be shaped and sized to correspond to a desired site of a body receiving biophotonic therapy. The skin of such desired site may be selected from (including but not limited to) skin, head, forehead, scalp, nose, cheek, lips, ears, face, neck, shoulder, armpit, arm, elbow, hand, finger, abdomen, chest, belly, back, hip, sacrum, genitals, leg, knee, foot, toe, nail, hair, any bony prominence, combinations thereof, and the like. Thus, the silicone-based biophotonic compositions of the present invention can be shaped and sized to be suitable for application to the skin of any part of the subject's body. For example, the silicone-based biophotonic composition may be in the form of a sock, hat, glove, or mitt shape. In embodiments where the silicone-based biophotonic composition is in an elastic, semi-rigid, or rigid form, it may be peeled away without leaving any residue on the tissue.

In certain embodiments, the silicone-based biophotonic composition is in the form of a preshapable elastic releasable face mask. In other embodiments, the silicone-based biophotonic composition is in the form of a non-elastic (rigid) facemask that may also be preformed. The mask may have apertures for one or both eyes, nose and mouth. In another embodiment, the opening is protected with a cover; the exposed skin of the nose, lips or eyes is protected with, for example, cocoa butter. In certain embodiments, the preformed facemasks are comprised of several parts, for example, an upper face portion and a lower face portion. In some embodiments, the uneven proximity of the face to the light source is compensated for by: for example by adjusting the thickness of the mask, or by adjusting the amount of chromophore in different parts of the mask, or by masking the skin in the immediate vicinity of the light. In certain embodiments, only one size fits all the forms of the preformed shape.

In certain embodiments, the silicone-based biophotonic composition is in the form of a wound dressing or bandage. It may be applied to wounds to prevent or limit scar formation, or to existing wounds to reduce the appearance of scars.

In certain aspects, the face mask (or patch) is not preformed and is administered, for example, by spreading the silicone-based biophotonic composition comprising the face mask (or patch) on the skin or target tissue, or by spreading, coating, or rolling the composition on the target tissue. It can then be converted to an exfoliated form after application by means such as, but not limited to, drying or inducing a temperature change upon application to the skin or tissue. After use, the mask (or patch) can then be peeled off without leaving any flakes on the skin or tissue, preferably without wiping or rinsing.

The silicone-based biophotonic compositions of the present invention may have a thickness of about 0.1mm to about 50mm, about 0.5mm to about 20mm, or about 1mm to about 10mm, for example, when provided in the form of a silicone-based biophotonic film, mask, or dressing. It should be appreciated that the thickness will vary based on the intended use. In some embodiments, the thickness ranges from about 0.1mm to about 1 mm. In some embodiments, the thickness ranges from about 0.5mm to about 1.5mm, from about 1mm to about 2mm, from about 1.5mm to about 2.5mm, from about 2mm to about 3.5mm, from about 3mm to about 4mm, from about 3.5mm to about 4.5mm, from about 4mm to about 5mm, from about 4.5mm to about 5.5mm, from about 5mm to about 6mm, from about 5.5mm to about 6.5mm, from about 6mm to about 7mm, from about 6.5mm to about 7.5mm, from about 7mm to about 8.5mm, from about 8mm to about 9mm, from about 8.5mm to about 9.5mm, from about 9mm to about 10mm, from about 10mm to about 11mm, from about 11mm to about 12mm, from about 12mm to about 13mm, from about 13mm to about 14mm, from about 14mm to about 15mm, from about 15mm to about 16mm, from about 16mm to about 17mm, from about 18mm to about 19mm, from about 22mm to about 24, About 26-28mm, about 28-30mm, about 30-35mm, about 35-40mm, about 40-45mm, about 45-50 mm.

The tensile strength of the silicone-based biophotonic composition will vary based on the intended use. Tensile strength can be determined by conducting a tensile test and recording the force and displacement. These can then be converted into stress (using cross-sectional area) and strain; the highest point of the stress-strain curve is the "ultimate tensile strength". In some embodiments, such as when in the form of a silicone-based biophotonic film, the tensile strength is measured using a 500N bench-top mechanical test system (#5942R4910,) Characterization was performed with a 5N maximum static load sensor (#102608, Instron). Pneumatic edge action grips can be used to hold the sample (#2712-019, Instron). In some embodiments, a constant stretch rate (e.g., about 2mm/min) may be applied until failure, and the tensile strength calculated from the stress versus strain data plot. In some embodiments, the tensile strength may be determined using american society for testing and materials tensile test methods, such as the methods described in ASTM D638, ASTM D882, and ASTM D412, or methods comparable to these methods.

In some embodiments, the silicone-based biophotonic composition has a tensile strength of at least about 50kPa, at least about 100kPa, at least about 200kPa, at least about 300kPa, at least about 400kPa, at least about 500kPa, at least about 600kPa, at least about 700kPa, at least about 800kPa, at least about 900kPa, at least about 1MPa, at least about 2MPa or at least about 3MPa, or at least about 5MPa, or at least about 6 MPa. In some embodiments, the silicone-based biophotonic composition has a tensile strength of up to about 10 MPa.

The tear strength of the silicone-based biophotonic composition will vary depending on the intended use. For example, when provided in the form of a silicone-based biophotonic film, the tear strength properties of the silicone-based biophotonic composition may be tested with a 5N maximum static load cell (#102608, Instron) using a 500N capacity bench top mechanical testing system (#5942R4910, Instron). Pneumatic edge action grips can be used to hold the sample (#2712-019, Instron). The sample may be tested using a constant stretch rate (e.g., about 2mm/min) until failure. According to the present invention, tear strength can be calculated as the force at failure divided by the average thickness (N/mm).

In some embodiments, the silicone-based biophotonic composition has a tear strength of about 0.1N/mm to about 5N/mm. In some embodiments, the tear strength is from about 0.1N/mm to about 0.5N/mm, from about 0.25N/mm to about 0.75N/mm, from about 0.5N/mm to about 1.0N/mm, from about 0.75N/mm to about 1.25N/mm, from about 1.0N/mm to about 1.5N/mm, from about 1.5N/mm to about 2.0N/mm, from about 2.0N/mm to about 2.5N/mm, from about 2.5N/mm to about 3.0N/mm, from about 3.0N/mm to about 3.5N/mm, from about 3.5N/mm to about 4.0N/mm, from about 4.0N/mm to about 4.5N/mm, from about 4.5N/mm to about 5.0N/mm.

The adhesive strength of the silicone-based biophotonic composition will vary depending on the intended use. The adhesive strength can be determined according to ASTM D-3330-78, PSTC-101, and is a measure of the force required to remove a silicone-based biophotonic composition from a test panel at a particular angle and removal rate. In some embodiments, a silicone-based biophotonic composition of a predetermined size, such as a silicone-based biophotonic film, is applied to a horizontal surface of a clean glass test plate. A hard rubber roller was used to firmly apply a piece of silicone-based biophotonic film and remove all discontinuities and entrapped air. The free end of the silicone-based biophotonic film of the sheet then almost engaged with itself, such that the removal angle of the sheet from the glass plate is 180 degrees. The free end of the silicone-based biophotonic membrane is attached to an adhesion tester scale (e.g., an Instron tensile tester or a Harvey tensile tester). The test plate is then clamped in a clamp of a tensile tester, which is able to be pulled away from the scale at a predetermined constant rate. When the silicone-based biophotonic film was peeled off the glass surface, a scale reading in kg was recorded.

In some embodiments, the adhesive strength can be measured by considering the static friction of the biophotonic composition. For some embodiments of the silicone-based biophotonic compositions of the present invention,the adhesive properties are related to its level of static friction or stiction. In these cases, the adhesive strength can be measured by placing a sample of a silicone-based biophotonic composition, such as a silicone-based biophotonic film, on a test surface and pulling one end of the sample at approximately 0 ° (substantially parallel to the surface) while applying a known downward force (e.g., weight) on the sample and measuring the weight of the sample slipping off the surface. Normal force F_nIs the force exerted by each surface on another surface perpendicular (normal) to the surface, and is multiplied by the total weight of the sample and weight by the gravitational constant (g) (9.8 m/s)²) And (6) performing calculation. The sample with the top weight is then pulled out of the balance until the sample slides off the surface and the weight is recorded on the scale. The weight recorded on the scale is equal to the force required to overcome the friction. Then, the weight recorded on the scale is multiplied by g to calculate the frictional force (F)_f). Due to F_f≤μF_n(Coulomb's law of friction), F_fDivided by F_nThe coefficient of friction μ can be obtained. Then, by multiplying the weight of the material by the friction coefficient, the stress (adhesive strength) required to shear the material from the surface can be calculated from the friction coefficient μ.

In some embodiments, the silicone-based biophotonic composition has an adhesive strength less than its tensile strength or its tear strength.

In some embodiments, the adhesive strength of the silicone-based biophotonic composition is about 0.01N/mm to about 0.60N/mm. In some embodiments, the bond strength is from about 0.20N/mm to about 0.40N/mm, or from about 0.25N/mm to about 0.35N/mm. In some embodiments, the bond strength is less than about 0.10N/mm, less than about 0.15N/mm, less than about 0.20N/mm, less than about 0.25N/mm, less than about 0.30N/mm, less than about 0.35N/mm, less than about 0.40N/mm, less than about 0.45N/mm, less than about 0.55N/mm, or less than about 0.60N/mm.

(6) Application method

The silicone-based biophotonic compositions of the present invention may have cosmetic and/or medical benefits. They are useful for promoting skin turnover and skin conditioning, or for promoting the treatment of skin disorders such as acne, eczema, dermatitis or psoriasis, or for promoting tissue repair, modulating inflammation, modulating collagen synthesis, reducing or avoiding scar formation, or promoting wound healing, including reducing the depth of the periodontal pocket. In certain embodiments, the silicone-based biophotonic compositions of the present invention may be used to treat acute inflammation, which may manifest itself as pain, heat, redness, swelling, and loss of function, and which include those found in allergies, such as insect bites, e.g., mosquito, bee, wasp bites, poison ivy stings, or post-ablation therapy.

Thus, in certain embodiments, the present invention provides a method of treating acute inflammation.

In certain embodiments, the present invention provides a method for providing skin rejuvenation or for improving skin condition, treating skin disorders, preventing or treating scar formation, and/or accelerating wound healing and/or tissue repair, the method comprising: the silicone-based biophotonic compositions of the present disclosure are applied to an area of skin or tissue in need of treatment, and the silicone-based biophotonic composition is irradiated with light having a wavelength that overlaps with an absorption spectrum of a chromophore present in the composition.

Any source of actinic light may be used in the process of the present invention. Any type of halogen lamp, LED lamp or plasma arc lamp or laser is suitable. A key feature of a suitable source of actinic light is that it emits light of a wavelength(s) suitable for activating one or more photoactivators present in the composition. In one embodiment, an argon laser is used. In another embodiment, a potassium titanyl phosphate (KTP) laser (e.g., Greenlight) is used^TMA laser). In another embodiment, the source of actinic light is an LED lamp, such as a light curing device. In yet another embodiment, the source of actinic light is a source of light having a wavelength of about 200 to 800 nm. In another embodiment, the source of actinic light is a source of visible light having a wavelength of about 400 to 600 nm. In another embodiment, the source of actinic lightIs a visible light source with a wavelength of about 400 to 700 nm. In yet another embodiment, the source of actinic light is blue light. In yet another embodiment, the source of actinic light is red light. In yet another embodiment, the source of actinic light is green light. In addition, the source of actinic light should have a suitable power density. A suitable power density for the non-collimated light source (LED lamp, halogen lamp or plasma lamp) is about 0.1mW/cm²To about 200mW/cm². A suitable power density for the laser light source is about 0.5mW/cm²To 0.8mW/cm²。

In some embodiments of the methods of the invention, the light has about 0.1mW/cm at the surface of the subject's skin²To about 500mW/cm²Or 0.1-300mW/cm²Or 0.1-200mW/cm²Wherein the energy applied depends at least on the condition to be treated, the wavelength of the light, the distance between the skin and the light source, and the thickness of the biophotonic material. In certain embodiments, the light at the skin of the subject is about 1-40mW/cm²Or 20-60mW/cm²Or 40-80mW/cm²Or 60-100mW/cm²Or 80-120mW/cm²Or 100-140mW/cm²Or 30-180mW/cm²Or 120-160mW/cm²Or 140-180mW/cm²Or 160-200mW/cm²Or 110-240mW/cm²Or 110-150mW/cm²Or 190-240mW/cm²。

Activation of chromophores within silicone-based biophotonic compositions can occur almost immediately upon irradiation (femtosecond or picosecond). Extended exposure periods may be beneficial to exploit the synergistic effects of absorbed, reflected and re-emitted light utilizing the silicone-based biophotonic compositions of the present invention and their interaction with the tissue being treated. In one embodiment, the tissue or skin or silicone-based biophotonic composition is exposed to actinic light for a period of time between 0.01 minutes and 90 minutes. In another embodiment, the tissue or skin or silicone-based biophotonic composition is exposed to actinic light for a period of time between 1 minute and 5 minutes. In some other embodiments, the silicone-based biophotonic agent is applied to a surface of the substrateThe sub-composition is irradiated for a period of 1 minute to 3 minutes. In certain embodiments, the period of light application is 1-30 seconds, 15-45 seconds, 30-60 seconds, 0.75-1.5 minutes, 1-2 minutes, 1.5-2.5 minutes, 2-3 minutes, 2.5-3.5 minutes, 3-4 minutes, 3.5-4.5 minutes, 4-5 minutes, 5-10 minutes, 10-15 minutes, 15-20 minutes, or 20-30 minutes. The treatment time may range from no more than about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes, or about 30 minutes. It will be appreciated that the treatment time may be adjusted by adjusting the rate of energy density (fluence) delivered to the treatment site to maintain the dose. For example, the delivered energy density can be about 4 to about 60J/cm²About 10 to about 60J/cm²About 10 to about 50J/cm²About 10 to about 40J/cm²About 10 to about 30J/cm²About 20 to about 40J/cm²About 15J/cm²To 25J/cm²Or about 10 to about 20J/cm²。

In some embodiments, the silicone-based biophotonic composition may be re-irradiated at certain intervals. In another embodiment, the source of actinic light is continuously moved over the treatment site for an appropriate exposure time. In another embodiment, the silicone-based biophotonic composition is irradiated until the biophotonic composition is at least partially photobleached or fully photobleached.

In certain embodiments, the chromophore may be photoexcited by ambient light, including from the sun and overhead lighting. In certain embodiments, the chromophore may be photoactivated by light in the visible range of the electromagnetic spectrum. Such light may be emitted by any light source, such as daylight, a light bulb, an LED device, an electronic display screen such as on a television, a computer, a telephone, a mobile device, a flashlight on a mobile device. Any light source may be used in the method of the invention. For example, ambient light and direct light or artificial direct light may be used in combination. Ambient light may include overhead lighting, such as LED bulbs, fluorescent lamps, etc., and non-direct sunlight.

In the methods of the present invention, the silicone-based biophotonic composition may be removed from the skin after application of light. In other embodiments, the silicone-based biophotonic composition remains on the tissue for an extended period of time and is reactivated with direct or ambient light at an appropriate time to treat the condition.

In certain embodiments of any of the above or below, the silicone-based biophotonic composition (such as a silicone-based biophotonic film) has a removable coating for covering one or both sides of the film. The removable coating may be peelable. The removable cover may comprise a sheet or film material, such as paper or foil. In certain embodiments, the removable cover is opaque and protects the membrane from irradiation until the treatment time. The cover may be partially removable. In certain embodiments, such as after a treatment time, the coating may be reapplied to the membrane surface so as to protect the membrane from further irradiation between treatments.

In certain embodiments of the methods of the present invention, the silicone-based biophotonic composition may be administered to the tissue, such as to the face, once per week, twice per week, three times per week, four times per week, five times per week, or six times per week, daily, or at any other frequency. The total treatment time may be one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or any other length of time deemed appropriate. In certain embodiments, the total tissue area to be treated may be divided into separate areas (cheek, forehead) and each area treated separately. For example, a silicone-based biophotonic composition may be topically applied to a first portion and the portion irradiated with light, and the composition removed. A silicone-based biophotonic composition is then applied to the second part, irradiated and removed. Finally, a silicone-based biophotonic composition is applied to the third portion, irradiated and removed.

In certain embodiments, the silicone-based biophotonic composition may be used after wound closure to optimize scar repair. In this case, the silicone-based biophotonic composition may be administered at regular intervals, such as once per week, or at intervals deemed appropriate by the physician.

In certain embodiments, the silicone-based biophotonic composition may be used after ablative skin rejuvenation treatment to maintain the condition of the treated skin. In this case, the silicone-based biophotonic composition may be administered at regular intervals, such as once per week, or at intervals deemed appropriate by the physician.

In the methods of the present invention, additional components may optionally be included in or used in combination with the silicone-based biophotonic composition. Such additional components may include, but are not limited to, healing factors, antimicrobial agents, oxygen-enriching agents, wrinkle fillers such as botulinum toxin, hyaluronic acid and polylactic acid, antifungal agents, antibacterial agents, antiviral agents, and/or agents that promote collagen synthesis. These additional components may be topically applied to the skin prior to, simultaneously with, and/or after topical application of the biophotonic composition of the present invention. Suitable healing factors include compounds that promote or enhance the healing or renewal process of tissue at the site of application. During photoactivation of the silicone-based biophotonic compositions of the present invention, they may increase the absorption of molecules of this additional component at the treatment site through the skin or mucosa. The healing factor may also modulate the biophotonic effect produced by the silicone-based biophotonic composition. Suitable healing factors include, but are not limited to, glucosamine, allantoin, saffron, agents that promote collagen synthesis, antifungal agents, antibacterial agents, antiviral agents, and wound healing factors, such as growth factors.

(i) Skin rejuvenation

The silicone-based biophotonic compositions of the present invention may be used to promote skin rejuvenation or improve skin condition and appearance. The dermis is the second layer of the skin and contains the structural elements connective tissue of the skin. There are various types of connective tissue with different functions. Elastic fibers give the skin elasticity, and collagen gives the skin strength.

The junction (junction) between the dermis and the epidermis is a very important structure. The dermal-epidermal junction interlocks to form a finger-like epidermal ridge. The cells of the epidermis receive their nutrients from the blood vessels within the dermis. The epidermal ridges increase the surface area of the epidermis exposed to these blood vessels and nutrients required.

Aging of the skin is accompanied by significant physiological changes in the skin. The production of new skin cells slows and the epidermal ridges at the dermal-epidermal junction flatten out. Although the number of elastic fibers increases, the structure and cohesiveness (coherence) thereof decreases. In addition, the amount of collagen and the thickness of the dermis decrease as the skin ages.

Collagen is a major component of the skin extracellular matrix, providing a structural framework. During the aging process, collagen synthesis decreases and collagen fibers become insoluble, resulting in thinning of the dermis and loss of the biomechanical properties of the skin.

Physiological changes in the skin lead to the appearance of significant symptoms of aging, commonly referred to as chronological aging, intrinsic aging, and photoaging. The skin becomes drier, rough and has increased desquamation, becoming duller in appearance, and most notably the appearance of fine lines and wrinkles. Other symptoms of skin aging include, but are not limited to: thinning and transparency of the skin, loss of underlying fat (leading to depression of the cheeks and deep-seated pits, and significant loss of firmness of the hands and neck), loss of bone (due to bone loss, bone contraction away from the skin, leading to skin laxity), dry (possibly itchy) skin, inability to perspire sufficiently to cool the skin, unwanted facial hair, freckles, age spots, spider veins, rough and leathery skin, fine wrinkles that disappear when stretched, skin laxity, or blotchy skin.

The dermal-epidermal junction is the basement membrane, separating keratinocytes in the epidermis from the extracellular matrix located beneath the epidermis. The film consists of two layers: a basal layer (lamina) in contact with keratinocytes and a lower reticular layer in contact with the extracellular matrix. The basal layer is rich in type IV collagen and laminin (laminin), which molecules play a role in providing a structural network and bioadhesive characteristics for cellular connectivity.

Laminins are glycoproteins that are only present in the basal membrane. It consists of three polypeptide chains (α, β and γ) arranged in an asymmetric cross shape, held together by disulfide bonds. These three chains exist in different isoforms, resulting in twelve different isoforms of laminin, including laminin-1 and laminin-5.

The dermis is anchored by collagen type VII fibers at the hemidesmosome of basement membrane keratinocytes, a specific junction located on keratinocytes, consisting of α -integrins and other proteins. Laminins, and in particular laminin-5, constitute the actual anchor point between the hemidesmoplasmic transmembrane protein and collagen type VII in basal keratinocytes.

It has been demonstrated that laminin-5 synthesis and collagen type VII expression are reduced in aging skin. This results in a loss of contact between the dermis and epidermis, causing the skin to lose elasticity and become loose.

Recently, another type of wrinkle, commonly referred to as expression lines, has gained widespread acceptance. Expression lines result from loss of elasticity, particularly in the dermis, so when facial muscles produce facial expressions, the skin is no longer able to recover its original state.

The silicone-based biophotonic compositions of the present invention promote skin rejuvenation. In certain embodiments, the silicone-based biophotonic compositions and methods of the present disclosure can promote skin conditioning, such as skin lightening, pore reduction, spot reduction, skin tone evening, dryness reduction, and skin firming. In certain embodiments, the silicone-based biophotonic compositions and methods of the present disclosure may promote collagen synthesis. In certain other embodiments, the silicone-based biophotonic compositions and methods of the present invention may reduce, eliminate, retard, or even reverse one or more signs of skin aging, including, but not limited to, the appearance of fine lines or wrinkles, thinning and transparency of the skin, loss of underlying fat (resulting in depression of the cheeks and deep pockets, and significant loss of firmness of the hands and neck), skin aging due to bone loss (where bone shrinks away from the skin resulting in skin laxity due to bone loss), dry skin (which may be itchy), inability to adequately perspire to cool the skin, unwanted facial hair, freckles, age spots, spider veins, rough and leathery skin, fine wrinkles that disappear when stretched, loose skin, or blotchy skin. In certain embodiments, the silicone-based biophotonic compositions and methods of the present disclosure may induce pore shrinkage, enhance sculpturing (sculpuring) of skin subsegments, and/or enhance skin translucency.

In certain embodiments, the silicone-based biophotonic compositions may be used in combination with a collagen promoter. Agents that promote collagen synthesis (i.e., procollagen synthesizing agents) include amino acids, peptides, proteins, lipids, small chemical molecules, natural products, and extracts from natural products.

For example, it has been found that ingestion of vitamin C, iron and collagen effectively increases the amount of collagen in the skin or bone. See, for example, U.S. patent application publication 20090069217. Examples of the vitamin C include derivatives of ascorbic acid such as L-ascorbic acid or sodium L-ascorbate, ascorbic acid preparations obtained by coating ascorbic acid with an emulsifier or the like, and mixtures containing two or more kinds of vitamin C in any ratio. In addition, natural products containing vitamin C, such as acerola or lemon, may also be used. Examples of iron preparations include: inorganic iron such as ferrous sulfate, sodium ferrous citrate, or ferric pyrophosphate; organic iron such as heme iron, ferritin iron, or lactoferrin iron; mixtures containing two or more of these iron preparations in any proportion. In addition, natural products containing iron, such as spinach or liver, may also be used. Further, examples of the collagen include: an extract obtained by treating bone, skin, etc. of a mammal (such as cattle or pig) with an acid or an alkali; peptides obtained by hydrolysis with a protease, such as pepsin, trypsin or chymotrypsin; and mixtures containing two or more of these collagens in any proportion. Collagen extracted from plant sources may also be used.

(ii) Skin diseases

The silicone-based biophotonic compositions and methods of the present invention may be used to treat skin disorders, which may include, but are not limited to, erythema, telangiectasia, actinic telangiectasia, basal cell carcinoma, contact dermatitis, fibrosarcoma of the skin, genital warts, hidradenitis suppurativa, melanoma, merkel cell carcinoma, nummular dermatitis, infectious diseases, psoriasis, psoriatic arthritis, rosacea, scabies, scalp psoriasis, sebaceous gland carcinoma, squamous cell carcinoma, seborrheic dermatitis, seborrheic keratosis, shingles, piebaldness, skin cancer, pemphigus, sunburn, dermatitis, eczema, rash, impetigo, herpes simplex, nasopharyngitis, perioral dermatitis, pseudofolliculitis, erythema multiforme, erythema nodosum, granuloma annulare, actinic keratosis, purpura, alopecia, stomatitis aphtha, drug eruptions, dry skin, and skin, Chapping, xerosis, ichthyosis vulgaris, fungal infection, herpes simplex, cataract, keloid, keratosis, miliaria, infective parotitis, pityriasis rosea, pruritus, urticaria and vascular tumors and malformations. Dermatitis includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, systemic exfoliative dermatitis, and stasis dermatitis (statis). Skin cancers include melanoma, basal cell carcinoma and squamous cell carcinoma.

(iii) Acne and acne scars

The silicone-based biophotonic compositions and methods of the present invention can be used to treat acne. "acne" as used herein refers to a skin disorder caused by inflammation of the skin glands or hair follicles. The silicone-based biophotonic compositions and methods of the present invention can be used to treat acne at an early pre-emergent stage, and can also be used to treat acne at a later stage when lesions from acne have become visible. Embodiments of the biophotonic compositions and methods are useful for treating mild, moderate, and severe acne. The early pre-emergence phase of acne usually begins with excessive secretion of sebum or skin oil by the sebaceous glands located within the pilosebaceous apparatus. Sebum passes through the follicular canal to the skin surface. The presence of excess sebum in the ducts and on the skin can clog or foul the normal flow of sebum of the follicular duct, thereby thickening and solidifying the sebum to form a solid plug known as a comedone. In the normal sequence of developing acne, excessive keratinization of the hair follicle opening is stimulated, completely blocking the canal. The common result is a papule, pustule or cyst, often contaminated with bacteria, resulting in a secondary infection. Acne is characterized in particular by the presence of comedones, inflammatory papules or cysts. The appearance of acne can be mild skin irritation to the crater points and can even develop into scars that affect appearance. Thus, the silicone-based biophotonic compositions and methods of the present invention may be used to treat one or more of skin irritation, pits, scar formation, comedones, inflammatory papules, cysts, excessive keratinization, and thickening and hardening of sebum associated with acne.

Some skin disorders present with different symptoms, including redness, reddening, burning, desquamation, pimples, papules, pustules, acne, spots, nodules, sacs, blisters, telangiectasia, spider veins, sores, surface irritation or pain, itching, inflammation, redness, purple or blue spots or discoloration, moles and/or tumors.

The silicone-based biophotonic compositions and methods of the present invention can be used to treat various types of acne. For example, some types of acne include acne vulgaris, cystic acne, acne atrophicans, acne bromosa, acne chloracna, acne conglobata, acne cosmetology, acne decontaminans, acne epidermis, acne summer, acne fulminans, acne halons, acne scleroderma, acne iodophors, acne keloids, acne mechanistica, acne papulosa, acne cerasus, acne premenstrual, acne pustulosa, acne scurvosa, acne tuberculosa, acne urticaria, acne smallpox, acne toxicata, acne propionate, acne artificially, acne gram-negative, acne steroids, and cystic acne nodosa.

In certain embodiments, the silicone-based biophotonic compositions of the present invention are used with systemic or local antibiotic therapy. For example, antibiotics for the treatment of acne include tetracycline, erythromycin, minocycline, doxycycline, which may also be used with the compositions and methods of the present invention. The use of silicone-based biophotonic compositions can reduce the time or dosage required for antibiotic therapy.

(iv) Wound healing

The silicone-based biophotonic compositions and methods of the present invention are useful for treating wounds, promoting wound healing, and promoting tissue. Wounds that may be treated by the silicone-based biophotonic compositions and methods of the present invention include, for example, injuries to the skin and subcutaneous tissue that are induced in different ways and have different characteristics (e.g., pressure ulcers from prolonged bed rest, wounds induced by trauma or surgery, burns, ulcers associated with diabetes or venous insufficiency, wounds induced by conditions such as periodontitis). In certain embodiments, the present invention provides silicone-based biophotonic compositions and methods for treating and/or promoting healing of wounds, such as burns, incisions, resections, injuries, tears, abrasions, puncture or penetrating wounds, surgical wounds, contusions, hematomas, pressure wounds, amputations, sores and ulcers.

The silicone-based biophotonic compositions and methods of the present invention are useful for treating chronic skin ulcers or wounds and/or promoting healing of these wounds, which are wounds that fail to achieve a durable structural, functional, and aesthetic closure through a series of ordered, timely events. The vast majority of chronic wounds can be classified into three categories according to their etiology: pressure ulcers, neuropathic (diabetic foot) ulcers and vascular (venous or arterial) ulcers.

For example, the present invention provides silicone-based biophotonic compositions and methods for treating and/or promoting healing of diabetic ulcers. Diabetic patients are prone to foot and other ulcers due to neurological and vascular complications. Peripheral neuropathy can lead to altered or complete loss of sensation in the foot and/or leg. Diabetic patients with advanced neuropathy lose full discrimination between severe-dull pain (sharp-dull). In patients with neuropathy, any laceration or trauma to the foot may be entirely unnoticed for days or weeks. Patients with advanced neuropathy lose the ability to sense sustained pressure injury with the result that tissue ischemia and gangrene may occur, which leads to, for example, plantar ulcers. Microvascular disease is one of the significant complications of diabetes and can also lead to ulcers. In certain embodiments, the present invention provides silicone-based biophotonic compositions and methods for treating chronic wounds, wherein the chronic wounds are characterized by diabetic foot ulcers and/or ulcers resulting from neurological and/or vascular complications of diabetes.

In other examples, the present invention provides silicone-based biophotonic compositions and methods for treating and/or promoting healing of pressure ulcers. Pressure ulcers include pressure sores, decubitus ulcers and ischial tuberosity ulcers, which can cause significant pain and discomfort to the patient. Pressure ulcers are caused by pressure applied to the skin for a prolonged period of time. Thus, pressure may be applied to the patient's skin due to the weight or mass of the individual. Pressure ulcers can form when the blood supply to an area of the skin is occluded or otherwise interrupted for more than two or three hours. The affected skin area becomes red, painful and necrotic. If left untreated, the skin can break open and become infected. Thus, pressure ulcers are skin ulcers that occur on an area of skin under pressure caused by prolonged bed rest, wheelchair and/or cast (cast). Pressure ulcers can occur when a person is bedridden, unconscious, unable to feel pain, or immobile. Pressure ulcers typically occur on bony prominences of the body, such as the hip region (on the sacrum or iliac crest) or on the heel.

The wound healing process has three distinct phases. First, during the inflammatory phase, usually from the first two to five days from the wound appearance, platelets aggregate to deposit granulation, promote fibrin deposition and stimulate growth factor release. The leukocytes migrate to the wound site and begin to digest and transport debris away from the wound site. During this inflammatory phase, monocytes are also converted into macrophages, which release growth factors, stimulating the formation of blood vessels and the production of fibroblasts.

Secondly, during the proliferation phase, which usually occurs between two and three weeks, granulation tissue is formed and epithelialization and contraction begins. Fibroblasts are a key cell type at this stage, filling the wound by proliferating and synthesizing collagen, providing a strong matrix for epithelial cell growth. When fibroblasts produce collagen, blood vessels are formed extending from nearby blood vessels, resulting in the formation of granulation tissue. Granulation tissue typically grows from the base of the wound. Epithelialization involves the migration of epithelial cells from the wound surface, thereby sealing the wound. Epithelial cells are driven by the need to contact cells of similar types and are guided by a network of fibrin chains that act as a lattice on which they migrate. Contractile cells called myofibroblasts appear at the wound site and help the wound to close. These cells exhibit collagen synthesis and contractility, and are relatively common in granulation wounds.

Again, in the remodeling stage, the final stage of wound healing, from three weeks to several years, the collagen in the scar undergoes repeated degradation and re-synthesis. At this stage, the tensile strength of the newly formed skin increases.

However, as the rate of wound healing increases, there is generally a corresponding increase in scar formation. Scarring is the result of the healing process in most adult animal and human tissues. Scar tissue, unlike the tissue it replaces, generally has poor functional quality. Types of scars include, but are not limited to, atrophic, hypertrophic and pityristic scars, and scar contractures. Atrophic scars are flat with the surface below the surrounding skin, forming valleys or holes. Hypertrophic scars are raised scars that remain within the boundaries of the original lesion and usually contain excess collagen arranged in an abnormal manner. A cicatricial scar is an elevated scar that spreads out of the edge of the original wound, invades in a site-specific manner near normal skin, usually containing collagen helices arranged in an abnormal manner.

In contrast, normal skin consists of collagen fibers arranged in a basket-basket (basketweave) fashion, which contributes to the strength and elasticity of the dermis. Therefore, in order to make the wound healing process smoother, a method is needed that not only stimulates the production of collagen, but also stimulates the production of collagen in a manner that reduces scar formation.

The silicone-based biophotonic compositions and methods of the present invention may promote wound healing by promoting substantially uniform epithelialization, promoting collagen synthesis, promoting controlled contraction, and/or reducing scar tissue formation. In certain embodiments, the biophotonic compositions and methods of the present disclosure may promote wound healing by promoting substantially uniform epithelialization. In some embodiments, the silicone-based biophotonic compositions and methods of the present invention can modulate or promote collagen synthesis. In some other embodiments, the silicone-based biophotonic compositions and methods of the present disclosure may promote controlled shrinkage. In certain embodiments, the silicone-based biophotonic compositions and methods of the present disclosure can promote wound healing, for example, by reducing the formation of scar tissue.

In the methods of the present invention, the silicone-based biophotonic compositions of the present invention may also be used with negative pressure assisted wound closure devices and systems.

In certain embodiments, the silicone-based biophotonic composition remains in place for up to one, two, or three weeks and is irradiated with light (which may include ambient light) at different intervals. In this case, the silicone-based biophotonic composition may be covered with an opaque material or exposed to light during the interval of exposure to light.

(6) Reagent kit

The present invention also provides kits for preparing the silicone-based biophotonic compositions of the present invention and/or providing any components required to form the silicone-based biophotonic compositions of the present invention.

In some embodiments, the kit comprises a container containing components or compositions useful for preparing the silicone-based biophotonic compositions of the present disclosure. In some embodiments, the kit comprises a silicone-based biophotonic composition of the present invention. The different components that make up the silicone-based biophotonic composition of the present invention may be provided in separate containers. For example, the surfactant phase may be provided in a container separate from the silicone phase. Examples of such containers are dual chamber syringes, dual chamber containers with removable compartments, pouches with sachets and multi-compartment blister packs. Another example is where one component is provided in a syringe, which can be injected directly into a container of another component.

In other embodiments, the kit comprises a systemic drug for enhancing the treatment of the silicone-based biophotonic compositions of the present invention. For example, the kit may include systemic or topical antibiotics, hormonal therapy drugs (e.g., for acne treatment or wound healing), or negative pressure devices.

In other embodiments, the kit comprises a device for mixing or administering the components of the silicone-based biophotonic composition.

In certain embodiments of the kit, the kit may further comprise a light source, such as a portable light having a wavelength suitable for activating the chromophore of the silicone-based biophotonic composition. The portable light may be battery operated or rechargeable.

Written instructions on how to use the silicone-based biophotonic compositions according to the present disclosure may be included in a kit, or may be included on or associated with a container containing or constituting a silicone-based biophotonic composition of the present disclosure.

Identification of equivalent silicone-based biophotonic compositions, methods, and kits in accordance with the teachings of the present disclosure is within the skill of the ordinary artisan and will require only routine experimentation.

Various modifications and alterations of this invention will become apparent to those skilled in the art upon reading this disclosure. The disclosed features may be implemented in any combination and subcombination (including multiple dependent combinations and subcombinations) with one or more other features described herein. The various features described or illustrated above, including any components thereof, may be combined or integrated into other systems. In addition, certain features may be omitted or not implemented. Those skilled in the art may make changes, substitutions, and alterations to these examples without departing from the scope of the disclosed information. All references cited herein are incorporated by reference in their entirety and constitute a part of this application.

The present invention will be more fully understood from the following examples, which are given by way of illustration only and should not be construed as limiting the invention in any way.

Examples of the invention

Example 1: silicone-based biophotonic compositions (25% Pluronic-F127)

25% by weight of Pluronic F127 solution (surfactant phase)

A typical preparation of a hot gel solution of Pluronic involves dissolving a measured mass of Pluronic F-127 in a measured volume of cold deionized water (about 4 ℃). Concentration of pluronic in H per volume₂The weight of O represents.

Thus, to prepare a thermal gel stock solution of pluronic (25% w/v), a batch of 25.00g pluronic F-127 was added to 100mLH in a 250mL Erlenmeyer flask under magnetic stirring₂And (4) in O. The Erlenmeyer flask was then cooled with the solution in an ice bath (at 2 to 4 ℃) while continuing to stir for about 1 hour until the pluronic F-127 was completely dissolved. The resulting solution was then stored in a refrigerator at about 4 ℃.

The gelation test was performed and showed that the solution formed a hydrogel after about 5 minutes at room temperature (about 22 ℃).

Preparation of Silicone-15/85 (Silicone phase)

The silicone-15/85 component for silicone-based biophotonics was prepared by mixing 15% Sylgard-184 elastomer kit and 85% Sylgard-527 gel kit. Thus, a mixture of silicone-15/85 was prepared by thoroughly mixing 2.667g Sylgard-184 (consisting of 2.423g part A of the Sylgard-184 kit and 0.244g part B of the Sibgard-184 kit) with 15.151g Sylgard-527 (consisting of 7.574g part A of the Sylgard-527 kit and 7.577g part B of the Sibgard-527 kit). The silicone-15/85 mixture was cooled to about 4 ℃ to maintain it in liquid form.

Preparation of silicone-based biophotonic compositions

To form a silicone-based biophotonic composition, 2.0mL of a cold pluronic-F127 gel solution containing 0.327mg eosin Y and 0.327g fluorescein was added to 9.221g of the freshly prepared silicone-15/85 mixture under vigorous stirring to produce a very fine emulsion. Thereafter, to form a silicone-based biophotonic membrane, the resulting mixture was poured onto a petri dish. The amount of casting was controlled so that the film thickness was 2 mm. The cast silicone-based biophotonic membrane mixture was then cured in an incubator at 40 ℃ under a humid atmosphere for 5 hours.

The emulsion formed when the mixing of the surfactant phase and the silicone phase is complete is a very fine and highly stable microemulsion or gel. Without being bound by a particular theory, it is believed that these properties of the microemulsion may be due to the hydrophobic nature of the silicone and the surfactant nature of pluronic-F127. When cast in petri dishes (Pertri dish) and after curing, the resulting silicone-based biophotonic membrane is uniform and flexible. The films were then tested to assess whether the chromophores (eosin Y and fluorescein) were likely to leach from the silicone-based biophotonic film (leach) because samples of the film were immersed in a Phosphate Buffered Saline (PBS) solution for 24 hours and no leaching of the chromophores was observed.

In a second experiment, 0.75mL of a Pluronic-F127 thermal gel solution containing 0.123mg eosin Y and 0.123mg fluorescein was added to 6.744g of silicone-15/85 (prepared as described above) with vigorous stirring. The homogeneous microemulsions obtained are very fine and show high stability. An aliquot of the microemulsion was poured onto a petri dish to obtain a thickness of 2mm, and then cured in an incubator at 40 ℃ for 5 hours under a humid atmosphere.

The light emitted from the silicone-based biophotonic film prepared in this second experiment was measured by using an SP-100 spectroradiometer (SP-100, ORB Optronix) while using light having a peak emission wavelength of 450nm (peak wavelength range of 400-470nm, power density of about 30-150 mW/cm)²) The irradiation was carried out for 5 minutes. As can be seen in fig. 1-4, the chromophore was not fully photobleached after 15 minutes of irradiation at 5 minute intervals.

Example 2 cytokines and growth factors in DHF

To obtain a more detailed picture of the biological effects mediated by the silicone-based biophotonic membrane of example 1 (second experiment), a human cytokine antibody array (RayBio C series, raybotech, Inc.). Cytokines, broadly defined as secreting cell-cell signaling proteins, play important roles in inflammation, innate immunity, apoptosis, angiogenesis, cell growth and differentiation. The simultaneous detection of multiple cytokines provides a powerful tool for studying cellular activity. The regulation of cellular processes by cytokines is a complex, dynamic process, usually involving multiple proteins. Positive and negative feedback loops, pleiotropic and redundant functions, spatial and temporal expression or synergistic interactions between various cytokines, even through modulation by the release of soluble forms of membrane-bound receptors, are common mechanisms of action in regulating cytokine signaling.

The effect of blue light in combination with light emitted by silicone-based biophotonic membranes on the secretion of inflammatory cytokines, chemokines and growth factors was studied using DHF (Derman human fibroblasts) and THP1 (human acute monocytic leukemia cells) as in vitro models. Excessive, uncontrolled inflammation is detrimental to the host and can impair wound healing processes, among other things. The objective of this study was to demonstrate that blue light in combination with fluorescence emitted by silicone-based biophotonic membranes can down-regulate the production of pro-inflammatory cytokines and chemokines and improve/accelerate the healing process.

Briefly, DHF cells were stimulated with a non-toxic concentration of TGF-1, and PMA-treated THP-1 cells were stimulated with IFN γ and LPS. The membrane of example 1 (second experiment) was then placed 5cm above the cell culture and irradiated with blue light (450 nm).

Cell culture media was collected 24 hours after irradiation and incubated with array antibody membranes according to the manufacturer's instructions (human cytokine antibody array, RayBio C series from raybitech). By usingThe software quantitated the signal. For each experiment, XTT assays (cell viability assays) were performed to normalize the amount of cytokine secreted to cell viability (in all cases, viability over 90% showed no toxic effect of treatment). All samples were performed as tetrads (quadruplets).

The effect of irradiated membranes on cytokine and growth factor secretion in DHF and THP-1 cells is summarized in tables 1 and 2 below.

TABLE 1 modulation of protein expression in TGF-beta 1 activated dermal human fibroblasts 24 hours after treatment with blue light + silicone based biophotonic membranes compared to control untreated cells.

↓ decrease less than 25% ↓ increase less than 25%

↓ [ 25-50% ] decrease [ 25-50% ] increase [ 25-50% ] [ ° ] increase

↓ ↓ ↓ reduced by more than 50% and increased by more than 50 ↓ ↓ ↓ ↓ ↓ ↓ × (

No regulation

Table 2 modulation of protein expression in THP1 cells differentiated into macrophages 24 hours after treatment with blue light + silicone-based biophotonic membranes compared to control untreated cells.

↓ decrease less than 25% ↓ increase less than 25%

↓ [ 25-50% ] decrease [ 25-50% ] increase [ 25-50% ] [ ° ] increase

↓ ↓ ↓ reduced by more than 50% and increased by more than 50 ↓ ↓ ↓ ↓ ↓ ↓ × (

No regulation

Results from the cytokine/chemokine array assay show that treatment with the silicone-based biophotonic membrane of example 1 negatively modulates the production of proinflammatory cytokines (such as TNF α, IL-6, IL-8, IL-1 α, IL-1 β, IFN γ) and proinflammatory chemokines (such as MCP-1, MCP-2, RANTES, GRO). The results also indicate that treatment with silicone-based biophotonic membranes showed the ability to down-regulate growth factor secretion (such as TGF-. beta.1 and PDGF-BB) in DHF cells.

Example 3-level of proliferation in DHF cells upon irradiation through a Silicone-based biophotonic Membrane

To obtain a more detailed picture of the biological effects mediated by the silicone-based biophotonic membrane of example 1 (second experiment) and its effect on the wound healing process, cell proliferation was assessed in a human dermal fibroblast (DHF) experimental system. Within four to five days after injury, matrix-producing cells, i.e., fibroblasts, move into granulation tissue. Their migration to and proliferation within the wound site is a prerequisite for granulation and continued healing of the wound. Fibroblasts then participate in the construction of scar tissue and its remodeling. Thus, viable, actively dividing fibroblasts are a key participant in healing progression (player).

This experiment utilizes the XTT assay to measure cell viability. XTT-based methods measure mitochondrial dehydrogenase activity of proliferating cells. Briefly, mitochondrial dehydrogenases of living cells reduce the tetrazole ring of XTT, producing water-soluble orange derivatives. The absorbance of the resulting orange solution was measured spectrophotometrically. An increase or decrease in the number of cells relative to control cells results in a concomitant change in the amount of orange derivative, indicating a change in the number of surviving dividing cells.

DHF cells were irradiated with the silicone-based biophotonic membrane of example 1 for 5 minutes. The XTT solution after 24 hours post-treatment was added to the cells. After four hours, the absorbance of the orange supernatant was measured spectrophotometrically. The difference in the number of actively proliferating fibroblasts compared to the non-irradiated control was calculated.

XTT assay showed that the silicone membrane of example 1 did not modulate DHF proliferation under the test conditions compared to the control (untreated cells).

Example 4-evaluation of the Silicone-based biophotonic thermal gels of the present disclosure for prevention of scar formation

Hypertrophic scars (HTS) are caused by excessive skin fibrosis involving myofibroblasts. They are produced after dermal injury. In addition to their injurious characteristics, scars can be itchy, stiff and painful. Overproduction of collagen and other extracellular matrix (ECM) proteins and/or insufficient degradation and remodeling of the ECM are major causes of scar formation. These phenomena occur when the inflammatory response to injury is prolonged. In HTS, growth factors, TGF β 1 and PDGF are overexpressed by fibroblasts. They are the major proteins in HTS (Avouac J et al. Inhibition of activator protein 1 signalling proteins transduction of growth factor b-mediated activation of fibrosis and fibrosis in excess of microorganisms, arthritis Rheumatosis, 2012, volume 64: 1642-4652; Trojanowska M, Role of PDGF in fibrous diseases and systemic bacteria, Rheumatology,2008, volume 47: v2-v 4). TGFb1 is responsible for excessive collagen secretion and Matrix Metalloproteinases (MMPs) such as collagenase (Curtron KR. TGF-beta-induced fibrosis and SMADsignalizing: oligo decoys as natural therapeutics for inhibition of Tissue fibrosis and scarring. Wound Regen 2007, volume 15: S54-60; Chen ZC, Raghuanth M. Focus on collagen: In vision systems to study fibrosis and diagnosis-state of the art. fibrosis Tissue Repair replair, 2009, volume 2: 7). PDGF is a potent chemoattractant for fibroblasts and constitutes a good target for the treatment of fibrosis (Beyer C, Distler jhw. tyrosine kinase signalling in fibrous disorders. transformation of basic research to human disease biochem biophysis Acta,2013, volume 1832: 897-904). HTS has high expression of MMP-2 and low expression of MMP-9 (Gaughtz GG et al Hypertrophphic screening and keloids: Pathomorphism and current and engineering molecular strategies. mol Med, 2011; volume 17: 113-125).

Design of experiments

a) Protein secretion-inflammation mediators, cytokines, growth factors

A Dermal Human Fibroblast (DHF) cell culture model was used as an in vitro model to study the effects that treatments can produce on the secretion of various proteins that act as inflammatory mediators or growth factors or that are involved in tissue remodeling such as Matrix Metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) by illuminating a silicone-based biophotonic membrane containing the chromophores eosin Y and fluorescein with a source of actinic light that emits incoherent blue light.

For this experimental model, the silicone-based biophotonic membranes described above were used with visible blue light at a distance of 5cm (KLOX multiple LED lamp) for a period of 5 minutes. The blue light and fluorescence dose received by the cells during the irradiation time are shown in table 3.

Table 3: dose of blue light and fluorescence received by cells during 5 min irradiation (J/cm2)

DHF cells were cultured on glass-bottomed dishes (approximately 2mm thick). 1 hour prior to irradiation, cells were treated with a non-toxic concentration of TGF β 1(5ng/ml) to induce the hyperproliferative state commonly observed during hypertrophic scar formation^TMLamp) was illuminated at a distance of 5 cm. Cells were also treated with light alone, which served as an internal control to ensure that the combination of light and silicone-based biophotonic films containing eosin Y and fluorescein chromophores exerted biological effects compared to light alone. At 24 hours post-treatment, supernatants were collected and arrayed to assess inflammatory cytokine, chemokine and growth factor production profiles (profiles) produced by the treatments. The proteins determined for each antibody array are listed in tables 4 and 5 below.

Antibody array characterization

TABLE 4 human cytokine antibody array C3

POS as positive control dot

NEG ═ negative control dot

BLANK ═ BLANK point

TABLE 5 human growth factor antibody array C1

POS as positive control dot

NEG ═ negative control dot

BLANK ═ BLANK point

To assess potential cytotoxicity of the treatments, supernatants from treated cell cultures were also screened for Lactate Dehydrogenase (LDH) activity. LDH is an intracellular enzyme that is released in the culture medium when cells are damaged. It is a marker of cytotoxicity. This assay quantifies the LDH activity in reducing NAD to NADH. NADH is specifically detected by colorimetry.

b) Cell proliferation (DHF cell culture)

Prior to treatment, cells were subjected to starvation conditions (serum and hormone deficient medium) for synchronization in G1 phase. After synchronization, DHF was exposed to biophotonic thermal gel including silicone-based and blue light irradiation (14.4J/cm at a distance of 5 cm)²Intensity of) of the light source. Proliferation of cells was monitored 24 hours, 48 hours and 72 hours after treatment using the CyQUANT direct cell proliferation assay.

c) In vivo studies using a skin fibrosis mouse-human skin graft model system

To evaluate the potential of the silicone-based biophotonic composition treatment of the present invention to promote wound healing and prevent scar formation, an in vivo mouse model system was used, more specifically, an in vivo mouse model system utilizing a dermal fibrosis mouse model in which full-thickness excision wounds with a split-thickness human skin transplanted onto the back of nude mice developed thickened, raised, shrunken scars similar to human HTS (see Montazi M et al, A nude motor model of hyperopic gear showstock and histologic characteristics of human hyperopic gear.

To evaluate treatments comprising a silicone-based biophotonic composition (containing eosin Y and fluorescein) (prepared according to example 1, experiment No. 2 above) and visible blue light (KLOX multiple LED lamp) illumination, the biophotonic composition-light illumination treatment (in the form of an unpolymerized gel or as a polymeric film) was applied using the illumination time and distance as described in the in vitro experiments of this example 4, whereas in this in vivo system the biophotonic composition was applied to the skin of a topical (physical) contact) transplant wound. Treatment with the photo-biophotonic composition was initiated on day 7 post-transplantation, where mice were administered under light general anesthesia via halothane nose. Treatment was performed twice a week for 3 weeks. Animals were sacrificed one week after the last treatment. Control animals received no treatment and the other group received only blue light. Wounds were monitored weekly by digital photography, then animals were euthanized 4 weeks after treatment and excised xenografts were examined.

Quantification of scar thickness and vascularity was performed on hematoxylin and eosin (H & E) stained section images. Using Image J, a measurement of dermal thickness is made in the high power Image, where dermal thickness is the distance between the epidermal-dermal junction and the dermal-adipose junction. Three measurements were made for each sample. The extent of vascularity was assessed by counting the number of vessels in five High Power Fields (HPFs) of the dermis.

Collagen fibers in the dermis were detected using Masson (Masson) trichrome staining as known in the art. The stained specimen was examined using polarized light microscopy, the collagen fibers were observed as green color, while the nuclei were visualized as black and the cytoplasm and keratin were visualized as red.

Results

a) Effect of Silicone-based biophotonic membranes treated with blue light irradiation on production of inflammatory mediators (mediators) in DHF cells

At 24 hours post-treatment, supernatants were collected and subjected to inflammatory cytokine profiling to evaluate inflammatory cytokine production characteristics when silicone-based biophotonic membrane (containing eosin Y and fluorescein) treatment was combined with KLOX multi LED lamps. The results of the array are summarized in table 6.

Analysis of LDH activity showed that no significant cytotoxic effects of treatment were observed in all silicone-based biophotonic membrane irradiated samples.

Table 6: in the production of inflammatory mediators (cytokines shown in red, chemokines andblue colorDisplay) and a summary of significant up (↓) and down (↓) were observed in growth factors (shown in black) compared to untreated controls.

PDGF-BB and TGFb1 and important growth factors are involved in the pathogenesis of scar formation. The ability to treat these factors significantly reduced is beneficial. In addition, many pro-inflammatory mediators were also observed to be reduced in treated cells compared to control cells, while certain anti-inflammatory cytokines were observed to be increased in treated cells such as IL-10.

b) Cell proliferation (DHF cell culture)

Referring to the data on the growth factors induced on the silicone-based biophotonic membranes of the present disclosure, as can be seen in table 6 (above), the induced growth factors are primarily involved in angiogenesis, rather than the growth factors involved in cell proliferation. Furthermore, the results of the cell proliferation assay performed in this example 4 also show that the silicone-based biophotonic membrane does not induce cell proliferation. Since hypertrophic scar formation is characterized by hyperproliferative disease, this lack of effect on fibroblast proliferation may be considered beneficial for hypertrophic scar formation.

c) In vivo studies using a skin fibrosis mouse-human skin graft model system

Morphologically, there were generally no visible significant differences between groups or in the wound contraction groups as measured by planimetry. However, at 4 weeks post-transplantation, significant reductions in scar thickness (1.35 ± 0.07, 1.35 ± 0.08 relative to 1.69 ± 0.13, 2.07 ± 0.08mm, P <0.05) were measured histologically in the silicone-based biophotonic composition (applied as an unpolymerized gel) and silicone-based biophotonic film plus light treated groups, with improvement in re-epithelialization compared to the control group and the group exposed to light alone. These results are also shown in graphical format in fig. 5.

Regarding the effect of treatment with silicone-based biophotonic compositions, morphological improvement of collagen fiber bundles and orientation (based on Masson trichrome staining) was associated with accelerated collagen remodeling in the gel-and membrane-plus-light treated groups compared to the control group and the group that was only illuminated (collagen orientation index, 0.18 ± 0.04, 0.21 ± 0.06 versus 0.50 ± 0.08, 0.52 ± 0.08, P < 0.05). These results are also shown in graphical format in fig. 6.

Based on the above findings of the mouse-human skin graft model of in vivo dermal fibrosis, these data demonstrate the potential of the silicone-based biophotonic compositions of the present invention for accelerating wound healing and reducing fibrosis in human fibroproliferative diseases (such as hypertrophic scar formation).

It should be understood that the invention is not limited to the particular embodiments described and illustrated herein, but encompasses all modifications and variations within the scope of the invention as defined by the following claims.

Claims (49)

1. A biophotonic composition comprising a silicone phase and a surfactant phase, wherein the surfactant phase comprises at least one chromophore solubilized in a surfactant.

2. The composition of claim 1, wherein said surfactant phase is emulsified in said silicone phase.

3. The composition of claim 1, wherein the surfactant comprises a block copolymer.

4. The composition of claim 3, wherein the block copolymer comprises at least one hydrophobic block and at least one hydrophilic block.

5. The composition of claim 4, wherein the surfactant phase comprises a thermally gellable surfactant.

6. The composition of any one of claims 1 to 5, wherein the surfactant is water soluble.

7. The composition of any one of claims 1 to 6, wherein the surfactant comprises at least one sequence of polyethylene glycol-propylene glycol ((PEG) - (PPG)).

8. The composition of any one of claims 1 to 7, wherein the surfactant is a poloxamer.

9. The composition of claim 8, wherein the poloxamer is pluronic F127.

10. The composition of any one of claims 1 to 9, wherein the silicone phase comprises

11. The composition of claim 10, wherein the silicone phaseThe content of (B) is 5-100 wt%。

12. The composition of claim 10 or claim 11, wherein the silicone phase further comprises

13. The composition of any one of claims 1 to 12, comprising about 60-95 wt% silicone phase and about 5-40 wt% surfactant phase, or about 80 wt% silicone phase and about 20 wt% surfactant phase.

14. The composition of any one of claims 1 to 13, wherein the surfactant comprises at least one sequence of (PEG) - (PLA) or (PEG) - (PLGA) or (PEG) - (PCL).

15. The composition of claim 14, wherein the chromophore absorbs and/or emits light in the visible range.

16. The composition of any one of claims 1 to 15, wherein the surfactant phase further comprises an anionic or cationic surfactant.

17. The composition of claim 16, wherein the anionic or cationic surfactant is selected from the group consisting of cetyltrimethylammonium bromide (CTAB) and Sodium Dodecyl Sulfate (SDS).

18. The composition of any one of claims 1 to 15, wherein the surfactant phase comprises an anionic surfactant.

19. The composition of claim 18, wherein the anionic surfactant comprises SDS.

20. The composition of any one of claims 1 to 19, wherein the chromophore is a cationic chromophore.

21. The composition of claim 20, wherein the cationic chromophore is selected from the group consisting of cyanine, acridine, pyronin Y, and derivatives thereof.

22. The composition of any one of claims 1 to 19, wherein the chromophore is an anionic chromophore.

23. The composition of claim 22, wherein the anionic chromophore is a xanthene dye.

24. The composition of any one of claims 1 to 23, wherein the surfactant phase further comprises a stabilizer.

25. The composition of claim 24, wherein the stabilizer comprises gelatin, HEC, CMC, or any other thickening agent.

26. The composition of any one of claims 1 to 25, wherein the composition is in the form of a gel.

27. The composition of any one of claims 1 to 25, wherein the composition is in the form of a film.

28. The composition of any one of claims 1 to 25, wherein the composition is in the form of a film.

29. The composition of any one of claims 1 to 25, wherein the composition is spreadable.

30. A method of treating a skin condition with biophotonic therapy, comprising:

placing a composition on a target skin tissue, wherein the composition comprises a silicone phase and a surfactant phase, and wherein the surfactant phase comprises at least one chromophore solubilized in a surfactant; and

illuminating the composition with light having a wavelength that overlaps with an absorption spectrum of the at least one chromophore.

31. The method of claim 30, wherein said composition emits fluorescence at a wavelength and intensity that promotes healing of said skin condition.

32. The method of claim 31, wherein the skin disorder is selected from acne, eczema, psoriasis or dermatitis.

33. A method of promoting wound healing, comprising:

placing a composition on a wound, wherein the composition comprises a silicone phase and a surfactant phase, and wherein the surfactant phase comprises at least one chromophore solubilized in a surfactant; and

illuminating the composition with light having a wavelength that overlaps with an absorption spectrum of the at least one chromophore.

34. The method of claim 33, wherein the composition emits fluorescence at a wavelength and intensity that promotes wound healing.

35. A method of promoting skin rejuvenation comprising:

placing a composition on a target skin tissue, wherein the composition comprises a silicone phase and a surfactant phase, and wherein the surfactant phase comprises at least one chromophore solubilized in a surfactant; and

illuminating the composition with light having a wavelength that overlaps with an absorption spectrum of the at least one chromophore.

36. The method of claim 35, wherein the composition fluoresces at a wavelength and intensity that promotes skin rejuvenation.

37. A method of preventing or treating a scar, comprising:

placing a composition on a target skin tissue, wherein the composition comprises a silicone phase and a surfactant phase, and wherein the surfactant phase comprises at least one chromophore solubilized in a surfactant; and

illuminating the silicone-based biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the at least one chromophore.

38. The method of claim 37 wherein the biophotonic composition emits fluorescence at a wavelength and intensity that treats the scar.

39. The method of any one of claims 30 to 38, wherein the composition is removed after irradiation.

40. The method of any one of claims 30 to 38, wherein the silicone-based biophotonic composition remains in situ after irradiation.

41. The method of any one of claims 30 to 40, wherein the chromophore is at least partially photobleached upon irradiation.

42. The method of any one of claims 30 to 40, wherein the chromophore is photobleached upon irradiation.

43. The method of any one of claims 30 to 40, wherein the composition is irradiated until the chromophore is at least partially photobleached.

44. The method of any one of claims 30 to 43, wherein the chromophore can absorb and/or emit light in the visible range.

45. The method of any of claims 30 to 44, wherein the chromophore is a xanthene dye.

46. The method of claim 45 wherein said xanthene dye is selected from the group consisting of eosin Y, eosin B, erythrosin B, fluorescein, rose bengal and phloxine B.

47. The method of any one of claims 30 to 46, wherein the light has a peak wavelength between about 400nm to about 750 nm.

48. The method of any one of claims 30 to 46, wherein the light has a peak wavelength between about 400nm to about 500 nm.

49. A composition comprising a silicone phase and a polyelectrolyte phase, wherein the polyelectrolyte phase comprises at least one chromophore solubilized in a surfactant.