HK1206774B - Biophotonic compositions, kits and methods - Google Patents

Description

Biophotonic compositions, kits and methods

Background

Light therapy has recently been recognized as having a wide variety of applications in the medical, cosmetic and dental fields for use in surgery, treatment and examination. For example, light therapy has been developed for the treatment of cancers and tumors with reduced invasiveness. Phototherapy has also been used as an antimicrobial treatment to disinfect target sites. Phototherapy has also been found to promote wound healing.

Photodynamic therapy is a type of light therapy that involves the step of systemic administration or uptake of a photosensitizer into diseased or injured tissue, followed by site-specific application of activating light (photodynamic therapy). However, such regimens are often associated with undesirable side effects, including systemic toxicity or localized toxicity due to direct contact of the photosensitizer with the tissue. Furthermore, such prior approaches often demonstrate low therapeutic efficacy due to, for example, poor uptake of the photosensitizer into the target tissue. Accordingly, it is an object of the present disclosure to provide new and improved compositions and methods useful in phototherapy.

Disclosure of Invention

The present disclosure provides biophotonic compositions and methods useful in phototherapy. In particular, the biophotonic compositions of the present disclosure may include chromophores in a medium, such as a gelling agent, that provides a barrier such that the chromophores and other components of the topical biophotonic composition are not substantially in contact with, and/or do not penetrate, the target tissue. In other words, the biophotonic compositions of the present disclosure may contain chromophores in a medium, such as a gelling agent, that provides a barrier that renders the composition substantially resistant to leaching in use. The use of such biophotonic compositions in phototherapy therefore does not involve significant direct contact of the target tissue with chromophores that may be potentially toxic to the tissue or may cause undesirable side effects.

According to one aspect, the present invention provides a biophotonic composition comprising: a first chromophore; and a gelling agent present in an amount sufficient to gel the composition and render the biophotonic composition substantially resistant to leaching such that less than 15% by weight of the total chromophore amount leaches from the biophotonic composition in use.

According to one aspect, the present invention provides a biophotonic composition comprising: a first chromophore; and a gelling agent present in an amount sufficient to gel the composition and render the biophotonic composition substantially resistant to leaching such that less than 15% by weight of the total chromophore amount leaches from the biophotonic composition in use, as measured by: (i) placing a 2mm thick layer of the biophotonic composition on top of a Polycarbonate (PC) film having a diameter of 2.4-3cm, a thickness of 10 microns, and a pore size of 3 microns, (ii) contacting the bottom surface of the PC film with an aqueous phosphate buffered saline solution contained in the receiving chamber, and (iii) measuring the chromophore content in the receiving chamber after a treatment time at room temperature and pressure.

According to another aspect, the present invention provides a biophotonic composition comprising at least a first chromophore and a gelling agent, wherein the biophotonic composition is a gel or semi-solid and is substantially resistant to leaching such that, upon contact with tissue in use, less than 15% of the total chromophore amount leaches from the biophotonic composition into the tissue. In certain embodiments, the biophotonic composition is spreadable such that it can conform to tissue topography.

According to another aspect, the present invention provides a biophotonic composition comprising at least a first chromophore and a gelling agent, wherein the biophotonic composition is substantially translucent and substantially resistant to leaching such that, when in contact with tissue in use, less than 15% of the total chromophore amount leaches from the biophotonic composition into the tissue. Substantially translucent means having a transmission of more than about 20%.

According to a further aspect, the present invention provides a biophotonic composition comprising at least a first chromophore and a gelator, wherein the biophotonic composition and/or gelator has a viscosity of about 10,000-80,000, 10,000-90,000, 10,000-80,000, 10,000-70,000, 15,000-80,000, 15,000-70,000, 15,000-50,000 or 15,000-45,000cP when measured at room temperature using a Wells-Brookfield HB cone/plate viscometer and a CP-51 cone at a rotational speed and torque of 2rpm > 10%, or a DV-II + Pro viscometer with spindle 7 at 50rpm for 1 minute.

According to a still further aspect, the present invention provides a biophotonic composition comprising a first chromophore in a carrier medium, wherein the composition is encapsulated in a film that limits leaching of the first chromophore such that less than 15% of the total chromophore amount leaches from the composition in use. In certain embodiments, the film is substantially translucent. The membrane may be selected from lipids, polymers, gelatin, cellulose and cyclodextrins. The composition may also comprise a dendritic polymer, for example comprising poly (allylamine). The carrier medium may be a liquid. It may also be a gel or a semi-solid.

According to another aspect, the present invention provides a biophotonic composition comprising a first chromophore and a gelling agent, wherein the biophotonic composition has a viscosity of about 10,000 to about 100,000cP, preferably about 10,000 to about 60,000cP, more preferably about 10,000 to about 50,000 cP. In certain embodiments, the first chromophore is a fluorophore that can absorb light from within the composition and emit light. Preferably, the biophotonic composition has a spreadable consistency.

According to yet a further aspect, the present invention provides a biophotonic composition comprising a first chromophore and a second chromophore in a medium, wherein at least one of the first chromophore and the second chromophore is a fluorophore. The first chromophore may be fluorescein and the second chromophore may be eosin Y. The first chromophore can be eosin Y and the second chromophore can be one or more of rose bengal, phloxine B, and erythrosine B.

According to another aspect, the present invention provides a biophotonic composition comprising a first chromophore and a second chromophore in a medium, wherein the first chromophore is a fluorophore, and wherein the second chromophore is photoactivatable by light emitted by the first chromophore upon photoactivation. In some embodiments of both aspects, the medium is a gel or gel-like. The medium may have a spreadable consistency.

By 'in use' is meant that during the treatment time, the treatment time may be up to about 5 minutes, up to about 10 minutes, up to about 15 minutes, up to about 20 minutes, up to about 25 minutes, or up to about 30 minutes. The treatment time may comprise the total length of time the composition is in contact with the tissue.

Substantially resistant to leaching is understood to mean that less than 15% of the total chromophore amount leaches from the biophotonic composition into the phosphate buffered saline solution contained in the receiving chamber through a Polycarbonate (PC) film 2.4-3cm in diameter, 10 microns in thickness and 3 microns in pore size, having a top side on which a 2mm thick layer of the biophotonic composition is placed for 5 minutes at room temperature and pressure, and a bottom side in direct contact with the phosphate buffered saline solution. It will be appreciated that if the treatment time is longer than 5 minutes, the leaching test needs to be extended to the treatment time.

In certain embodiments of any of the above or below, the biophotonic topical composition allows less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1% or substantially no leaching of the chromophore content from the biophotonic composition.

In certain embodiments of any of the above or below, the biophotonic composition is a topical composition. Preferably, the composition is a gel, semi-solid or viscous liquid that can be spread on the treatment site. In some embodiments, the composition may remain on the treatment site when the treatment site is inverted or tilted during the treatment time.

In certain embodiments of any of the above or below, the biophotonic composition is substantially translucent or transparent. Substantially translucent means having a transmission of more than about 20%. In some embodiments, translucency means at least 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90%, 95%, or 100% light transmission through a 2mm thick composition.

In certain embodiments of any of the above or below, wherein the composition and/or gellant has a viscosity of about 10,000-70,000, 10,000-90,000, 10,000-80,000, 10,000-70,000, 15,000-80,000, 15,000-70,000, 10,000-50,000, 10,000-40,000, 15,000-50,000, or 15,000-40,000cP when measured at room temperature using a Wells-Brookfield HB cone/plate viscometer and a CP-51 cone at a rotational speed and torque of 2rpm > 10%, or a DV-II + Pro viscometer with spindle 7 at 50rpm for 1 minute.

In certain embodiments of any of the above or below, the gelling agent is selected from cross-linked polymers. The polymers may be covalently crosslinked or physically crosslinked. The gelling agent may be selected from at least one of hydrophilic materials, hygroscopic materials, or hydrated polymers. The gelling agent may be polyanionic in charge characteristics. In some embodiments, the gelling agent comprises carboxylic acid functional groups, which may contain 2 to 7 carbon atoms per functional group.

The gelling agent may be a synthetic polymer selected from the group consisting of: vinyl polymers, polyoxyethylene polyoxypropylene copolymers, poly (ethylene oxide), acrylamide polymers and derivatives or salts thereof. The gelling agent may be a vinyl polymer selected from polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone or polyvinyl alcohol. The gelling agent may be a carboxyvinyl polymer or a carbomer obtained by polymerization of acrylic acid. The carboxyvinyl polymer or carbomer may be crosslinked.

In certain embodiments, the gelling agent is a high molecular weight, crosslinked polyacrylic acid polymer having a viscosity within the following range: about 10,000 and 100,000; 10,000-80,000; 15,000-80,000; 10,000-70,000; 15,000-; 15,000-40,000, 10,000-60,000; 10,000-50,000; 10,000-40,000; 20,000-100,000; 25,000-90,000; 30,000-80,000; 30,000-; 30,000-60,000; 25,000 and 40,000 cP. The polymer may be selected from, but is not limited to, the following:940、980、ETD 2020NF、1382 polymer, 71GNF, 971PNF, 974PNF, 980NF, 981NF, 5984EP, ETF 2020NF, ultrez 10NF, ultrez 20, ultrez 21, 1342NF, 934PNF, 940NF, 941 NF.

In certain embodiments, the gelling agent is a polyacrylic acid polymer crosslinked with an alkyl acrylate or allylpentaerythritol and is present in an amount of from about 0.05% to about 5% by weight of the final composition, preferably from about 0.5% to about 2% by weight of the final composition.

In certain embodiments of any of the above or below, the gelling agent comprises a protein-based polymer, which may be selected from at least one of sodium hyaluronate, gelatin, and collagen. The gelling agent may be gelatin and is present in an amount equal to or greater than about 4% by weight of the final composition. The gelling agent may be collagen and is present in an amount equal to or greater than about 5% by weight of the final composition.

In certain embodiments of any of the above or below, the gelling agent comprises a polysaccharide that can be selected from at least one of starch, chitosan, chitin, agar, alginate, xanthan gum, carrageenan, guar gum, gellan gum, pectin, and locust bean gum. The gelling agent may be present in an amount equal to or greater than about 0.01% by weight of the final composition.

In certain embodiments of any of the above or below, the gelling agent comprises at least one glycol. The glycol may be selected from ethylene glycol and propylene glycol. The glycol may be polyethylene glycol.

In certain embodiments, the biophotonic composition may further comprise a humectant, such as glycerin. The biophotonic composition may further comprise healing factors, preservatives, pH modifiers, chelating agents, and the like.

In certain embodiments of any of the above or below, the biophotonic composition is encapsulated in a membrane, which may be impermeable or breathable to allow gas, but not liquid, to permeate. The film may be translucent. The membrane may comprise a lipid, a polymer or gelatin.

In certain embodiments of any of the above or below, the biophotonic composition further comprises an oxygen releasing agent, which may be a peroxide or a peroxide releasing agent, or water. The oxygen-releasing agent may be selected from the group consisting of hydrogen peroxide, urea peroxide, benzoyl peroxide, peroxy acids, alkali metal peroxides, alkali metal percarbonates, peroxy acetic acids and alkali metal perborates.

In certain embodiments of any of the above or below, the first chromophore can be in an aqueous or alcoholic solution in the composition. The gelling agent and the chromophore solution may form a hydrocolloid.

In certain embodiments of any of the above or below, the first chromophore absorbs light at the wavelengths 200-600nm or 400-800 nm. In certain embodiments of any of the above or below, the first chromophore absorbs light having a wavelength in the visible spectral range. In some embodiments, the first chromophore is a fluorescent chromophore (fluorophore). The first chromophore can be a xanthene dye. The first chromophore may be selected from eosin Y, eosin B, erythrosin B, fluorescein, rose bengal and phloxine B. The first chromophore may be present in an amount of from about 0.001% to about 40% by weight of the total composition, preferably from about 0.005% to about 2% by weight of the total composition, more preferably from about 0.01% to about 2% by weight of the total composition.

In certain embodiments of any of the above or below, the composition further comprises a second chromophore. The first chromophore can have an emission spectrum that overlaps at least 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70% of the absorption spectrum of the second chromophore. In some embodiments, the first chromophore of the biophotonic topical composition 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%, or 60-70% with the absorption spectrum of the second chromophore (when present).

In certain embodiments of any of the above or below, the first chromophore transfers energy to the second chromophore upon irradiation with light. Irradiation of the biophotonic topical composition with light causes energy to be transferred from the first chromophore to the second chromophore. In some embodiments, upon absorption of energy from the first chromophore, the second chromophore fluoresces and/or generates reactive oxygen species. At least one of the chromophores, such as the first chromophore, can be photobleached during irradiation with light. At least one of the chromophores, such as the first chromophore, can fluoresce upon illumination with light. In certain embodiments, the biophotonic composition does not generate a substantial amount of heat after irradiation with light. In some embodiments, the energy emitted by the biophotonic composition does not cause tissue damage.

In certain embodiments of any of the above or below, the second chromophore can absorb light having a wavelength in the visible spectrum. In some embodiments, the second chromophore has an absorption wavelength that is relatively longer than the first chromophore, e.g., 10-100nm, 20-80nm, 25-70nm, or 30-60nm in length.

In certain embodiments of any of the above or below, the first chromophore is eosin Y and the second chromophore is one or more selected from the group consisting of fluorescein, phloxine B and erythrosine B. In certain embodiments of any of the above or below, the first chromophore is fluorescein and the second chromophore is eosin Y. Optionally, a third fluorophore such as rose bengal may be present. In other embodiments, the first chromophore is rose bengal. In some embodiments, the biophotonic composition comprises eosin and fluorescein. In other embodiments, the biophotonic composition comprises eosin and rose bengal. In other embodiments, the biophotonic composition comprises fluorescein and rose bengal. In other embodiments, the biophotonic composition comprises fluorescein and rose bengal.

The second chromophore may be present in an amount of from about 0.0001% to about 40% by weight of the total composition, preferably from about 0.0001% to about 2% by weight of the total composition.

In certain embodiments of any of the above or below, the composition comprises a third chromophore. The third chromophore may be chlorophyll (e.g. chlorophyllin, chlorophyll a, chlorophyll b) or saffron.

In certain embodiments of any of the above or below, the pH of the composition is in the range of 4.0 to 7.0, preferably in the range of 4.0 to 6.5, more preferably in the range of 4.0 to 5.0. The pH of the composition may also be in the range of 6.0 to 8.0, preferably in the range of 6.5 to 7.5.

In certain embodiments of any of the above or below, the biophotonic composition may be applied to or impregnated within a material, such as a pad, dressing, woven or non-woven fabric, and the like. The soaked material can be used as a mask (e.g., face mask) or dressing.

In certain embodiments of any of the above or below, the biophotonic composition further comprises at least one waveguide within or adjacent to the composition. The waveguide may be a particle, fiber or filament network made of a material that is transmissive to and/or emits light.

In certain embodiments of any of the above or below, the composition does not comprise opaque particles such as silica.

According to a further aspect, the present invention provides a biophotonic composition as described above for skin rejuvenation; for use in the treatment of wounds; for treating or preventing skin disorders (e.g., acne, psoriasis); for the treatment or prevention of periodontitis; for the treatment of acute inflammation; or for the treatment of fungal, bacterial or viral infections.

According to a still further aspect, the present invention provides a biophotonic composition as described above for skin rejuvenation, for the treatment of wounds; for treating or preventing skin disorders (e.g., acne, psoriasis); for the treatment or prevention of periodontitis; for the treatment of acute inflammation; or for the treatment of a fungal, bacterial or viral infection.

In another aspect, the present invention provides a method for providing cosmetic treatment, the method comprising topically applying to the skin a biophotonic composition as defined above; and irradiating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the first chromophore. The skin caring treatment can promote skin rejuvenation.

In a further aspect, the present invention provides a method for promoting wound healing, the method comprising: topically applying to the wound a biophotonic composition as defined above; and irradiating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the first chromophore. In certain embodiments of the method, the wound as described herein comprises, for example, a chronic or acute wound, such as a diabetic foot ulcer, a pressure ulcer, a venous ulcer, or an amputation. In some embodiments of the method for providing biophotonic therapy to a wound, the method promotes a reduction in scar tissue formation.

In a still further aspect, the present invention provides a method for biophotonic treatment of a skin disorder, the method comprising topically applying to a target skin tissue having a skin disorder a biophotonic composition as defined above; and irradiating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the first chromophore.

In a further aspect, the present invention provides a method for biophotonic treatment of acne, the method comprising: topically applying a biophotonic composition as defined above to a target tissue, wherein the tissue is an acne lesion or acne scar; and irradiating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the first chromophore.

In another aspect, the invention provides a method for biophotonic treatment of periodontal disease, the method comprising: topically applying to the periodontal pocket a biophotonic composition as defined above; and irradiating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of the first chromophore.

In certain embodiments of any of the methods of the present disclosure, the biophotonic composition is irradiated for any period of time/treatment, wherein the biophotonic composition is activated, e.g., for 1 to 30 minutes, preferably less than 20 minutes, 15 minutes, 10 minutes, or about 5 minutes. The treatment time may correspond to or be longer than the time taken for the first chromophore to photobleach. In certain embodiments, the methods of the present disclosure comprise the step of irradiating the biophotonic composition for a period of at least 30 seconds, 2 minutes, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes. In some embodiments, the biophotonic composition is irradiated for a period of at least 3 minutes. Preferably, the biophotonic composition is illuminated with visible incoherent light, such as violet and/or blue light. Any other suitable light source may be used.

The distance of the light source from the biophotonic composition may be any distance, such as 5, 10, 15, or 20cm, that can deliver a suitable optical power density to the biophotonic composition and/or skin tissue. The biophotonic composition is topically applied at any suitable thickness. Typically, the biophotonic composition is topically applied to the skin or wound at a thickness of at least about 2mm, from about 2mm to about 10 mm.

In certain embodiments of the methods of the present disclosure, the biophotonic composition is removed from the treatment site after the application of light. Accordingly, the biophotonic composition is removed from the treatment site within at least 30 seconds, 2 minutes, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes after application. In some embodiments, the biophotonic composition is removed after a period of at least 3 minutes after the biophotonic composition is applied to the treatment site.

In certain other embodiments, the composition remains within the treatment area and may be re-irradiated as desired. The biophotonic composition may remain in situ for up to one, two, or three weeks. The composition may be re-irradiated with light at various intervals, which may include ambient light. In this case, the composition may be masked between exposures to light. For example, the biophotonic composition may be soaked in a dressing and placed inside or over a wound and left in place for an extended period of time (e.g., more than one day).

In certain embodiments of the methods for biophotonic treatment of acne, the treatment may be applied once, twice, three times, four times, five times, or six times a week, once per day, or at any other frequency to the skin tissue, e.g., on the face. 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 face may be divided into individual regions (cheek, forehead) and each region treated separately. For example, the composition may be applied topically to the first portion and the portion irradiated with light, and the biophotonic composition subsequently removed. The composition is then applied to a second part, irradiated and removed. Finally, the composition is applied to the third portion, irradiated and removed.

In certain embodiments of the methods for biophotonic treatment of wounds, the treatment may be applied once, twice, three times, four times, five times, or six times a week, once per day, or at any other frequency in or on the wound. 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.

The disclosed methods for treating acne, wounds, or other skin conditions may also include the administration of systemic or topical medications, for example, prior to, during, or after biophotonic therapy. The medicament may be an antibiotic, hormonal therapy, or any other pharmaceutical preparation that can help treat acne or wounds. The combination of systemic treatment along with local biophotonic treatment may reduce the duration of the systemic treatment time.

According to another aspect, the invention provides a kit comprising: a composition as described above, and one or more of a light source for activating the chromophore, instructions for use of the composition and/or light source, a dressing, and a device for applying and/or removing the composition from the treatment area.

According to another aspect, the invention provides a kit comprising: a first component comprising a first chromophore; and a second component comprising a gelling agent present in an amount sufficient to gel or thicken the composition and render the biophotonic composition substantially resistant to leaching such that less than 15% by weight of the total chromophore amount leaches from the biophotonic composition in use.

According to a still further aspect, the present invention provides a kit comprising: a first component comprising a first chromophore; and a second component comprising a gelling agent, wherein the first component and the second component combine to form a biophotonic composition that is substantially resistant to leaching such that less than 15% by weight of the total chromophore amount leaches from the biophotonic composition in use. The first component and/or the second component may also be individually resistant to leaching.

According to another aspect, the invention provides a kit comprising: a first component comprising a composition as described above, and a second component comprising an oxygen-releasing agent. In particular, the first component may comprise a first chromophore and a gelling agent, wherein the composition of the first component and the combined first and second component compositions are substantially resistant to leaching such that less than 15% by weight of the total chromophore amount leaches in use.

Drawings

FIG. 1 depicts light absorption in layers of skin (Samson et al experience Report/technology Association 2004,111, pages 1-97).

Fig. 2 shows the stokes shift.

Fig. 3 shows the absorption and emission spectra of the donor chromophore and the acceptor chromophore. The spectral overlap between the absorption spectrum of the acceptor chromophore and the emission spectrum of the donor chromophore is also shown.

FIG. 4 is a schematic diagram showing a jabronsted diagram involving a coupling transition between donor emission and acceptor absorption.

Fig. 5 depicts an experimental setup of an in vitro release test for evaluating chromophore leaching of biophotonic compositions (example 6).

Fig. 6a and 6b are absorption and emission spectra, respectively, of a composition including eosin and fluorescein in a gel, according to certain embodiments of the present disclosure (example 1).

Figures 7a and 7b are absorption and emission spectra, respectively, of a composition including eosin and fluorescein in aqueous solution, according to certain embodiments of the present disclosure (example 2).

Fig. 8a and 8b are absorption and emission spectra, respectively, of a composition including eosin, fluorescein, and rose bengal in a gel, according to certain embodiments of the present disclosure (example 3).

Fig. 9a and 9b are absorption and emission spectra, respectively, of a composition comprising eosin, fluorescein, and rose bengal in aqueous solution, according to certain embodiments of the present disclosure (example 4).

FIG. 10 is an emission spectrum showing the intensity of light emitted by the biophotonic compositions of the present disclosure tested in example 5 over time.

FIG. 11 is an emission spectrum showing the intensity of light emitted by the biophotonic compositions of the present disclosure tested in example 7 over time.

Figure 12 shows the effect of biophotonic compositions of the present disclosure on Ki67 expression (example 10).

Figure 13 shows that for eosin Y (top) and fluorescein (bottom), the fluorescence emitted by the chromophore in the composition increases rapidly with increasing composition, but slowly decreases to a plateau with further increasing concentration (example 13).

Figure 14 shows eosin and rose bengal acting in a synergistic manner (example 14).

Detailed Description

(1) Overview

Photodynamic therapy protocols have been developed to promote wound healing, facial rejuvenation and to treat various skin disorders. However, these methods require direct application of the photosensitizer to the target skin and/or uptake of the photosensitizer into the skin cells. As noted above, direct contact of the photosensitizer with the tissue can lead to undesirable side effects including cell damage/destruction and systemic or localized toxicity to the patient. Furthermore, many existing photodynamic therapy regimens often demonstrate low therapeutic efficacy due to, for example, poor uptake of the photosensitizer into skin cells at the target site. For this reason, many solutions require a waiting time of about one to 72 hours to allow internalization of the photosensitizer.

On the other hand, phototherapy utilizes the therapeutic effect of light. However, expensive and sophisticated light sources are typically required to provide the treatment wavelength and light intensity.

The present disclosure provides biophotonic compositions that are useful in phototherapy and that include photoactive exogenous chromophores that can emit therapeutic light or can facilitate therapeutic efficacy at a treatment site by activating other components of the biophotonic composition. The present disclosure also provides methods useful for promoting wound healing, cosmetic treatment of skin, e.g., rejuvenation of skin, treatment of acne and treatment of other skin disorders, treatment of acute inflammation, which are distinct from conventional photodynamic therapy.

Biophotonic therapies using the present compositions do not rely on the internalization of chromophores into cells or extensive contact with cells or target tissues. Thus, undesirable side effects caused by direct contact may be reduced, minimized, or prevented. At best, the chromophore has surface contact with the tissue to which the composition is applied, which can last for a very short time due to the short treatment time. Furthermore, unlike photodynamic therapy, biophotonic therapy with embodiments of the present biophotonic compositions is independent of cell death or damage. Indeed, applicants have shown in vitro studies that biophotonic compositions according to embodiments of the present disclosure reduce cellular necrosis (see example 10).

(2) Definition of

Before proceeding with the more detailed description of the present disclosure, it is to be understood that this disclosure is not limited to specific 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.

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

It is convenient to note herein that "and/or" as used herein should be viewed as a specific disclosure that each of the two named features or components may or may not contain the other. For example, "a and/or B" shall be considered a specific disclosure of each of (i) a, (ii) B, and (iii) a and B, as each is individually set forth herein.

"biophotonic" means 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. A "biophotonic composition" is a composition as described herein that can be activated by light to produce photons for biologically relevant applications.

"gel" is defined as a substantially dilute cross-linked system. The gel may be semi-solid and exhibit substantially no flow when in a steady state at room temperature (e.g., about 20-25 ℃). Steady state is herein meant during the treatment time and under the treatment conditions. As defined herein, gels may be physically or chemically crosslinked. As defined herein, a gel also includes a gel-like composition such as a viscous liquid.

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

The terms "chromophore", "photoactivating agent" and "photoactivating agent" are used interchangeably herein. Chromophore refers to a chemical compound that is capable of absorbing light when contacted by light irradiation. Chromophores readily undergo photoexcitation and can subsequently transfer their energy to other molecules or emit them as light.

"photobleaching" means photochemical destruction of the chromophore.

By "leaching" is meant the release of one or more components of the biophotonic composition (e.g., chromophores) from the composition into the surrounding environment, such as a wound site or tissue to be treated by the composition. The leaching properties of the biophotonic composition may be measured by: (i) placing a 2mm thick layer of the biophotonic composition on a top side of a 2.4-3cm diameter Polycarbonate (PC) membrane having a thickness of 10 μm and a pore size of 3 μm, the bottom side of the membrane being in contact with an aqueous solution of phosphate buffered saline in a receiving chamber, (ii) allowing the biophotonic composition to stand on the top surface of the membrane at room temperature and pressure for a time corresponding to a treatment time with the biophotonic composition, and (iii) removing a sample of the solution from the receiving chamber and measuring the concentration of chromophores in the solution.

The term "actinic light" means 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 as defined above). In a preferred embodiment, the actinic light is visible light.

As used herein, a "hygroscopic" substance is a substance that is capable of absorbing water, for example by absorption or adsorption, even at a relative humidity as low as 50% at room temperature (e.g., about 20-25 ℃).

By "impermeable membrane" is meant that the material contained within the membrane is sufficiently or substantially impermeable to the surrounding environment such that migration of such material out of the membrane and/or migration of environmental components (e.g., water) into the membrane is so low as to have substantially no adverse effect on the function or activity of the material retained within the membrane. An impermeable membrane may be "breathable" in that gas flow through the membrane is permitted, while liquid flow is not. The impermeable membrane may also selectively allow some materials to migrate through the membrane but not others.

By "wound" is meant any tissue injury, including, for example, acute, subacute, delayed or difficult to heal wounds, as well as chronic wounds. Examples of wounds may include both open wounds and closed wounds. Wounds include, for example, burns, incisions, resections, lesions, lacerations, abrasions, puncture or penetrating wounds, gunshot wounds, surgical wounds, contusions, hematomas, crush injuries, ulcers (e.g. pressure, venous, pressure or diabetes), wounds caused by periodontitis (periodontal tissue inflammation).

By "rejuvenating skin" is meant a process that reduces, diminishes, retards or reverses one or more signs of skin aging. For example, common signs of skin aging include, but are not limited to, the appearance of fine lines or wrinkles, thin and transparent skin, loss of subcutaneous fat (resulting in sunken cheeks and eye sockets and significant loss of tightness on the hands and neck), bone loss (causing the bones to atrophy away from the skin due to bone loss, which causes sagging skin), dry skin (which may be itchy), inability to sweat sufficiently to cool the skin, unwanted facial hair, freckles, age spots, spider veins, thick and hard skin, fine lines that disappear when stretched, sagging skin, or mottled skin. In accordance with the present disclosure, one or more of the above-mentioned signs of aging may be reduced, diminished, retarded, or even reversed by the compositions and methods of the present disclosure.

(3) Biophotonic topical compositions

The present disclosure provides biophotonic compositions. A biophotonic composition is a composition that is activated in a broad sense by light (e.g., photons) of a particular wavelength. These compositions contain at least one exogenous chromophore that is activated by light and accelerates the dispersion of light energy, which results in the light continuing its own therapeutic effect, and/or photochemical activation of other agents contained in the composition (e.g., acceleration in the decomposition of such compounds when a peroxide (oxygen-releasing agent) is present in the composition or at the treatment site, resulting in the formation of oxygen radicals, such as singlet oxygen). The composition may include an oxygen-releasing agent that, when mixed with the first chromophore and subsequently activated by light, is photochemically activatable, which may result in the formation of oxygen radicals, such as singlet oxygen.

In some aspects, the present disclosure provides a biophotonic composition comprising at least a first chromophore in a medium, wherein the composition is substantially resistant to leaching such that a low or negligible amount of the chromophore leaches from the biophotonic composition into a treatment site (e.g., tissue) to which the composition is applied during treatment. In certain embodiments, this is achieved by a medium comprising a gelling agent that slows or limits migration or leaching of the chromophore. In other embodiments, this is achieved by providing an encapsulating film around the first chromophore in the medium. In this way, contact of the chromophore with the tissue can be minimized or avoided.

In some aspects, the biophotonic compositions of the present disclosure do not stain tissue to which they are topically applied during treatment. Staining was determined by visually assessing whether the biophotonic composition colored a white test paper saturated with 70% ethanol by volume/30% aqueous solution by volume, left in contact with the biophotonic composition for a period of time corresponding to the desired treatment time. In some embodiments, the biophotonic composition of the present disclosure does not visually color a white test strip saturated with 70% ethanol by volume/30% aqueous solution by volume, placed in contact with the biophotonic composition at atmospheric pressure for a period of time corresponding to a desired treatment time. In certain embodiments, the time corresponding to the treatment time is at least about 5 minutes, at least about 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.

When a chromophore absorbs a photon of a certain wavelength, it becomes excited. This is an unstable state and the molecule tries to return to the ground state, sending out excess energy. For some chromophores, it is advantageous to emit the excess energy as light when converting back to the ground state. This process is called fluorescence. The peak wavelength of the emitted fluorescence is shifted towards longer wavelengths ("stokes" shift) compared to the absorption wavelength. The emitted fluorescent energy may then be transferred to other components of the composition, or to a treatment site to which the biophotonic composition is topically applied. Fig. 1 shows different penetration depths for different light wavelengths. Different wavelengths of light may have different and complementary effects on tissue. The stokes shift is shown in figure 2.

Without being bound by theory, it is believed that the fluorescence emitted by the photoactivated chromophore may have therapeutic properties due to its femtosecond, picosecond, or nanosecond emission properties that can be recognized by biological cells and tissues, resulting in favorable biological modulation. Furthermore, the emitted fluorescence has a longer wavelength than the activation light and thus penetrates deeper into the tissue. Irradiating tissue with such a wide range of wavelengths (including, in some embodiments, activating light through the composition) can have different and complementary effects on cells and tissue. Furthermore, in embodiments of compositions containing an oxygen-releasing agent, the present inventors have observed micro-foaming within the composition that may be associated with the generation of oxygen species by photoactivation of the chromophore. This can have a physical effect on the tissue to which the composition is applied, for example by removing debridement of biofilm and necrotic tissue or providing a pressure stimulus. The biofilm may also be pretreated with an oxygen releasing agent to weaken the biofilm prior to treatment with the composition of the present disclosure.

Certain embodiments of the biophotonic compositions of the present disclosure are substantially transparent/translucent and/or have a high light transmittance so as to allow light to dissipate into and through the composition. In this way, the tissue area under the composition can be treated with both fluorescence emitted by the composition and light illuminating the composition to activate it, which can benefit from different effects of light having different wavelengths.

The% transmittance of the biophotonic composition may be measured over a wavelength range of 250nm to 800nm using, for example, a Perkin-Elmer Lambda 9500 series ultraviolet-visible spectrophotometer. Alternatively, a Synergy HT spectrophotometer (BioTek Instrument, Inc.) may be used in the wavelength range of 380nm to 900 nm.

The transmittance was calculated according to the following formula:

wherein A is the absorbance, T is the transmittance, I₀Is the intensity of the radiation before passing through the material and I is the intensity of the light passing through the material.

This value can be normalized for thickness. As described herein, the% transmittance (translucency) is measured at 526nm wavelength for a 2mm thick sample. It is clear that other wavelengths may be used.

In some embodiments, the biophotonic composition has a transparency or translucency of greater than 15%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the transparency is greater than 70%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. All transmittance values reported herein were as measured using a Synergy HT spectrophotometer on a 2mm thick sample at a wavelength of 526 nm.

Embodiments of the biophotonic compositions of the present disclosure are for topical use. The biophotonic composition may be in the form of a semi-solid or viscous liquid, having the property of limiting leaching of the chromophore from the composition to less than 15% by weight. Preferably, the biophotonic composition is a gel or gel-like, comprises a viscous liquid, and has a spreadable consistency at room temperature (e.g., about 20-25 ℃) prior to irradiation. By spreadable is meant that the composition can be applied topically to the treatment site at a thickness of about 2 mm. The spreadable composition may conform to the topography of the treatment site, e.g. a wound. This may have advantages over non-conforming materials in that better and/or more complete irradiation of the treatment portion may be achieved.

These compositions may be described based on the components that make up the composition. Additionally or alternatively, the compositions of the present disclosure have functional and structural properties, and these properties can also be used to define and describe the compositions. The individual components of the compositions of the present disclosure are described in detail below.

(a) Chromophores

The biophotonic topical compositions of the present disclosure comprise one or more chromophores that can be considered exogenous, e.g., not naturally present in skin or tissue. The chromophores are contained or retained within the biophotonic composition such that they do not substantially contact a target tissue to which the composition is applied during a treatment time. In this way, the beneficial and therapeutic properties of the chromophore can be exploited without the potentially damaging effects caused by chromophore cell contact.

Suitable chromophores can be fluorescent dyes (or dyes), although other dye sets or dyes (biological and histological dyes, food colorants, carotenoids, naturally occurring fluorescent dyes, and other dyes) can also be used. Suitable chromophores may be Generally Regarded As Safe (GRAS) chromophores, although chromophores not well tolerated by the skin or other tissue may also be included in the biophotonic composition, as contact with the skin is minimized in use due to the leaching-barrier properties of the composition.

In certain embodiments, the biophotonic topical compositions of the present disclosure comprise a first chromophore that undergoes partial or complete photobleaching upon the application of light. Photo-bleaching means photochemical destruction of chromophores which can generally manifest as discoloration.

In some embodiments, the first chromophore absorbs at a wavelength within the visible spectral range, such as at a wavelength of about 380-800nm, 380-700 nm, or 380-600 nm. In other embodiments, the first chromophore absorbs at a wavelength of about 200-800nm, 200-700nm, 200-600nm, or 200-500 nm. In one embodiment, the first chromophore absorbs at a wavelength of about 200-600 nm. In some embodiments, the first chromophore absorbs at a wavelength of about 200-300nm, 250-350nm, 300-400nm, 350-450nm, 400-500nm, 400-600nm, 450-650nm, 600-700nm, 650-750nm, or 700-800 nm.

One skilled in the art will appreciate 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 disclosure.

The biophotonic compositions disclosed herein may include at least one additional chromophore. The combined chromophore can increase light absorption by the combined dye molecule and enhance absorption and photobiomodulatory selectivity. This creates multiple possibilities for generating new mixtures of photosensitive and/or selective chromophores.

When such multiple chromophore compositions are irradiated with light, energy transfer can occur between the chromophores. This process is called resonance energy transfer and is a photophysical process whereby its 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 targeting of resonance energy transfer depends on the spectral characteristics of the donor chromophore and the acceptor chromophore. In particular, the fluence between chromophores depends on the spectral overlap reflecting the relative positioning and shape of the absorption and emission spectra. For energy transfer to occur, the emission spectrum of the donor chromophore overlaps with the absorption spectrum of the acceptor chromophore (fig. 3).

Energy transfer manifests itself by a reduction or quenching of the emission by the donor and a simultaneous reduction in the lifetime of the excited state with an increase in the intensity of the emission by the acceptor. FIG. 4 is a jabronsted diagram showing the coupling transition between donor emission and acceptor absorption.

To enhance the energy transfer efficiency, the donor chromophore should have good ability to absorb photons and emit photons. Furthermore, it is believed that the more overlap that exists 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.

In certain embodiments, the biophotonic topical compositions of the present disclosure further comprise a second chromophore. In some embodiments, the first chromophore has an emission spectrum that overlaps at least about 80%, 50%, 40%, 30%, 20%, 10% with the absorption spectrum of the second chromophore. In one embodiment, the first chromophore has an emission spectrum that 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%, or 60-70% of the absorption spectrum of the second chromophore.

As used herein,% spectral overlap means the% overlap of the emission wavelength range of the donor chromophore with the absorption wavelength range of the acceptor chromophore, measured at the full width quarter peak (FWQM) of the spectrum. For example, FIG. 3 shows normalized absorption and emission spectra for a donor chromophore and an acceptor chromophore. The spectrum FWQM of the absorption spectrum of the acceptor chromophore is from about 60nm (515nm to about 575 nm). The overlap of the spectrum of the donor chromophore with the absorption spectrum of the acceptor chromophore is about 40nm (from 515nm to about 555 nm). Therefore, the% overlap may be calculated as 66.6% for 40nm/60nmx 100.

In some embodiments, the second chromophore absorbs at a wavelength in the visible spectral range. In certain embodiments, the second chromophore has a relatively longer absorption wavelength than the first chromophore in the range of about 50-250, 25-150, or 10-100 nm.

As described above, application of light to the compositions of the present disclosure can result in an energy transfer cascade between chromophores. In certain embodiments, such an energy transfer cascade provides photons that penetrate the epidermis, dermis, and/or mucosa at a target tissue, including, for example, a wound site or a tissue with acne or a skin disorder. In some embodiments, such energy transfer cascades are not accompanied by concurrent generation of heat. In some other embodiments, the cascade of energy transfer does not result in tissue damage.

Optionally, when the biophotonic topical composition comprises a first chromophore and a second chromophore, the first chromophore is present in an amount of about 0.005-40% per weight of the composition and the second chromophore is present in an amount of about 0.001-40% per weight of the composition. In certain embodiments, the total weight/weight of chromophore or chromophore combination may be in an amount of about 0.005-40.001%/weight of the composition. In certain embodiments, the first chromophore is present in an amount of about 0.005-1%, 0.01-2%, 0.02-1%, 0.02-2%, 0.05-1%, 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% per weight of the composition. In certain embodiments, the second chromophore is present in an amount of about 0.001-1%, 0.001-2%, 0.001-0.01%, 0.01-0.1%, 0.1-1.0%, 1-2%, 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 composition. In certain embodiments, the total weight/chromophore or combination of chromophores may be present in an amount of about 0.005-1%, 0.01-2%, 0.05-2%, 0.5-1%, 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 35-40.05% by weight per composition.

In some embodiments, the one or more chromophores are selected such that they fluoresce upon photoactivation within one or more of the green, yellow, orange, red, and infrared portions of the electromagnetic spectrum, e.g., having a peak wavelength in the range of about 490nm to about 800 nm. In certain embodiments, the emitted fluorescence has a fluorescence of 0005 to about 10mW/cm²About 0.5 to about 5mW/cm²The power density of (a).

Suitable chromophores that can be used in the biophotonic topical compositions of the present disclosure include, but are not limited to, the following:

chlorophyll dyes

Exemplary chlorophyll dyes include, but are not limited to, chlorophyll a; chlorophyll b; oil-soluble chlorophyll; 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 (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, monoanion) 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 (tribromo-fluorescein, dianion); eosin derivatives (2',4',5',7' -tetrachloro-fluorescein, dianion); eosin; eosin-dicylpyrazine 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); jiaoning G, Jiaoning J, Jiaoning Y; rhodamine dyes such as rhodamine include 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 blue (16 μm); methylene blue (14 μm); methylene violet; methylene bromide 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 (azorubine S), carmine (azorubine, food red 3, acid red 14), allura red AC (FD & C40), tartrazine (FD & yellow 5), orange G (acid orange 10), ponceau 4R (food red 7), methyl red (acid red 2), and ammonium taurocide-ammonium rhodanate.

In some aspects of the disclosure, one or more chromophores of the biophotonic compositions disclosed herein can be independently selected from any one of Acid Black 1, Acid blue 22, Acid blue 93, Acid magenta, Acid Green 1, Acid Green 5, Acid magenta (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 Red), Acid Red, Acid Violet 19, Acid yellow 1, Acid yellow 9, Acid yellow 23, Acid yellow 24, Acid yellow 36, Acid yellow 73, Acid Red 22, Acid Red, Acid yellow S, acridine orange, acridine yellow, acrylblue, apine yellow, alcohol-soluble eosin, alizarin blue 2RC, alizarin carmine, alizarin cyanine green BBS, alizarin cyanine green R, alizarin red S, alizarin purpurin, aluminum reagent, amino black 10 8978, aniline blue WS, anthracene blue SWR, auramine O, azocarmine B, azocarmine G, azodiazo 5, azodiazo 48, sky blue A, sky blue B, sky blue C, alkali blue 8, alkali blue 9, alkali blue 12, alkali blue 15, alkali blue 17, alkali blue 20, alkali blue 26, alkali brown 1, alkali magenta, alkali green 4, alkali orange 14, alkali red 2 (safranin O); alkali blue (safranin O) 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, fabry scarlet, fabry brown Y, brilliant scarlet 6R, calcium red, carmine, carminic acid (acid red 4), celestite blue B, chinese blue, carmine, celestine (Coelestine) blue, chromium violet CG, chromotropic 2R, chromium cyanine R, congo corice red, congo red, cotton blue, cotton red, safranin, crocetin, crystalline ponceau 6R, crystal violet, dahlia, malachite green 8978 6, direct blue 14, direct blue 58, direct red 10, direct red 28, direct red 80, direct yellow 7, crystal violet, malachite green 8978, direct blue 14, direct blue 58, direct red 10, direct red 28, direct red 80, direct yellow 7, crystal violet, or crystal violet, crystal violet, Eosin B, eosin light blue, eosin Y, eosin pale yellow, Eosinol, illicium red B, eriochrome 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, alizarin violet (Gallein), galloamine (Gallamine) blue, gallocyanine, gentian violet, hematoxylin oxide, hematoxylin violet, hematoxylin, helium nuclear fast red (Helio fast bin) BBL, methylene blue (Helvetia blue), hematoxylin, hoxiletine, hoffian red, indocyanine green (indocyanine green), alisnew blue 1, alisnew yellow 1, INT, Kermes, kermesic acid (kermesic acid), Fast red, Lac, Lac acid, laue' S violet, light green, lissamine green SF, lux fast blue, carmine 0, carmine I, carmine II, carmine III, malachite green, Manchester brown, Mahuh yellow, merbromin, mercurous chloride, metaramine yellow, methylene sky blue A, methylene sky blue B, methylene sky 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 red 3, natural red 4, natural red 8, natural red, Natural Red 16, Natural Red 25, Natural Red 28, Natural yellow 6, NBT, neutral Red, New fuchsin, Niagara blue 3B, night blue, Nile blue A, Nile blue oxazinone, Nile blue sulfate, Nile Red, Nitro BT, nitro blue tetrazolium, Nuclear fast Red, oil Red O, orange yellow G, lichen Red, Pararosaniline (Pararosanilin), Fluorochrome B, phycobilichrome, phycocyanin, Phycoerythrin (PEC), Phthalocyanin, picric acid, Lichun 2R, Lichun 6R, Lichun B, Anilin Dirichun (Ponceau de Xylidine), Lichun S, Primulus, purpurin, pyronin B, pyronin G, pyronin Y, rhodamine B, Rose Benzenil (Rosanilin), Rose bengal, saffron, safranin O, Scarlet R, Scarlet (Scarlet red), Charles red R, shellac, sirius red F3B, monochromium cyanine R, soluble blue, solvent Black 3, solvent blue 38, solvent Red 23, solvent Red 24, solvent Red 27, solvent Red 45, solvent yellow 94, alcohol-soluble eosin, Sudan III, Sudan IV, sudan black B, sulfur S, swiss blue, lemon yellow, thioflavin S, thioflavin T, thionine, toluidine blue, Toluyline red, globeflower orange G, trypan yellow, trypan blue, fluorescein sodium, victoria blue 4R, victoria blue B, victoria green B, water blue I, water-soluble eosin, xylidine ponceau or yellowish eosin.

In certain embodiments, the compositions of the present disclosure include any one or combination of the chromophores listed above in order to provide a biophotonic effect at the application site. This is a unique application of these agents and is distinct from the use of chromophores as simple dyes or catalysts for photopolymerization.

Chromophores can be selected, for example, in the case of fluorophores, based on their emission wavelength characteristics, based on their energy transfer potential, their ability to generate reactive oxygen species, or their antimicrobial effects. These needs may vary depending on the condition to be treated. For example, chlorophyll may have an antimicrobial effect on bacteria found on the face.

In some embodiments, the composition includes eosin Y as the first chromophore and any one or more of rose bengal, erythrosin, phloxine B as the second chromophore. These combinations are believed to have a synergistic effect in that eosin Y can transfer energy to rose bengal, erythrosine, or phloxine B when activated. This transferred energy is then emitted as fluorescence or by reactive oxygen species generation. This absorbed and re-emitted light is believed to be transmitted throughout the composition and also into the treatment site.

In a further embodiment, the composition comprises a synergistic combination of: eosin Y and fluorescein; fluorescein and rose bengal; erythrosine in combination with eosin Y, rose bengal or fluorescein; phloxine B in combination with one or more of eosin Y, rose bengal, fluorescein, and erythrosine. Other synergistic chromophore combinations are also possible.

By virtue of the synergistic effect of the chromophore combination in the composition, chromophores that are not normally activated by activating light (e.g., blue light from an LED) can be activated by energy transfer from chromophores activated by activating light. In this way, different properties of the photoactivated chromophores can be exploited or modified depending on the desired cosmetic or medical treatment.

For example, rose bengal can generate high yields of singlet oxygen when photoactivated in the presence of molecular oxygen, however, it has low quantum yields in terms of the fluorescence emitted. Rose bengal has a peak absorption around 540nm and is therefore typically activated by green light. Eosin Y has a high quantum yield and can be activated by blue light. By combining rose bengal with eosin Y, a composition is obtained that emits therapeutic fluorescence and generates 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 as fluorescence.

The chromophore combination may also have a synergistic effect with respect to its photoactivated state. For example, two chromophores can be used, one of which fluoresces when activated in the blue and green range and the other of which fluoresces in the red, orange and yellow range, thereby complementing each other and illuminating the target tissue with a broad range of light wavelengths having different penetration depths into the target tissue and different therapeutic effects.

(b) Gelling agent

The present disclosure provides biophotonic compositions comprising at least a first chromophore and a gelling agent, wherein the gelling agent provides a barrier such that the chromophore of the biophotonic topical composition is substantially not in contact with a target tissue. When present in the biophotonic compositions of the present disclosure, the gelling agent may render the composition substantially resistant to leaching such that the chromophore or photosensitizer of the biophotonic topical composition is not substantially in contact with the target tissue.

In certain embodiments, the biophotonic topical composition allows less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1% or substantially none of the chromophore content to leach out of the biophotonic composition.

In some embodiments, the biophotonic composition limits leaching of the first chromophore such that less than 15% of the total chromophore amount can leach into the tissue during a treatment time in which the composition is topically applied to the tissue and illuminated with light. In some embodiments, the biophotonic composition limits leaching of the first chromophore such that less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount can leach into the tissue during a treatment time in which the composition is topically applied to the tissue and irradiated with light. In some embodiments, the treatment time is at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, or at least about 30 minutes.

Leaching can be determined as described in example 6 (see figure 5). In some embodiments, the biophotonic composition of the present disclosure allows less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount to leach from the biophotonic composition through the porous membrane into the aqueous solution when the biophotonic composition is placed in contact with the aqueous solution through the porous membrane for a time corresponding to the desired treatment time. In certain embodiments, the time corresponding to the treatment time is at least about 5 minutes, at least about 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.

The gelling agent used according to the present disclosure may comprise any ingredient suitable for use in a topical biophotonic formulation as described herein. The gelling agent may be an agent capable of forming a crosslinked matrix including physical and/or chemical crosslinking. The gelling agent is preferably biocompatible and may be biodegradable. In some embodiments, the gelling agent is capable of forming a hydrogel or hydrocolloid. Suitable gelling agents are gelling agents that can form viscous liquids or semi-solids. In a preferred embodiment, the gelling agent and/or composition has suitable light transmission characteristics. It is also important to select a gelling agent that allows for the biophotonic activity of the chromophore. For example, some chromophores require a hydrated environment in order to fluoresce. The gelling agent may be capable of forming a gel, either alone or in combination with other ingredients, such as water or another gelling agent, or when applied to a treatment site or when irradiated with light.

Gelling agents according to various embodiments of the present disclosure may include, but are not limited to, polyalkylene oxides, particularly polyethylene glycols and poly (ethylene oxide) -poly (propylene oxide) copolymers, including block copolymers and random copolymers; polyols substituted with one or more polyalkylene oxides such as glycerol, polymeric glycerol (especially highly branched polymeric glycerol), propylene glycol and trimethylene glycols such as mono-, di-and trimeric ethylene oxide glycerol, mono-and dimeric ethylene oxide allyl glycol, and mono-and dimeric ethylene oxide trimethylene glycol; polyoxyethylene sorbitol, polyoxyethylene glucose; acrylic polymers and analogs and copolymers thereof, such as polyacrylic acid itself, polymethacrylic acid, poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate), poly (methyl alkyl sulfoxide methacrylate), poly (methyl alkyl sulfoxide acrylate), and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and ethyl mono-2- (acryloyloxy) succinate; polymaleic acid; poly (acrylamides) such as polyacrylamide itself, poly (methacrylamide), poly (dimethylacrylamide), and poly (N-isopropylacrylamide); poly (enol) s such as poly (vinyl alcohol); poly (N-vinyl lactams) such as poly (vinylpyrrolidone), poly (N-vinyl caprolactam) and copolymers thereof, polyoxazolines including poly (methyl oxazoline) and poly (ethyl oxazoline); and polyvinylamine.

The gelling agent according to certain embodiments of the present disclosure may include a polymer selected from any one of the following: synthetic or semi-synthetic polymeric materials, polyacrylate copolymers, cellulose derivatives and polymethyl vinyl ether/maleic anhydride copolymers. In some embodiments, the hydrophilic polymer comprises a polymer that is of high molecular weight (i.e., greater than about 5,000, and in some cases, greater than about 10,000, or 100,000 or 1,000,000 molar mass) and/or a crosslinked polyacrylic acid polymer. In some embodiments, the polymer is a polyacrylic acid polymer and has a molecular weight of between about 10,000 and 100,000; 10,000-80,000; 15,000-80,000; 10,000-70,000; 15,000-; 10,000-60,000; 10,000-50,000; 10,000-40,000; 20,000-100,000; 25,000-90,000; 30,000-80,000; 30,000-; 30,000-60,000; viscosity in the range of 25,000-40,000 cP. In certain embodiments, the polymer is a high molecular weight and/or crosslinked polyacrylic acid polymer, wherein the polyacrylic acid polymer has a viscosity in the range of about 10,000-80,000 cP.

In some embodiments, the gelling agent comprises carbomer. Carbomers are synthetic high molecular weight polymers of acrylic acid having about 3x10⁶Allyl ethers of allyl sucrose or pentaerythritol. The gelling mechanism depends on the neutralization of the carboxylic acid moiety to form soluble salts. The polymer is hydrophilic and produces a clear gel that flashes when neutralized. Carbomer gels have good thermal stability because the gel viscosity and yield values are substantially unaffected by temperature. Carbomer gels have optimal rheological properties as topical products. Intrinsic pseudoplastic flow allows immediate recovery of viscosity when shear is terminated, and high yield values and rapid fracture make it compatibleIt is desirable to distribute. Due to the presence of the free carboxylic acid residue,the aqueous solution of (a) is acidic in nature. Neutralization of the solution crosslinks and gels the polymer to form a viscous monolithic structure having the desired viscosity.

Carbomers are available as a fine white powder which is dispersed in water to form a low viscosity acidic colloidal suspension (1% dispersion has about pH 3). Neutralization of these suspensions with bases such as sodium, potassium or ammonium hydroxide, low molecular weight amines and alkanolamines results in the formation of a translucent gel. Nicotine salts such as nicotine chloride form stable water-soluble complexes with carbomers at about pH 3.5 and are stable at an optimum pH of about 5.6.

In some embodiments of the disclosure, the carbomer is carbopol. Such polymers are referred to by71GNF, 420, 430, 475, 488, 493, 910, 934P, 940, 971PNF, 974PNF, 980NF, 981NF, and the like, commercially available from b.f. goodrich or Lubrizol. Carbopol is a universal controlled release polymer as described by Brock (Pharmacotherapy, 14:430-7(1994)) and Durrani (Pharmaceutical Res. (Supp.)8: S-135(1991)), and belongs to the carbomer family of synthetic, high molecular weight, nonlinear acrylic polymers crosslinked with polyalkenyl polyethers. In some embodiments, the carbomer is974PNF, 980NF, 5984EP, ETD2020NF, Ultrez 10NF, 934PNF, or 940 NF. In certain embodiments, the carbomer is980NF, ETD2020NF, Ultrez 10NF, Ultrez 21 or 1382 Polymer, 1342NF, 940 NF. For example, from 0.05 to 1 by weight of the final composition0%, preferably 0.5 to 5%, more preferably 1 to 3% of high molecular weight carbopols may be present as gelling agents and may form a gel having a viscosity in excess of about 10,000cP, or preferably in excess of about 15,000 cP.

In certain embodiments, the gelling agent comprises a hygroscopic material and/or a hydrophilic material, which may be used for its water-attracting properties, and may also prevent or limit leaching of the chromophore. The hygroscopic or hydrophilic material may include, but is not limited to, glucosamine, polysaccharides, glycosaminoglycans, poly (vinyl alcohol), poly (2-hydroxyethyl methacrylate), polyethylene oxide, collagen, chitosan, alginates, poly (acrylonitrile) -based hydrogels, poly (ethylene glycol)/poly (acrylic acid) interpenetrating polymer network hydrogels, polyethylene oxide-polybutylene terephthalate, hyaluronic acid, high molecular weight polyacrylic acid, poly (hydroxyethyl methacrylate), poly (ethylene glycol), tetraethylene glycol diacrylate, polyethylene glycol methacrylate, and poly (methacrylate-co-hydroxyethyl acrylate).

The one or more gelling agents may be selected for their ability to prevent leaching of the chromophore. For example, a gelling agent can be selected that increases the viscosity of the biophotonic composition. In some embodiments, the viscosity of the biophotonic composition is 15,000-100,000, 15,000-90,000, 15,000-80,000, 20,000-70,000, 20,000-50,000, 10,000-50,000, 15,000-50,000, 10,000-40,000, 15,000-40,000 cP. Compositions having sufficiently high viscosity parameters may prevent or limit leaching of the chromophore from the composition. The viscosity of the biophotonic compositions of the present disclosure was measured using CP-51 and at a speed of 2rpm and ensured a torque of > 10% as measured using a cone/plate viscometer (Wells-Brookfield). The spindle must be rotated at least 5 times before a viscosity reading is obtained. Alternatively, a Brookfield DV-II + Pro viscometer with spindle 7, 50rpm, 1 minute can be used.

Gelling agents including lipids or other coating agents (which may coat chromophores) may also be used to limit or prevent leaching. The gelling agent may be a protein-based/naturally derived material, such as sodium hyaluronate, gelatin or collagen, and the like. The gelling agent may be a polysaccharide such as starch, chitosan, chitin, agarose, agar, locust bean gum, carrageenan, gellan gum, pectin, alginate, xanthan gum, guar gum, and the like.

In one embodiment, the composition may include up to about 2% sodium hyaluronate by weight of the final composition as a single gelling agent. In another embodiment, the composition may include more than about 4%, preferably more than about 5%, by weight of the final composition, of gelatin as the single gelling agent. In another embodiment, the composition may include up to about 10%, preferably up to about 8%, starch as the sole gelling agent. In another embodiment, the composition may include more than about 5%, preferably more than about 10%, by weight of the final composition, of collagen as the gelling agent. In further embodiments, from about 0.1% to about 10%, or from about 0.5% to about 3%, by weight of the final composition, of chitin may be used as the gelling agent. In other embodiments, from 0.5% to 5% by weight of the final composition of corn starch, or from 5% to 10% by weight of the final composition of starch may be used as a gelling agent. In certain other embodiments, more than 2.5% by weight of alginate, based on the weight of the final composition, may be used as a gelling agent in the composition. In other embodiments, the percent gelling agent by weight percent of the final composition may be as follows: cellulose gel (about 0.3-2.0%), konjac gum (0.5-0.7%), carrageenan (0.02-2.0%), xanthan gum (0.01-2.0%), arabic gum (3-30%), agar (0.04-1.2%), guar gum (0.1-1%), locust bean gum (0.15-0.75%), pectin (0.1-0.6%), tara gum (0.1-1.0%), polyvinylpyrrolidone (1-5%), sodium polyacrylate (1-10%). The other gelling agents may be used in an amount sufficient to gel or sufficiently thicken the composition to avoid or minimize leaching of the chromophore. It will be appreciated that lower amounts of the above gelling agents may be used in the presence of another gelling agent or thickener.

The biophotonic compositions of the present disclosure may also be, for example, encapsulated in a film. Such films may be transparent and/or substantially or completely impermeable. The membrane may be impermeable to liquids, but permeable to gases such as air. In certain embodiments, the composition may form a film encapsulating the chromophore of the biophotonic topical composition, wherein the film may be substantially impermeable to liquid and/or gas.

In certain embodiments, chromophore retention in the composition during the treatment time may be achieved by providing a film around the chromophore in the carrier medium. In this case it is a membrane that limits or stops chromophore leaching, for example by providing a barrier. The carrier medium may be a liquid encapsulated by a membrane, wherein the membrane is sufficiently resistant to chromophore leaching such that less than 15% of the total chromophore amount leaches from the encapsulated composition. The membrane may be formed from one or more lipid agents, polymers, gelatin, cellulose or cyclodextrin, and the like. Preferably, the film is translucent or transparent to allow light to penetrate to or from the chromophore. In one embodiment, the composition is a dendrimer having an outer membrane comprising poly (allylamine). In another embodiment, the outer membrane comprises gelatin.

(c) Oxygen releasing agent

According to certain embodiments, the compositions of the present disclosure may optionally further comprise one or more additional components, such as an oxygen-releasing agent. For example, the biophotonic topical compositions of the present disclosure may optionally include an oxygen releasing agent as a source of oxygen. The peroxide compound is an oxygen releasing agent containing a peroxy group (R-O-R) which is a chain structure containing two oxygen atoms and an atomic group or some elements, each of the two oxygen atoms being bonded to each other.

When the biophotonic compositions of the present disclosure comprising an oxygen releasing agent 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, thus causing the emission of light at longer wavelengths (stokes shift). In the appropriate environment, some of this energy release is transferred to oxygen or reactive hydrogen peroxide and promotes the formation of oxygen radicals, such as singlet oxygen. Singlet oxygen and other reactive oxygen species generated by the activation of biophotonic compositions are believed to operate in a strategic manner (a thermodynamic fast). That is, by low exposure to normally toxic stimuli (e.g., reactive oxygen species), health beneficial effects are brought about by stimulation and modulation of stress response pathways in cells of the target tissue. The endogenous response to exogenously generated free radicals (reactive oxygen species) is regulated in an increased defense capacity against the exogenous free radicals and induces an acceleration of the healing and regeneration processes. In addition, activation of the composition may also produce an antibacterial effect. The extreme sensitivity of bacteria to exposure to free radicals makes the compositions of the present disclosure practical as germicidal compositions.

As noted above, in some embodiments, concomitant micro-foaming is generated by the oxygen species of the composition, which may contribute to biofilm debridement or removal at the application site. This may allow improved penetration of the activating light and/or fluorescence to the treatment site, for example to inactivate bacterial colonies, resulting in a reduced number thereof.

Suitable oxygen-releasing agents that may be included in the composition include, but are not limited to:

hydrogen peroxide (H)₂O₂) Is a raw material for preparing organic peroxide. H₂O₂Is a powerful oxygen-releasing agent and the unique property of hydrogen peroxide is that it decomposes into water and oxygen and does not form any residual compounds that continue to be toxic. The hydrogen peroxide used in the composition can be used, for example, in a gel with 6% hydrogen peroxide. Suitable concentrations at which hydrogen peroxide may be used in the present compositions range from about 0.1% to about 6%.

Urea hydrogen peroxide (also known as urea peroxide, carbamide peroxide or percarbamide) is soluble in water and contains about 35% hydrogen peroxide. The carbamide peroxide used in the composition can be used as a gel with, for example, 16% carbamide peroxide (which represents 5.6% hydrogen peroxide) or 12% carbamide peroxide. Suitable concentrations at which urea peroxide may be used in the present compositions range from about 0.3% to about 16%. Urea peroxide can be bufferedThe slow release mode, which can be accelerated by thermal or photochemical reactions, decomposes into urea and hydrogen peroxide. Released urea [ urea, (NH)₂)CO₂)]Are highly soluble in water and are potent protein denaturants. Urea hydrogen peroxide increases the solubility of some proteins and enhances skin and/or mucosal rehydration.

Benzoyl peroxide consists of two benzoyl groups (benzoic acid in which the H of the carboxylic acid is removed) linked by a peroxide group. Benzoyl peroxide is found in acne treatments at concentrations varying from 2.5% to 10%. The released peroxide groups are effective in killing bacteria. Benzoyl peroxide also promotes skin turnover and pore cleaning, which also promotes a reduction in bacterial counts and reduces acne. Benzoyl peroxide decomposes upon contact with the skin into benzoic acid and oxygen, neither of which is toxic. Suitable concentrations at which benzoyl peroxide may be used in the present compositions range from about 2.5% to about 5%.

Specific oxygen-releasing agents that are preferred for use in the materials or methods of the present disclosure include, but are not limited to, hydrogen peroxide, urea peroxide, or benzoyl peroxide. Peroxy acids, alkali metal peroxides, alkali metal percarbonates, peroxyacetic acids, and alkali metal perborates may also be included as oxygen-releasing agents. The oxygen releasing agent may be provided in the form of a powder, liquid or gel. Alternatively, the oxygen-releasing agent may be applied to the tissue site separately from the composition. Alternatively, the composition may include an amount of an oxygen-releasing agent that is enhanced by the separate application of the oxygen-releasing agent to the treatment site.

In the compositions and methods of the present disclosure, additional components may optionally be included, or used in combination with the biophotonic compositions as described herein. Such additional components include, but are not limited to, healing factors, growth factors, antimicrobial agents, wrinkle fillers (e.g., botulinum, hyaluronic acid, or polylactic acid), collagen, antiviral agents, antifungal agents, antibiotics, drugs, and/or agents that promote collagen synthesis. These additional components may be applied topically to a wound, skin, or mucosa prior to, simultaneously with, and/or after topical application of the biophotonic compositions of the present disclosure, and may also be administered systemically. Suitable healing factors, antimicrobial agents, collagen, and/or agents that promote collagen synthesis are discussed below:

(d) healing factor

The healing factor comprises a compound that promotes or enhances the healing or regeneration process of the tissue at the site of application of the composition. During photoactivation of the compositions of the present disclosure, there is an increase in absorption of molecules at the treatment site by the skin, wound, or mucosa. An increase in blood flow at the treatment site was observed over an extended period of time. With the inclusion of healing factors, the increase in lymphatic drainage and possible changes in osmotic balance may be enhanced or even intensified due to dynamic interactions of the free radical cascade. Suitable healing factors include, but are not limited to:

hyaluronic acid (hyaluronic acid, hyaluronate): non-sulfated glycosaminoglycans, widely distributed throughout connective, epithelial and neural tissue. It is one of the major components of the extracellular matrix and contributes significantly to cell proliferation and migration. Hyaluronic acid is the major component of skin, where it is involved in tissue repair. It is abundant in the extracellular matrix, contributing to tissue hydrodynamics, cell motility and proliferation, and participating in a number of cell surface receptor interactions, including in particular the primary receptor CD 44. Hyaluronidase enzyme degrades hyaluronic acid. At least seven classes of hyaluronidase-like enzymes are present in humans, several of which are tumor suppressors. Degradation products of hyaluronic acid, oligosaccharides and hyaluronic acid of very low molecular weight, show pro-angiogenic properties. In addition, recent studies have shown that hyaluronic acid fragments, rather than native high molecular weight hyaluronic acid, can induce inflammatory responses in macrophages and dendritic cells in tissue injury. Hyaluronic acid is well suited for biological applications targeting the skin. Due to its high biocompatibility, hyaluronic acid is used to stimulate tissue regeneration. Studies have shown that hyaluronic acid appears early in healing to physically create a space for leukocytes to mediate an immune response. It is used in bioscaffold synthesis for wound healing applications and wrinkle treatment. Suitable concentrations at which hyaluronic acid may be used in the present compositions range from about 0.001% to about 3%.

Glucosamine: is one of the most abundant monosaccharides in human tissue and is a precursor in the biosynthesis of glycosylated proteins and lipids. It is commonly used in the treatment of osteoarthritis. The common glucosamine form is its sulfate salt, and includes glucosamine sulfate sodium salt. Glucosamine exhibits a variety of effects, including anti-inflammatory activity, stimulation of proteoglycan synthesis, and synthesis of proteolytic enzymes. Suitable concentrations at which glucosamine can be used in the present compositions range from about 0.01% to about 3%.

Allantoin: is a diurea of glyoxylic acid (glyosic acid). It has an exfoliative effect, increases the water content of the extracellular matrix, enhances the exfoliation of upper dead (apoptotic) skin cells, and promotes skin proliferation and wound healing.

Additionally, saffron can act as both a chromophore and a healing factor as well as acting as an enhancer. Other healing agents such as growth factors may also be included.

(e) Antimicrobial agents

The antimicrobial agent kills or inhibits the growth or accumulation of microorganisms. Exemplary antimicrobial agents (or antimicrobial agents) are described in U.S. patent application publications 20040009227 and 20110081530. Suitable antimicrobial agents for use in the methods of the present disclosure include, but are not limited to, phenol and chlorinated phenol compounds, resorcinol and its derivatives, bisphenol compounds, benzoates (parabens), halocarboxanilides (carbonilides), polymeric antimicrobial agents, thiazolines (thiazolines), trichloromethylthioimides, natural antimicrobial agents (also known as "natural aromatic oils"), metal salts, and broad spectrum antibiotics.

Specific phenol and chlorinated phenol antimicrobial agents useful in the present disclosure 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 polyalkyl and aromatic halophenols; p-chlorophenol; methyl p-chlorophenol; ethyl p-chlorophenol; n-propyl p-chlorophenol; n-butyl p-chlorophenol; n-pentyl p-chlorophenol; sec-amyl 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 o-chlorophenol; n-heptyl-o-chlorophenol; o-benzyl p-chlorophenol; o-benzyl (benzyl) -m-methyl p-chlorophenol; o-benzyl-m, m-dimethyl-p-chlorophenol; o-phenethyl 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-amyl 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-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 useful in the present disclosure include, but are not limited to: 2,2' -methylenebis- (4-chlorophenol); under trade name2,4,4 'trichloro-2' -hydroxy-diphenyl ether sold by Ciba Geigy, Florham Park, n.j; 2,2' -methylenebis- (3,4, 6-trichlorophenol); 2,2' -methylenebis- (4-chloro-6-bromophenol); bis- (2-hydroxy-3, 5-dichlorophenyl) sulfide; and bis- (2-hydroxy-5-chlorobenzyl) sulfide.

Specific benzoates (parabens) useful in the present disclosure 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 disclosure include, but are not limited to: 3,4,4' -Trichlorocarboxanilides, for example by Ciba-Geigy, Florham Park, N.J. under the trade name3- (4-chlorophenyl) -1- (3, 4-dichlorophenyl) urea sold under the trade name; 3-trifluoromethyl-4, 4' -dichlorocarbanilide; and 3,3',4-Trichlorocarbanilide.

Specific polymeric antimicrobial agents useful in the present disclosure include, but are not limited to: polyhexamethylene biguanide hydrochloride; and in the trade namePoly (iminoiminocarbonyliminocarbonyliminohexamethylene hydrochloride) sold under IB.

Specific thiazolines useful in the present disclosure include, but are not limited to, those under the trade name Micro-Thiazoline sold under the market; and in the trade name2-n-octyl-4-isothiazolin-3-one sold under IT-3000 DIDP.

Specific trichloromethylthioimides useful in the present disclosure include, but are not limited to: under trade nameN- (trichloromethylthio) phthalimide sold under the name of (i); and in the trade nameN-trichloromethylthio-4-cyclohexene-1, 2-dicarboximide is sold.

Specific natural antimicrobial agents that may be used in the present disclosure include, but are not limited to, the following oils: anise oil; lemon oil; orange oil; rosemary oil; wintergreen oil; thyme oil; lavender oil; clove oil; hop oil; tea tree oil; citronella oil; wheat oil; barley oil; lemon grass oil; cedar leaf oil; cedar wood oil; cinnamon oil; fleagrass oil; geranium oil; sandalwood oil; violet oil; cranberry oil; eucalyptus oil; verbena oil; peppermint oil; benzoin gum oil; basil oil; fennel oil; fir oil; balm oil; menthol oil; origanum vulgare (ocmea origanum) oil; oil of Hypestis caragans (hysastasis); berberidaceae (berberidaceae) oil; ratanhiae longa oil; and turmeric oil. Also included in such natural antimicrobial agents are key chemical components of vegetable oils, which have been found to provide antimicrobial benefits. These chemicals include, but are not limited to: anethole; catechol (catechole); camphene; thymol; eugenol; eucalyptol; ferulic acid; farnesol; hinokitiol; tropolone; limonene; menthol; methyl salicylate; carvacol (carvacol); terpineol; verbenone; berberine; ratanhiae extract; caryophyllene oxide (caryophylene); citronellac acid; curcumin; nerolidol; and geraniol.

Specific metal salts that may be used in the present disclosure include, but are not limited to, metal salts in groups 3a-5a, 3b-7b, and 8 of the periodic table. Specific examples of metal salts include, but are not limited to, the following salts: an aluminum salt; a zirconium salt; a zinc salt; a silver salt; gold salt; a copper salt; a lanthanum salt; a tin salt; a mercury salt; a bismuth salt; a selenium salt; a strontium salt; scandium salt; yttrium salt; a cerium salt; praseodymium (praseodymiun) salt; a neodymium salt; promethium (promethum) salt; samarium salt; europium salt; a gadolinium salt; a terbium salt; a salt of dysprosium; a holmium salt; erbium salt; thallium (thallium) salts; a ytterbium salt; a lutetium salt; and mixtures thereof. Examples of metal ion based antimicrobial agents are those under the trade nameSold under the trade and sold by health Shield Technology, Wakefield, Mass. [ other examples are given here such as smith and nephew]And (4) manufacturing.

Specific broad spectrum antimicrobial agents that can be used in the present disclosure include, but are not limited to, the antimicrobial agents described in the other classes of antimicrobial agents herein.

Additional antimicrobial agents that may be used in the methods of the present disclosure include, but are not limited to: pyrithione and particularly under the trade nameSold under the trade including pyridineZinc complexes of pyrithiones; under trade nameDimethyldimethyldimethylol hydantoin sold as follows; under the trade name KathonMethylchloroisothiazolinone/methylisothiazolinone sold under the market; sodium sulfite; sodium bisulfite; under the trade name GermallImidazolidinyl urea sold under the market; under the trade name GermallDiazo alkyl ureas sold under the following; under trade nameBenzyl alcohol v 2-bromo-2-nitropropane-l, 3-diol sold under the name "Wako"; formalin or formaldehyde; under the trade name of polypaseIodoallyl butylcarbamate sold under the following list; chloroacetamide; a methylamine; under trade nameThe methyldibromonitrile glutaronitrile (1, 2-dibromo-2, 4-dicyanobutane) sold under the following conditions; glutaraldehyde; under trade name5-bromo-5-nitro-1, 3-dioxane sold under (b); phenyl ethyl alcohol; under the trade name SuttocideO-phenylphenol/sodium o-phenylphenol sodium hydroxymethylglycine sold under (b); under the trade name NuoseptPolymethoxybicylic oxazolidines sold under the trade name of Polymethoxybicylic oxazolidines; acetyl dimethylol; thimerosal; dichlorobenzyl alcohol; a carputan; chlorphenenesin (chlorphenenesin); a bischlorophenol; chlorobutanol; lauric acid glyceride; halogenated diphenyl ethers; under trade name2,4,4 '-trichloro-2' -hydroxydiphenyl ether sold under the trade name Ciba-Geigy, Florham Park, n.j.; and 2,2 '-dihydroxy-5, 5' -dibromodiphenyl ether.

Additional antimicrobial agents that may be used in the methods of the present disclosure include, but are not limited to, those disclosed by U.S. patent nos. 3,141,321; 4,402,959, respectively; 4,430,381, respectively; 4,533,435, respectively; 4,625,026, respectively; 4,736,467, respectively; 4,855,139, respectively; 5,069,907, respectively; 5,091,102, respectively; 5,639,464, respectively; 5,853,883, respectively; 5,854,147, respectively; 5,894,042, respectively; and 5,919,554 and U.S. patent application publication nos. 20040009227 and 20110081530.

(f) Collagen and agent for promoting collagen synthesis

Collagen is a fibrous protein produced in dermal fibroblasts and constitutes 70% of the dermis. Collagen is responsible for the smoothness and firmness of the skin. Therefore, when collagen synthesis is reduced, skin aging will occur, and thus tightening and smoothness of the skin will be rapidly reduced. Thus, the skin will relax and wrinkle. On the other hand, when collagen metabolism is activated by stimulation of collagen synthesis in the skin, the components of the dermal matrix will increase, resulting in effects such as wrinkle improvement, firmness improvement, and skin strengthening. Thus, collagen and agents that promote collagen synthesis may also be used in the present disclosure. Agents that promote collagen synthesis (i.e., procollagen synthesis agents) include amino acids, peptides, proteins, lipids, small chemical molecules, natural products, and extracts from natural products.

For example, it has been found that the intake of vitamin C, iron and collagen is effective in increasing the amount of collagen in the skin or bone. See, e.g., U.S. patent application publication 20090069217. Examples of the vitamin C include ascorbic acid derivatives 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 of these vitamin C in any ratio. In addition, natural products containing vitamin C such as acerola and 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; and mixtures containing two or more of these irons in any ratio. In addition, natural products containing iron such as spinach or liver may also be used. Further, examples of collagen include: an extract obtained by treating bones, skin, and the like of mammals such as cattle or pigs with an acid or an alkali; peptides obtained by hydrolyzing the extract with a protease such as pepsin, trypsin or chymotrypsin; and mixtures containing two or more of these collagens in any ratio. Collagen extracted from plant sources may also be used.

Additional procollagen synthesis reagents are described, for example, in U.S. patents 7598291, 7722904, 6203805, 5529769, etc., and U.S. patent application publications 0060247313, 20080108681, 20110130459, 20090325885, 20110086060, etc.

The composition may also include other ingredients such as humectants (e.g., glycerin and propylene glycol), preservatives such as parabens, and pH adjusters such as sodium hydroxide.

(4) Application method

The biophotonic compositions of the present disclosure have numerous uses. Without being bound by theory, the biophotonic compositions of the present disclosure may promote wound healing or tissue repair. The biophotonic compositions of the present disclosure may also be used to treat skin disorders. The biophotonic compositions of the present disclosure may also be used to treat acne. The biophotonic compositions of the present disclosure may also be used for skin rejuvenation. The biophotonic compositions of the present disclosure may also be used to treat acute inflammation. It is therefore an object of the present disclosure to provide a method for providing biophotonic therapy to a wound, wherein the method promotes wound healing. It is also an object of the present disclosure to provide a method for providing biophotonic therapy to skin tissue suffering from acne, wherein the method is for treating acne. It is also an object of the present disclosure to provide a method for providing biophotonic therapy to skin tissue having a skin disorder, wherein the method is for treating a skin disorder. It is also an object of the present disclosure to provide a method for providing biophotonic therapy to skin tissue, wherein the method is for promoting skin rejuvenation.

In certain embodiments, the present disclosure provides a method for providing biophotonic therapy to a wound, the method comprising: the biophotonic compositions of the present disclosure are applied (e.g., by topical application) to a wound site, and the biophotonic composition is irradiated with light having a wavelength that overlaps with an absorption spectrum of a chromophore of the biophotonic composition.

In one aspect, the present disclosure provides a method for providing biophotonic therapy to a wound, the method comprising: topically applying a biophotonic composition comprising a first chromophore; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it limits leaching of the chromophore into tissue during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment.

In another aspect, the present disclosure provides a method for treating or providing biophotonic therapy to a wound, the method comprising: topically applying a biophotonic composition comprising a first chromophore and a gelling agent to a wound site; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the gelling agent blocks substantial leaching of the chromophore into the wound site during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment.

In another aspect, the present disclosure provides a method for promoting skin rejuvenation. In certain embodiments, the present disclosure provides a method for providing skin rejuvenation, the method comprising: the biophotonic compositions of the present disclosure are applied (e.g., by topical application) to skin, and the biophotonic composition is illuminated with light having a wavelength that overlaps with an absorption spectrum of a chromophore of the biophotonic composition.

In other embodiments, the present disclosure provides methods for promoting skin rejuvenation, the method comprising: topically applying to the skin a biophotonic composition comprising a first chromophore; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it limits leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment.

In another aspect, the present disclosure provides a method for promoting skin rejuvenation, the method comprising: topically applying to the skin a biophotonic composition comprising a first chromophore and a gelling agent; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it blocks substantial leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the skin during treatment.

In another aspect, the present disclosure provides a method for providing biophotonic therapy to a target skin tissue having a skin disorder. In certain embodiments, the present disclosure provides a method for providing biophotonic therapy to a target skin tissue, the method comprising: the biophotonic compositions of the present disclosure are applied (e.g., by topical application) to a target skin tissue, and the biophotonic composition is illuminated with light having a wavelength that overlaps with an absorption spectrum of a chromophore of the biophotonic composition.

In other embodiments, the present disclosure provides methods for treating a skin disorder, the method comprising: topically applying a biophotonic composition to a target skin tissue having a skin disorder, wherein the biophotonic composition comprises a first chromophore; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it limits leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the skin during treatment.

In another aspect, the present disclosure provides a method for treating a skin disorder, the method comprising: topically applying to skin having a skin disorder a biophotonic composition comprising a first chromophore and a gelling agent; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it blocks substantial leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the skin during treatment.

In another aspect, the present disclosure provides a method for providing biophotonic therapy to a target skin tissue having acne. In certain embodiments, the present disclosure provides methods for providing biophotonic therapy to a target skin tissue having acne, the method comprising: the biophotonic compositions of the present disclosure are applied (e.g., by topical application) to a target skin tissue, and the biophotonic composition is illuminated with light having a wavelength that overlaps with an absorption spectrum of a chromophore of the biophotonic composition.

In other embodiments, the present disclosure provides methods for treating acne, the methods comprising: topically applying a biophotonic composition to a target skin tissue having acne, wherein the biophotonic composition comprises a first chromophore; illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it limits leaching of the chromophore into tissue during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the tissue during treatment.

In another aspect, the present disclosure provides a method for treating acne, the method comprising: topically applying a biophotonic composition comprising a first chromophore to skin having acne; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it blocks substantial leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment.

In other embodiments, the present disclosure provides methods for treating acute inflammation, comprising: topically applying a biophotonic composition to a target skin tissue having an acute inflammation, wherein the biophotonic composition comprises a first chromophore; illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it limits leaching of the chromophore into tissue during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the tissue during treatment.

In another aspect, the present disclosure provides a method for treating acute inflammation, the method comprising: topically applying a biophotonic composition comprising a first chromophore to skin having acute inflammation; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it blocks substantial leaching of the chromophore into the skin during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment.

In another aspect, the present disclosure provides a method for treating a fungal infection, the method comprising: topically applying a biophotonic composition comprising a first chromophore to a target site having acute inflammation; and illuminating the biophotonic composition with light having a wavelength that overlaps with an absorption spectrum of a first chromophore; wherein the biophotonic composition is substantially resistant to leaching such that it blocks substantial leaching of the chromophore into the target site during treatment. In some embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.8%, 0.5%, or 0.1%, or substantially 0% of the total chromophore amount leaches out of the biophotonic composition into the wound or tissue during treatment. In some embodiments, the target site may be skin or a nail.

Biophotonic compositions suitable for use in the methods of the present disclosure may be selected from any of the embodiments of biophotonic compositions described above. For example, biophotonic compositions useful in the methods of the present disclosure may include a first chromophore that undergoes at least partial photobleaching upon the application of light. The first chromophore may absorb at a wavelength of about 200-800nm, 200-700nm, 200-600nm, or 200-500 nm. In one embodiment, the first chromophore absorbs at a wavelength of about 200-600 nm. In some embodiments, the first chromophore absorbs 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. In other examples, suitable biophotonic compositions for use in the methods of the present disclosure may further comprise at least one additional chromophore (e.g., a second chromophore). The absorption spectrum of the second chromophore overlaps at least about 80%, 50%, 40%, 30%, or 20% of the emission spectrum of the first 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%, or 60-70% of the absorption spectrum of the second chromophore.

Irradiation of the biophotonic composition with light may cause energy to be transferred from the first chromophore to the second chromophore. Subsequently, the second chromophore can emit energy as fluorescence and/or generate reactive oxygen species. In certain embodiments of the methods of the present disclosure, the energy transfer induced by the application of light is not accompanied by the concurrent generation of heat, or results in tissue damage.

Biophotonic compositions useful in the present methods include a gelling agent. Gelling agents may include, but are not limited to, lipids such as glycerol, glycols such as propylene glycol, hyaluronic acid, glucosamine sulfate, cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and the like), non-cellulosic polysaccharides (galactomannan, guar gum, carob gum, gum arabic, karaya gum, agar, alginates, and the like), and acrylic acid polymers.

When the method involves a biophotonic composition having at least two chromophores, the first chromophore is present in an amount of about 0.01-40% per weight of the composition and the second chromophore is present in an amount of about 0.001-40% per weight of the composition. In certain embodiments, the first chromophore is present in an amount of about 0.01-1%, 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 composition. In certain embodiments, the second chromophore is present in an amount of about 0.001-1%, 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 composition. In certain embodiments, the total weight/chromophore or combination of chromophores may be present in an amount of about 0.01-1%, 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 35-40.05% by weight per composition.

Any source of actinic light may be used in the methods of the present disclosure. Any type of halogen, LED or plasma arc lamp or laser may be suitable. The main feature of suitable sources of actinic light will be that they emit light at a wavelength (or wavelengths) suitable for activating the photoactivator(s) 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, sunlight may be used. In another embodiment, the LED light curing device is an actinic light source. In another embodiment, the actinic light source is a light source having a wavelength between about 200 and 800 nm. In another embodiment, the source of actinic light is a source of visible light having a wavelength between about 400 and 600 nm. In addition, the actinic light source should have a suitable power density. For non-collimated light sources (LED, halogen)Elemental or plasma lamps) at a power density of about 1mW/cm²To about 200mW/cm²Within the range of (1). Suitable power densities for the laser source are about 0.5mW/cm²To about 0.8mW/cm²Within the range of (1).

In some embodiments of the methods of the present disclosure, the light has about 1mW/cm at the skin, wound, or mucosal surface of the subject²To about 500mW/cm²、1-300mW/cm²Or 1-200mW/cm²Wherein the energy applied is dependent on at least the condition to be treated, the wavelength of the light, the distance of the subject's skin from the light source, and the thickness of the biophotonic composition. 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 120-160mW/cm²Or 140 ion power of 180mW/cm²Or 160 ion power of 200mW/cm²Or 110-240mW/cm²Or 110-150mW/cm²Or 190 ion power 240mW/cm²。

In some embodiments, a mobile device is used to activate an embodiment of a biophotonic composition of the present disclosure, wherein the mobile device can emit light having an emission spectrum that overlaps with an absorption spectrum of a chromophore in the biophotonic composition. The mobile device may have a display through which light is emitted, and/or the mobile device may emit light from a flash lamp that can photoactivate the biophotonic composition.

In some embodiments, a display screen on a television or computer monitor can be used to activate the biophotonic composition, wherein the display screen can emit light having an emission spectrum that overlaps with an absorption spectrum of the photoactivating agent in the photoactivatable composition.

In certain embodiments, the first chromophore and/or the second chromophore (when present) may be photoactivated by ambient light, which may originate from the sun or other light source. Ambient light can be considered general lighting from all directions in a room, which has no visible light source. In certain embodiments, the first chromophore and/or the second chromophore (when present) may be photoactivated by light in the visible range of the electromagnetic spectrum. The exposure time to ambient light may be longer than the exposure time to direct light.

In certain embodiments, different light sources may be used to activate the biophotonic composition, such as a combination of ambient light and direct LED light.

The duration of exposure to actinic light required depends on the surface of the treatment area, the type of lesion, wound or lesion to be treated, the power density, the wavelength and bandwidth of the light source, the thickness of the biophotonic composition and the treatment distance from the light source. Irradiation of the treatment area by fluorescence can occur in fractions of seconds or even seconds, but an extended period of exposure is beneficial to take advantage of the synergistic effect of absorbed, reflected and re-emitted light on the composition of the present disclosure and its interaction with the tissue to be treated. In one embodiment, the tissue, skin or wound to which the biophotonic composition has been applied is exposed to actinic light for a period of from 1 minute to 5 minutes. In another embodiment, the tissue, skin, or wound to which the biophotonic composition has been applied is exposed to actinic light for a period of 1 minute to 5 minutes. In some other embodiments, the biophotonic composition is irradiated for a period of 1 minute to 3 minutes. In certain embodiments, the light is applied for a period of 1 to 30 seconds, 15 to 45 seconds, 30 to 60 seconds, 0.75 to 1.5 minutes, 1 to 2 minutes, 1.5 to 2.5 minutes, 2 to 3 minutes, 2.5 to 3.5 minutes, 3 to 4 minutes, 3.5 to 4.5 minutes, 4 to 5 minutes, 5 to 10 minutes, 10 to 15 minutes, 15 to 20 minutes, 20 to 25 minutes, or 20 to 30 minutes. In another embodiment, the source of actinic light is in continuous motion over the treatment area for a suitable exposure time. In another embodiment, multiple applications of the biophotonic composition and actinic light are performed. In some embodiments, the tissue, skin, or wound is exposed to actinic light at least two, three, four, five, or six times. In some embodiments, fresh application of the biophotonic composition is applied prior to exposure to actinic light.

In the methods of the present disclosure, the biophotonic composition may optionally be removed from the treatment site after the application of light. In certain embodiments, the biophotonic composition is allowed to rest on the treatment site for more than 30 minutes, more than one hour, more than 2 hours, more than 3 hours. It may be illuminated with ambient light. To prevent drying, the composition may be covered with a transparent or translucent cover, such as a polymer film or an opaque cover, which may be removed prior to irradiation.

(5) Wound and wound healing

The biophotonic compositions and methods of the present disclosure are useful for treating wounds and promoting wound healing. Wounds that can be treated by the biophotonic compositions and methods of the present disclosure include, for example, injuries to the skin and subcutaneous tissue that originate in different ways (e.g., pressure ulcers from prolonged bed rest, wounds induced by trauma, wounds induced by conditions such as periodontitis) and have various characteristics. In certain embodiments, the present disclosure provides biophotonic compositions and methods for treating and/or promoting healing of: such as burns, incisions, resections, lacerations, abrasions, puncture or penetrating wounds, surgical wounds, contusions, hematomas, crush injuries, sores and ulcers.

The biophotonic compositions and methods of the present disclosure are useful for treating and/or promoting healing of chronic skin ulcers or wounds that fail to progress through an ordered and timely series of events to create a durable structural, functional, and cosmetic closure of the wound. A wide variety of chronic wounds can be classified into three categories based on their etiology: pressure ulcers, neuropathic (diabetic foot) ulcers and vascular (venous or arterial) ulcers.

In certain other embodiments, the present disclosure provides biophotonic compositions and methods for treating and/or promoting healing of a class I-IV ulcer. In certain embodiments, the present application provides compositions suitable for use particularly with stage II ulcers. Ulcers can be classified according to wound depth into one of four classes: i) stage I: the wound is confined to the epithelium; II) stage II: the wound extends into the dermis; III) grade III: the wound extends into the subcutaneous tissue; and IV) grade IV (or full thickness wound): in which wounds to the bone (e.g., bone pressure points such as the greater trochanter or sacrum) are exposed.

For example, the present disclosure provides biophotonic compositions and methods for treating and/or promoting healing of diabetic ulcers. Diabetic patients are prone to foot and other ulcers due to both nervous system and vascular complications. Peripheral neuropathy can cause altered sensation or complete loss of sensation in the foot and/or leg. Diabetic patients with advanced neuropathy lose all ability to differentiate between sharpness and non-sharpness. Any incision or trauma to the foot may be performed entirely unnoticed for days or weeks in patients with neuropathy. Patients with advanced neuropathy lose the ability to perceive sustained pressure trauma and tissue ischemia and necrosis can occur, leading to the formation of, for example, plantar ulcers. Microvascular disease is one of the significant complications of diabetes that can also lead to ulcer formation. In certain embodiments, provided herein are compositions and methods for treating a chronic wound, wherein the chronic wound is characterized by diabetic foot ulcers and/or ulcer formation due to diabetic neurological and/or vascular complications.

In other examples, the present disclosure provides biophotonic compositions and methods for treating and/or promoting healing of pressure ulcers. Pressure ulcers include pressure sores, decubitus ulcers and ischial tuberosity ulcers, and can cause considerable pain and discomfort to the patient. Pressure ulcers can occur as a result of prolonged pressure applied to the skin. Thus, pressure may be exerted on the patient's skin due to the weight or mass of the individual. Pressure ulcers can develop when the blood supply to an area of skin is blocked or cut off for more than two or three hours. The affected skin area may turn red, become painful and may become necrotic. If untreated, the skin tears and can become infected. Ulcer sores are thus skin ulcers that occur in skin areas that are under pressure from, for example, lying in bed, sitting in a wheelchair, and/or wearing a cast (cast) for extended periods of time. Pressure ulcers can occur when an individual is bedridden, unconscious, unable to sense pain, or unable to move. Pressure ulcers typically occur in bony processes of the body, such as the hip region (on the sacrum or iliac crest), or on the heel.

In other examples, the present disclosure provides biophotonic compositions and methods for treating and/or promoting acute wound healing.

Additional types of wounds that may be treated by the biophotonic compositions and methods of the present disclosure include wounds disclosed by U.S. patent application publication No. 20090220450, which is incorporated herein by reference.

Wound healing in adult tissue is a complex repair process. For example, the healing process of the skin involves the recruitment of a variety of specialized cells to the wound site, extracellular matrix and basement membrane deposition, angiogenesis, selective protease activity and re-epithelialization.

There are three distinct phases in the wound healing process. First, during the inflammatory phase, which typically occurs from the time of wound onset until the first two to five days, platelets aggregate to deposit particulates, promote fibrin deposition and stimulate growth factor release. Leukocytes migrate to the wound site and begin to digest and transport debris away from the wound. During this inflammatory phase, monocytes are also converted to macrophages, which release growth factors for stimulating angiogenesis and producing fibroblasts.

Second, during the proliferative phase, which typically occurs from two to three weeks, granulation tissue forms and epithelialization and contraction begins. Fibroblasts are a key cell type in this phase, proliferating and synthesizing collagen to fill the wound and provide a firm matrix on which epithelial cells grow. As fibroblasts produce collagen, vascularization extends from nearby blood vessels, resulting in granulation tissue. Granulation tissue typically grows from the bottom of the wound. Epithelialization involves the migration of epithelial cells from the wound surface to seal the wound. Epithelial cells are driven by this need to contact similar types of cells and are guided by a network of fibrin chains that act as a lattice over which these cells migrate. Contractile cells, called myofibroblasts, appear in the wound and help the wound to close. These cells exhibit collagen synthesis and contractility and are common in granulation wounds.

Third, in the remodeling stage (the final stage of wound healing) which can occur from three weeks up to years, the collagen in the scar undergoes repeated degradation and resynthesis. During this phase, the tensile strength of the newly formed skin increases.

However, as the rate of wound healing increases, there is often a related increase in scarring. Scarring is a result of the healing process in most adult animal and human tissues. Scar tissue is different from the tissue it replaces because it generally has lower functional properties. Types of scars include, but are not limited to: atrophic scars, hypertrophic and keloid scars, and keloid contractures. Atrophic scars are flat and concave under the surrounding skin, such as valleys or holes. Hypertrophic scars are raised scars that remain within the boundaries of the original lesion and often contain excess collagen arranged in an abnormal pattern. Keloid scars are raised scars that are distributed outside the boundaries of the original wound and invade the surrounding normal skin in a site-specific manner and usually contain a spiral ring of collagen arranged in an abnormal pattern.

In contrast, normal skin consists of collagen fibers arranged in a basket-like form that contributes to the strength and elasticity of the dermis. Thus, to achieve a smoother wound healing process, methods are needed that not only stimulate collagen production, but also achieve this in a manner that reduces scarring.

The biophotonic compositions and methods of the present disclosure promote wound healing by: promoting substantially uniform epithelialization; promoting collagen synthesis; facilitating controlled shrinkage; and/or reduce the formation of scar tissue. 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 biophotonic compositions and methods of the present disclosure promote collagen synthesis. In some other embodiments, the biophotonic compositions and methods of the present disclosure facilitate controlling contraction. In certain embodiments, the biophotonic compositions and methods of the present disclosure promote wound healing, for example, by reducing the formation of scar tissue or by accelerating the wound closure process. In certain embodiments, the biophotonic compositions and methods of the present disclosure promote wound healing, for example, by reducing inflammation. In certain embodiments, the biophotonic composition may be used after wound closure to optimize scar repair. In this case, the biophotonic composition may be applied at regular intervals, for example once per week or at intervals deemed appropriate by a physician.

The biophotonic composition may be soaked in a woven or nonwoven material or sponge and applied as a wound dressing. A light source, such as an LED or waveguide, may be provided within or adjacent the wound dressing or composition to illuminate the composition. The waveguide may be an optical fiber that can transmit light not only from its end but also from its body. For example, made of polycarbonate or polymethyl methacrylate.

Adjunctive therapies, which may be local or systemic, such as antibiotic therapy, may also be used. Negative pressure assisted wound closure may also be used to assist in wound closure and/or removal of compositions.

(6) Acne and acne scar

The biophotonic compositions and methods of the present disclosure may be used to treat acne. As used herein, "acne" means a skin disorder caused by inflammation of the skin glands or hair follicles. The biophotonic compositions and methods of the present disclosure may be used to treat acne at an early pre-emergent stage or at a late stage where lesions from acne are visible. Mild, moderate, and severe acne can be treated with embodiments of the biophotonic compositions and methods. The early pre-acne stage usually begins with excessive secretion of sebum or dermal oil from the sebaceous glands located in the pilosebaceous apparatus. Sebum passes through the follicular canal to the skin surface. The presence of excess sebum in the canal and on the skin tends to block or stagnate normal flow of sebum from the small sac ducts, thus producing thickening and solidification of sebum to produce a solid plug known as acne. In the normal sequence of acne development, hyperkeratosis of the opening of the small sac is stimulated, thus completing the blockage of the tube. The common result is a papule, pustule or cyst that is often contaminated with bacteria that cause secondary infections. Acne is characterized in particular by the presence of comedones, inflammatory papules or cysts. Acne occurs in a range from mild skin irritation to sagging and even developing disfiguring scars. Accordingly, the biophotonic compositions and methods of the present disclosure may be used to treat one or more of skin irritation, depressions, scar development, acne, inflammatory papules, cysts, hyperkeratosis, and sebum thickening and hardening associated with acne.

The composition may be soaked in or applied to a woven or nonwoven fabric or sponge and applied as a mask to a body part such as the face, torso, arms, legs, etc. A light source, such as an LED or waveguide, can be provided within or adjacent the mask or composition to illuminate the composition. The waveguide may be an optical fiber that can transmit light not only from its end but also from its body. For example, made of polycarbonate or polymethyl methacrylate.

The biophotonic compositions and methods of the present disclosure may be used to treat various types of acne. Some types of acne include, for example, acne vulgaris, cystic acne, atrophic acne, bromoacne, chloroacne, acne conglobata, acne cosmetology, acne decontaminata, acne epidermis, acne summer, fulminant acne, haloacne, acne scleroma, iodoacne, keloid acne, mechanical acne, papulo acne, pomade acne, premenstrual acne, pustular acne, scurvy acne, tuberculous acne, urticaria acne, acne vulgaris, toxic acne, acne propionate, acne artificially, gram-negative acne, steroid acne, and cystic acne.

(7) Skin aging and skin rejuvenation

The dermis is the second layer of the skin and contains the structural elements of the skin, connective tissue. There are various types of connective tissue with different functions. Elastin fibres give the skin its elasticity, and collagen gives the skin its strength.

The junction between the dermis and epidermis is an 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 in the dermis. The epidermal ridges increase the surface area of the epidermis exposed to these blood vessels and nutrients required.

Skin aging is accompanied by significant physiological changes to the skin. The production of new skin cells slows down and the epidermal ridge at the dermal-epidermal junction flattens. While the number of elastin fibers increases, their structure and consistency decreases. In addition, collagen amount and dermal thickness decrease with skin aging.

Collagen is a major component of the extracellular matrix of the skin, providing a structural network. During the aging process, the reduction of collagen synthesis and insolubility of collagen fibers contributes to thinning of the dermis and loss of the biomechanical properties of the skin.

Physiological changes to the skin result in significant symptoms of aging commonly referred to as age-related aging, intrinsic aging, and photoaging. The skin becomes drier, the roughness and desquamation increases, the appearance becomes dull, and the appearance of fine lines and wrinkles is most pronounced. Other symptoms or signs of skin aging include, but are not limited to: thin and transparent skin, loss of subcutaneous fat (resulting in depressed cheeks and eye sockets and significant loss of tightness on hands and neck), bone loss (causing bones to atrophy away from the skin due to bone loss, which causes sagging skin), dry skin (which may be itchy), inability to sweat sufficiently to cool the skin, unwanted facial hair, freckles, age spots, spider veins, coarse and hard skin, fine lines that disappear when stretched, sagging skin, mottled skin.

The dermal-epidermal junction is the basement membrane that separates keratinocytes in the epidermis from the extracellular matrix located beneath the dermis. The film consists of two layers: a substrate in contact with keratinocytes, and an underlying mesh panel in contact with extracellular matrix. The substrate is rich in type IV collagen and laminin, molecules that play a role in providing a structural network and bioadhesive properties for cell attachment.

Laminins are glycoproteins that are only present in basement membranes. It consists of three polypeptide chains (α, β and γ) arranged in an asymmetric cruciform shape and bonded together by disulfide bonds. The three chains exist as distinct isoforms that result in twelve different laminin isoforms, including laminin-1 and laminin-5.

The dermis is anchored by collagen type VII fibers to hemidesmosomes at the keratinocytes of the basement membrane, which are specific connection points on the keratinocytes, consisting of alpha integrins and other proteins. Laminins and in particular laminin-5 constitute the true anchor point between hemidesmoplastic transmembrane proteins and collagen VII in basal keratinocytes.

Laminin-5 synthesis and collagen VII expression have been shown to be reduced in aging skin. This causes the contact between the dermis and epidermis to be lost and the skin to lose elasticity and become sagging.

Recently, another category of wrinkles, commonly referred to as expression lines, has been generally recognized. These wrinkles require a loss of resilience, particularly in the dermis, which, when the facial muscles that produce the facial expression exert stress on the skin, can no longer restore its original state, resulting in expression lines.

The compositions and methods of the present disclosure promote skin rejuvenation. In certain embodiments, the compositions and methods of the present disclosure promote collagen synthesis. In certain other embodiments, the compositions and methods of the present disclosure may reduce, diminish, delay, or reverse one or more signs of skin aging, including, but not limited to, the appearance of fine lines or wrinkles, thin and transparent skin, loss of subcutaneous fat (resulting in depressed cheeks and eye sockets and significant loss of firmness on the hands and neck), bone loss (causing bone to atrophy away from the skin due to bone loss, which causes sagging of the skin), dry skin (which may be itchy), inability to sweat sufficiently to cool the skin, unwanted facial hair, freckles, age spots, spider veins, thick and hard skin, fine lines that disappear upon stretching, sagging of the skin, or mottled skin tone. In certain embodiments, the compositions and methods of the present disclosure may induce a reduction in pore size, enhance sculpting of skin details, and/or enhance skin translucency.

(8) Skin disorder

The biophotonic compositions and methods of the present disclosure may be used to treat skin disorders including, but not limited to, erythema, telangiectasia, actinic telangiectasia, psoriasis, skin cancer, pemphigus, sunburn, dermatitis, eczema, rash, impetigo, chronic lichen simplex, hypertrophic rosacea, perioral dermatitis, pseudofolliculitis barbae palpebrae, drug eruptions, erythema multiforme, erythema nodosum, granuloma annulare, actinic keratosis, purpura, alopecia areata, aphthous stomatitis, drug eruptions, dry skin, chapping, xerosis, ichthyosis vulgaris, fungal infections, parasitic infections, herpes simplex, mesotheliosis, keloids, keratosis, miliaria, molluscum contagiosum, pityriasis rosea, pruritus, urticaria, and angioma and vascular malformations. The dermatitis includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, and stasis dermatitis. Skin cancers include melanoma, basal cell carcinoma and squamous cell carcinoma.

Some skin disorders exhibit a variety of symptoms, including redness, flushing, burning, desquamation, pimples, papules, pustules, acne, spots, nodules, vesicles, blisters, telangiectasia, spider veins, sores, surface irritation or pain, itching, inflammation, red, purple or blue spots or discoloration, moles and/or tumors. Accordingly, the biophotonic compositions and methods of the present disclosure may be used to treat redness, flushing, burning, desquamation, pimples, pustules, acne, spots, nodules, vesicles, blisters, telangiectasias, spider veins, sores, surface irritation or pain, itching, acute inflammation, red, purple or blue spots or discoloration, moles, and/or tumors. Acute inflammation may manifest itself as pain, heat, redness, swelling, and loss of function. It includes those visible in allergic reactions, such as: insect bite (mosquito, bee, wasp, ant, spider, etc.), reaction to poison ivy or stinging nettle, etc., and post-ablation treatment.

The composition can be soaked in or applied to a woven or nonwoven fabric or sponge, and applied to a body part as a mask to treat skin disorders. A light source, such as an LED or waveguide, can be provided within or adjacent the mask or composition to illuminate the composition. The waveguide may be an optical fiber that can transmit light not only from its end but also from its body. For example, the waveguide may be made of polycarbonate or polymethylmethacrylate.

(9) Reagent kit

The present disclosure also provides kits for preparing and/or applying any of the compositions of the present disclosure. The kit may comprise a biophotonic topical composition as defined above, together with one or more of the following: a light source, a device for applying or removing a composition, and/or instructions for use of the light source. In some embodiments, the composition comprises at least a first chromophore in the gelling agent. The chromophore can be present in an amount of about 0.001-0.1%, 0.05-1%, 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 composition. In embodiments where the composition comprises more than one chromophore, the first chromophore may be present in an amount of about 0.01 to 40% per weight of the composition and the second chromophore may be present in an amount of about 0.0001 to 40% per weight of the composition. In certain embodiments, the first chromophore is present in an amount of about 0.01-0.1%, 0.05-1%, 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 composition. In certain embodiments, the second chromophore is present in an amount of about 0.001-0.1%, 0.05-1%, 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 composition. In certain embodiments, the amount of chromophore or combination of chromophores can be in the range of about 0.05 to 40.05% per weight of the composition. In certain embodiments, the amount of chromophore or combination of chromophores may be about 0.001-0.1%, 0.05-1%, 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 35-40.05% per weight of the composition. The composition may include an oxygen-releasing agent present in an amount of about 0.01% -40%, 0.01% -1.0%, 0.5% -10.0%, 5% -15%, 10% -20%, 15% -25%, 20% -30%, 15.0% -25%, 20% -30%, 25% -35%, or 30% -40% by weight of the composition. Alternatively, the kit may include the oxygen-releasing agent as a separate component of the composition containing the chromophore.

In some embodiments, the kit includes more than one composition, e.g., a first composition and a second composition. The first composition may include an oxygen-releasing agent, and the second composition may include a first chromophore in a gelling agent. The first chromophore can have an emission wavelength of about 400nm to about 570 nm. The oxygen releasing agent may be present in the first composition in an amount of about 0.01% -1.0%, 0.5% -10.0%, 5% -15%, 10% -20%, 15% -25%, 20% -30%, 15.0% -25%, 20% -30%, 25% -35%, 30% -40%, or 35% -45% by weight of the first composition. The chromophore may be present in the second composition in an amount of about 0.001-0.1%, 0.05-1%, 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 second composition. In embodiments where the second composition comprises more than one chromophore, the first chromophore may be present in an amount of about 0.01 to 40% per weight of the second composition, and the second chromophore may be present in an amount of about 0.0001 to 40% per weight of the second composition. In certain embodiments, the first chromophore is present in an amount of about 0.001-0.1%, 0.05-1%, 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 second composition. In certain embodiments, the second chromophore is present in an amount of about 0.001-0.1%, 0.05-1%, 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 second composition. In certain embodiments, the amount of chromophore or combination of chromophores may be in the range of about 0.05 to 40.05% per weight of the second composition. In certain embodiments, the amount of chromophore or combination of chromophores may be about 0.001-0.1%, 0.05-1%, 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 35-40.05% per weight of the second composition.

In some other embodiments, the first composition may comprise the first chromophore in a liquid or as a powder, and the second composition may comprise a gelling composition for thickening the first composition. The oxygen releasing agent may be included in the second composition or the third composition in the kit. In some embodiments, the kit comprises a container comprising a composition of the present disclosure. In some embodiments, the kit comprises a first container comprising a first composition comprising an oxygen-releasing agent and a second container comprising a second composition comprising at least one chromophore. The container may be light-tight, air-tight and/or leak resistant. Exemplary containers include, but are not limited to, syringes, vials, or bags. The first and second compositions may be included in the same container, but separated from each other until the user mixes the compositions. For example, the container may be a dual chamber syringe, wherein the contents of the chambers mix as the composition is expelled from the chambers. In another example, the bag may include two chambers separated by a frangible membrane. In another example, one component may be contained in a syringe and may be injected into a container containing a second component.

The biophotonic composition may also be provided in a container comprising one or more chambers for containing one or more components of the biophotonic composition, and an outlet in communication with the one or more chambers for expelling the biophotonic composition from the container. In one embodiment, expelling the biophotonic composition causes components of the composition to mix to form the biophotonic composition having less than 15% leaching characteristics.

In other embodiments, the kit includes a systemic or topical medicament for enhancing treatment of the composition. For example, the kit may include systemic or local antibiotic or hormone therapy for acne treatment or wound healing.

Written instructions on how to use the biophotonic compositions in accordance with the present disclosure may be included in the kit, or may be included on or associated with a container that contains the composition of the present disclosure.

In certain embodiments, the kit may comprise a further component which is a dressing. The dressing may be a porous or semi-porous structure for receiving the biophotonic composition. The dressing may comprise a woven or non-woven fibrous material.

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

In certain embodiments, the kit may further comprise one or more waveguides.

The identification of equivalent compositions, methods and kits are well within the skill of the ordinary practitioner and will require no more than routine experimentation in light of the teachings of the present disclosure. The practice of the present disclosure will be more fully understood from the following examples, which are presented herein for purposes of illustration only, and are not to be construed as limiting the present disclosure in any way.

Examples

The following examples are presented in order to illustrate the practice of various embodiments of the present disclosure. They are not intended to limit or define the overall scope of the disclosure.

Example 1

The following photodynamic properties were evaluated in gels (containing approximately 12% carbamide peroxide) according to embodiments of the present disclosure: (i) a sodium fluorescein salt at about 0.09mg/mL, (ii) eosin Y at about 0.305mg/mL, and (iii) a mixture of sodium fluorescein salt at about 0.09mg/mL and eosin Y at about 0.305 mg/mL. A flexstation 384II spectrometer with the following parameters was used: fluorescence mode, excitation 460nm, emission spectrum 465 and 750 nm. The absorption and emission spectra are shown in fig. 6a and 6b, which fig. 6a and 6b indicate the energy transfer between the chromophores in the combination.

Example 2

The following photodynamic properties were evaluated in aqueous solution: (i) a sodium fluorescein salt at a final concentration of 0.18mg/mL, (ii) eosin Y at about 0.305mg/mL, and (iii) a mixture of sodium fluorescein salt at about 0.18mg/mL and eosin Y at about 0.305 mg/mL. A flexstation 384II spectrometer with the following parameters was used: fluorescence mode, excitation 460nm, emission spectrum 465 and 750 nm. The absorption and emission spectra are shown in fig. 7a and 7b, which fig. 7a and 7b indicate the energy transfer between the chromophores in the combination.

Example 3

The following photodynamic properties were evaluated in a gel (group a) comprising about 12% carbamide peroxide according to an embodiment of the invention: (i) rose bengal at about 0.085mg/mL, (ii) fluorescein sodium salt at a final concentration of about 0.44mg/mL, (iii) eosin Y at about 0.305mg/mL, and (iv) a mixture of (i), (ii) and (iii). A flexstation 384II spectrometer with the following parameters was used: fluorescence mode, excitation 460nm, emission spectrum 465 and 750 nm. The absorbance and emission spectra are shown in fig. 8a and 8b, which fig. 8a and 8b indicate the energy transfer between the chromophores in the chromophore combination.

Example 4

The following photodynamic properties were evaluated in aqueous solutions (group a): (i) rose bengal at about 0.085mg/mL, (ii) fluorescein sodium salt at a final concentration of about 0.44mg/mL, (iii) eosin Y at about 0.305mg/mL, and (iv) a mixture of (i), (ii) and (iii). A flexstation 384II spectrometer with the following parameters was used: fluorescence mode, excitation 460nm, emission spectrum 465 and 750 nm. The absorbance and emission spectra are shown in fig. 9a and 9b, which fig. 9a and 9b indicate the energy transfer between the chromophores in the chromophore combination in the absence of the oxygen-releasing agent.

Energy transfer is also seen between: eosin Y and rose bengal in other combinations; phloxine B and eosin Y; phloxine B, eosin Y and fluorescein. It is reasonable to conclude that energy transfer can also occur in the biophotonic compositions of the present disclosure.

Example 5

A 12 week randomized, split-face clinical trial was performed in 90 patients with moderate to severe facial acne (age 14-30 years). Moderate facial acne is defined as having "investigator general evaluation (IGA)3 with 20-40 foci of inflammation and no more than 1 nodule". Severe facial acne is defined as having "IGA 4 with the presence of more than 40 inflammatory lesions along with more than 2 nodules and/or severe erythema and inflammatory cicatrization lesions". For each patient, one randomly selected facial side was treated twice a week for six weeks with a spreadable and translucent biophotonic composition comprising a fluorophore (eosin Y) in a carbomer polymer-based gel comprising urea peroxide. The biophotonic gel demonstrated less than 15% chromophore leaching when tested according to example 6 for up to 30 minutes. The treatment included topical application of the biophotonic composition to the treatment area and exposure of the composition to light from an LED light source (peak wavelength range 400-. The other half of the face remained untreated for a period of 6 weeks. Both treated and untreated facings were evaluated after 12 weeks. The results are presented in tables 1-5 below. The fluorescence spectra observed when the biophotonic gel was irradiated during treatment are shown in fig. 10. The treatment was completely tolerated by the patient and no serious adverse events were present. 80% of the patients completed the study and no adverse events were reported. At week 4, there was a 30% reduction in inflammatory foci (including papules, pustules, and nodules) for the treated group compared to the untreated 9.0% reduction. At week 6, the reduction was 46.8% for treatment and 18.4% for untreated, and at week 12, the reduction was 59.2% for treatment and 35.6% for untreated.

TABLE 1 Total reduction from baseline at 2,4, 6, 8, 10 and 12 weeks in ≧ 2IGA class for treated and untreated half-faces.

*P<0.0001

TABLE 2 Total reduction from baseline at weeks 2,4, 6, 8, 10 and 12 in ≧ 1IGA rating for treated and untreated half-faces.

P value < 0.0001; + P value <0.0001

Table 3 total reduction from baseline to IGA 0 or grade 1 at weeks 2,4, 6, 8, 10 and 12 for treated and untreated half-faces.

+ P value 0.0213; p value <0.0001

Table 4 shows the proportion of patients who decreased from baseline by at least 40% in inflammatory lesion counts (including papules, pustules, and nodules) at weeks 6 and 12 for treated and untreated half-faces.

+ P value < 0.0001. P value <0.0001

TABLE 5 summary of inflammatory lesion counts and absolute changes by half-face

Including papules, pustules and

node (B)

FIG. 10 is an emission spectrum showing the intensity of light emitted by a biophotonic composition over time.

Example 6 Leaching test Using polycarbonate film

Fig. 5 depicts an experimental setup of an in vitro release test used to assess leaching of chromophores or other components (e.g., oxygen-releasing agents) from the biophotonic compositions of the present disclosure. In this in vitro test, a 2mm thick layer of biophotonic composition was applied on top of a circular Polycarbonate (PC) membrane of 2.4-3cm diameter, 10 microns thickness and 3 microns pore size. The bottom side of the membrane was brought into direct contact with Phosphate Buffered Saline (PBS) contained in the closed chamber (i.e. the receiving chamber). Samples (100 μ lx2) were then removed from the receiving chamber at various time points (e.g., at 5, 10, 20, and 30 minutes) and the concentration of the chromophore or any other component of the biophotonic composition was assessed using spectrophotometry or any other suitable method.

For example, when the chromophore to be tested is eosin, a wavelength (absorbance) of about 517nm may be used. The concentration of the chromophore can then be calculated based on known concentrations of chromophore standards prepared and measured simultaneously in PBS. The presence of Peroxide (i.e., an oxygen-releasing agent indicator) can also be assessed using a Peroxide test stick (e.g., Quantofix Peroxide 25, Sigma Aldrich).

Table 6 summarizes the leaching data for different biophotonic compositions according to the present disclosure. All compositions were spreadable, translucent gels having viscosities of about 10,000-80,000 cP. The amount of hydrogen peroxide found in the receiving chamber was very low for all the compositions in table 6 containing peroxide. Chromophore concentration from 0.2 μ g/ml can be measured by spectrophotometric chromophore detection methods. For all of the biophotonic compositions tested, the release of the chromophore increased over time. For all compositions, there was less than 15% leaching of the chromophore after 5 minutes, 10 minutes, 15 minutes, and 25 minutes of incubation. With the exception of eosin Y (0.2%) in the carbopol polymer gel including urea peroxide, all tested compositions had less than 15% chromophore leaching even after 30 minutes incubation, which was longer than the treatment time according to many embodiments of the present disclosure.

The effect of irradiation on chromophore leaching from biophotonic compositions was also investigated. It was found that irradiating the biophotonic composition with light at a distance of 5cm for 5 minutes induced photobleaching of the chromophore. In fact, the chromophore photobleaches in about 2-3 minutes. In these cases, the chromophore is not detectable in the receiving chamber. Thus, during treatment involving light irradiation, even lower chromophore leaching than the results presented in table 9 can be reasonably expected.

Table 6: percentage of chromophores released from the biophotonic compositions according to embodiments of the present disclosure over incubation time.

Example 7-angiogenic potential of biophotonic compositions of the present disclosure

A human skin model was developed to evaluate the angiogenic potential of the biophotonic compositions of the present disclosure. Briefly, a biophotonic composition comprising fluorophores (eosin Y and erythrosine) in a carbomer polymer-based gel comprising urea peroxide was placed on a human skin model containing fibroblasts and keratinocytes. When tested separately according to example 6, the spreadable and translucent biophotonic composition has less than 15% chromophore leaching for up to 30 minutes. Skin model and composition passing through a 20 micron pore sizeThe nylon mesh is separated. The composition was then irradiated with blue light ('activating light') for 5 minutes at a distance of 5cm from the light source. The activating light consisted of light emitted from the LED lamp having an average peak wavelength of about 400-470nm and 7.7J/cm measured at 10cm²To 11.5J/cm²The power intensity of (c). Upon irradiation with activating light, the biophotonic composition fluoresces (fig. 4). Because of the limited contact of the biophotonic composition with the cells, fibroblasts and keratinocytes are primarily exposed to the activating light and the fluorescence emitted by the biophotonic composition. Conditioned media from the treated human 3D skin model was then applied to human aortic endothelial cells previously plated in matrigel. Tube formation by endothelial cells was observed and monitored by microscopy after 24 hours. Conditioned media from 3D skin models treated with light irradiation induced endothelial formation in vitro, suggesting that light treatment (blue light and fluorescence) produced an indirect effect on angiogenesis via factors passing through fibroblasts and keratinocytes. Simple medium and conditioned medium from untreated skin samples were used as controls and did not induce endothelial formation.

FIG. 11 is an emission spectrum showing the intensity of light emitted by a biophotonic composition over time.

Example 8 protein secretion and Gene expression profiling

Injured and uninjured 3D human skin models (EpiDermFT, MatTek Corporation) were used to evaluate the potential of biophotonic compositions of the present disclosure to trigger different protein secretion and gene expression profiles. Briefly, a biophotonic composition comprising eosin and erythrosine in a carbomer polymer-based gel comprising urea peroxide was placed on injured and uninjured 3D human skin models cultured under different conditions (with growth factor, 50% growth factor, and no growth factor). According to example 6, the spreadable and translucent biophotonic gel has less than 15% leaching of the chromophore during a 30 minute test time. Skin model and composition passing through a 20 micron pore sizeThe dragon net is separated. Each skin model composition was then combined and irradiated with blue light ('activating light') for 5 minutes at a distance of 5cm from the light source. The activating light consists of light emitted from the LED lamp having an average peak wavelength of about 440-470nm, 60-150mW/cm at 5cm²And about 18-39J/cm after 5 minutes²The total intensity of (c). The control consisted of a 3D skin model that was not illuminated with light.

Gene expression and protein secretion profiles were measured 24 hours after light exposure. Cytokine secretion was analyzed by antibody array (RayBio human cytokine antibody array), gene expression was analyzed by PCR array (PAHS-013A, SABioscience), and cytotoxicity was determined by GAPDH and LDH release. The results (tables 7 and 8) show that light treatment can increase secreted proteins and involved gene expression levels in the early inflammatory stages of wound healing in wounded skin inserts and non-starving conditions. Under starvation conditions mimicking chronic wounds, there was no increase in secreted inflammatory protein levels when compared to controls. Interestingly, the effect of light treatment on the intact skin model had a much lower impact at the cellular level than the injured skin insert, suggesting an effect of light treatment at the cellular effector level. It appears to accelerate the inflammatory phase of the wound healing process. Due to the absence of other cell types such as macrophages in the 3D skin model, anti-inflammatory feedback is not present and may account for delays in wound closure. No cytotoxicity was observed in the light treatment.

Table 7-list of proteins with statistically significant differences in secretion ratios between treated and untreated controls at day 3. Double arrows mean ratios exceeding 2 times.

Table 8-list of genes with statistically significant differences in expression ratios between treated and untreated controls during the first 24 hours. Double arrows mean ratios exceeding 2 times.

Example 9 collagen formation in skin

Randomized, placebo-controlled, single-blind, split-face and one-armed studies of 32 patients divided into 4 groups (A, B, C and D) evaluated the safety and efficacy of treatment once a week for 4 weeks: (A) "Individual light" -light according to embodiments of the present disclosure for 5 minutes, the light comprising light from an LED source at less than 150mW/cm²Has an average peak wavelength of about 400-490 nm; and a placebo formulation; (B) "light + gel" -light as in (a) plus biophotonic gel according to embodiments of the present disclosure; (C) "separate gels" -biophotonic gels as in (B) and false lights (white LED lights); and (D) a cream based on 0.1% tretinoin. The biophotonic gel includes a fluorophore in a carbopol gel and urea peroxide, the gel having a viscosity of about 10,000cP to 50,000cP and demonstrating less than 15% leaching when tested according to example 6 for up to 30 minutes. The gel is translucent and spreadable. Skin biopsies were obtained from the treatment site before and 12 weeks after treatment. Histological samples of skin biopsy samples were graded by independent and experienced pathologists blinded to treatment assignment. The results are presented in table 9 below, and show an increase from 287% and 400% of baseline in collagen clusters in treated skin regions, respectively, with and without light treatment of biophotonic gels according to embodiments of the present disclosure, as visualized by trichrome staining. There were no serious adverse events. No photosensitivity, inflammation or pain was reported or observed.

TABLE 9 semi-quantitative histological collagen assessment

Treatment of	Increase in collagen%
		Photoactivatable compositions excited with light having a peak wavelength of 460nm	400
Placebo composition + light with a peak wavelength of 460nm	287
		Photosenfree tretinoin cream	189
Placebo composition containing white light	150

EXAMPLE 10 valve closure

A caudal-based rectangular valve was raised in the back of a Wistar rat. A silicone patch was inserted under the flap to prevent adhesion and reperfusion of the flap to the underlying tissue. After flap closure, biophotonic gels according to embodiments of the present disclosure were applied as a thin monolayer (2mm) onto the back flap and exposed to light from an LED light source having a peak wavelength of about 440-470nm for 5 minutes. A spreadable biophotonic gel including a fluorophore in carbopol gel and urea peroxide, the gel having a viscosity of about 10,000cP to 50,000cP and demonstrating less than 15% leaching when tested according to example 6 for up to 30 minutes. Nine days after treatment, the biophotonic gel was removed and skin samples were collected from different areas in the flap for histological analysis. The treated group demonstrated a significantly greater number of Ki67 positive staining events (P ═ 0.02) compared to these results in the untreated group, suggesting that treatment may modulate cell proliferation involved in wound healing (fig. 12). After examination by an external pathologist, the treated group was associated with a significant (P <0.05) decrease in coagulation necrosis in the epidermis and an increase in fibrous matrix (dermis) compared to the control group.

Example 11 evaluation of biophotonic composition removal from ethanol soaked paper

Conventional white printing paper was soaked in 70% ethanol (EtOH), various embodiments of biophotonic compositions according to the present disclosure (table 10) of 2mm thickness were placed on the soaked paper, and left to stand for 5 minutes. After 5 minutes, the composition was washed off with 70% EtOH. Compositions comprising eosin (0.017%), silica particles, modified starch and hydrogen peroxide were also tested.

The results show that the biophotonic composition of the present disclosure including carbomer gel does not stain white paper. The composition comprising eosin and another hydrophilic polymer (starch) in combination with silica particles does stain paper.

TABLE 10 evaluation of biophotonic composition removal from paper

Example 12-evaluation of athermalization during irradiation of biophotonic compositions

A3 mm thick biophotonic composition according to embodiments of the present disclosure (fluorescent chromophore contained in a carbopol gel according to embodiments of the present disclosure)) The layers were applied to the skin of the hands of volunteers with different skin types and at a distance of 5cm from the light with a thickness of about 50 to 150mW/cm²The blue LED light of power density of (1) was irradiated for 5 minutes. The biophotonic gel is spreadable and has less than 15% leaching by weight when tested according to example 6. A thermometer probe is placed within the composition at the skin surface and the temperature is monitored in real time during irradiation of the composition. Skin temperature without composition but with the same light irradiation was also measured for the same volunteers. The skin types tested were type III (white skin, sometimes burned and gradually suntanned), type IV (beige to tan skin, rarely burned and easily suntanned) and type VI (black skin, never burned, very easily suntanned) according to the Fitzpatrick classification scale. The results are shown in table 11.

TABLE 11 skin temperature under biophotonic composition during 5 minute irradiation compared to skin temperature without composition and irradiation alone

All skin types with biophotonic composition application demonstrated a slower temperature increase compared to bare skin (no biophotonic composition) and thus the biophotonic composition imparted a buffering effect. After 5 minutes of light irradiation, the skin temperature reached a maximum of 39.9 ℃ for all volunteers with biophotonic compositions compared to 40 ℃ for light alone and bare skin. The volunteers felt no pain, burning or discomfort overall.

Example 13 selection of chromophore concentration in biophotonic compositions

The fluorescence spectra of biophotonic compositions with different chromophore concentrations were studied using a spectrophotometer and activated blue light. Exemplary fluorescence spectra of eosin Y and fluorescein are presented in fig. 13. The fluorescence emitted by the chromophore was found to increase rapidly with increasing concentration, but slowly decrease to a plateau with further increasing concentration. The activation light through the composition decreases as the chromophore composition increases, as more is absorbed through the chromophore. Thus, based on this example, the chromophore concentration in the biophotonic compositions of the present disclosure may be selected according to the desired ratio and level of activation light and fluorescence of the treated tissue. In some embodiments, it will be after a rapid increase zone, i.e., between 0.5 and 1mg/mL for eosin Y (fig. 13).

Thus, the concentration can be selected according to the desired activation light and fluorescence. In some embodiments, it will be after a rapid increase zone, i.e., between 0.5 and 1mg/mL for eosin Y (fig. 13). The skilled person will also take into account the effect of other ingredients in the composition on fluorescence and modify the concentration of the chromophore accordingly. For example, certain gelling agents bind to certain chromophores, which can reduce their fluorescence. An example is albumin. In such cases, higher chromophore concentrations may be used in the composition.

Example 14 eosin and Rose Bengal function in a synergistic manner

The synergy between two chromophores according to various embodiments of the present disclosure was investigated by preparing the following:

1-eosin Y (0.035%) + Rose Bengal (0.085%) in a 12% urea gel

2-Rose Bengal in 12% Urea gel (0.085%)

Rose bengal is known to have a high quantum yield in terms of oxygen production when photoactivated by green light in the presence of an oxygen releasing agent. Eosin Y is known to have a high quantum yield in terms of fluorescence emitted when photo-activated and may be at least partially activated by blue light when in a gel. Photoactivated eosin Y does not have a high quantum yield in terms of oxygen production in the presence of an oxygen releasing agent. When eosin Y and rose bengal are combined, it appears that both chromophores are activated by the same blue light, as demonstrated by figure 14.

Figure 14, left panel, shows a photograph of the composition when viewed under an optical microscope (x250) before exposure to activating light. Very few bubbles were visible in both compositions. After irradiation with blue light, the right panel, a sharp increase in bubbles was seen for the composition comprising eosin Y and rose bengal in combination, but not for the composition comprising rose bengal alone. This suggests that there is an energy transfer from eosin Y to rose bengal, resulting in the formation of oxygen species.

Example 15 viscosity of spreadable compositions

Gels based on carbopol polymers with different concentrations were evaluated for their suitability for use in embodiments of the biophotonic compositions of the present disclosure. The gels were evaluated for viscosity, spreadability, and ability to remain in place on the tissue. The gel comprises carbopol 940, glycerol, propylene glycol, water, and small amounts of chelating agents, pH adjusting agents, healing factors, and preservatives. Ten gel compositions with different amounts of carbopol 940 were tested, all other ingredient concentrations remaining the same. Using (1) a Brookfield DV-II + Pro viscometer: spindle 7, 50rpm, 1 minute; and (2) a Brookfield HN viscometer: spindle CP51, 2rpm to evaluate viscosity. The ability to be easily smeared was evaluated based on the ease of forming a 2mm thick layer on the surface and the ability to conform to the topography of the surface. The ability to stay in place was assessed by placing 2mm thick layers of each gel on the surface of a pork chop with an 8mm diameter biopsy punch to simulate a wound. The steak is then placed so that the surface with the gel thereon is at about 90 ° to the horizontal (i.e., the gel is substantially vertical), and then allowed to stand in place for 5 minutes at room temperature. The results are summarized in table 12.

TABLE 12 evaluation of viscosity, spreadability and ability to stay in place of gels with different carbopol concentrations.

Gels that do not flow when placed vertically are obtained with a weight% of carbopol above 0.5% and higher. Gels with a weight% of carbopol of more than 0.5% and less than 2% by weight can be applied in a 2mm thick layer. These gels may be suitable gelling agents for the biophotonic compositions of the present invention. Other carbopol concentrations may also be used in the biophotonic compositions of the present disclosure in combination with a thickener or diluent. In addition, other carbopol grades, polymers, and other gellants may also have properties suitable for use as gellants in the present compositions.

It is understood that the invention is not limited to the particular embodiments described and illustrated herein, but includes all modifications and variations falling within the scope of the invention as defined in the appended claims.

Claims (12)

1. Use of a biophotonic composition for topical administration to reduce scarring, wherein the biophotonic composition comprises a chromophore and a gelling agent and is activatable by irradiation with actinic light.

2. The use of claim 1, wherein the gelling agent ensures that less than 15% by weight of the total chromophore amount leaches from the biophotonic composition in use.

3. The use of claim 1, wherein the chromophore is a fluorescent chromophore selected from eosin Y, eosin B, erythrosin B, fluorescein, rose bengal, and phloxine B.

4. The use of claim 1, wherein the gelling agent comprises at least one of glycerol, propylene glycol, a high molecular weight crosslinked polyacrylic acid polymer, hyaluronic acid, glucosamine sulfate, and a hydrophilic polymer.

5. The use of claim 1, wherein the composition further comprises an oxygen-releasing agent.

6. Use according to claim 5, wherein:

the oxygen releasing agent is selected from hydrogen peroxide, carbamide peroxide and benzoyl peroxide; or

The oxygen-releasing agent is benzoyl peroxide present in an amount of 2.5% to 5% by weight of the composition.

7. The use of claim 5, wherein the chromophore is eosin Y; the oxygen-releasing agent is hydrogen peroxide; and the gelling agent comprises a high molecular weight crosslinked polyacrylic acid polymer.

8. The use of claim 1, wherein the biophotonic composition reduces scarring associated with wound healing.

9. The use of claim 8, wherein the scar is associated with a wound selected from the group consisting of a chronic wound, a burn, an incision, an excision, a lesion, a laceration, an abrasion, a puncture or penetration wound, a surgical wound, a contusion, a hematoma, and an ulcer.

10. The use according to claim 5, wherein the scar is selected from the group consisting of atrophic scar, hypertrophic scar, keloid scar and cicatricial contracture.

11. The use of any one of claims 1-10, wherein the scar is associated with acne.

12. The use of claim 11, wherein the acne is selected from the group consisting of acne vulgaris, acne cystalis, acne atrophia, acne bromosa, acne chloracna, acne conglobata, acne cosmetica, acne decontaminant, acne epidermis, acne summer, acne fulminans, acne haloacne, acne scleroderma, acne iodonium, acne keloids, acne mechanistica, acne papulosa, acne balm, acne premenstrual, acne pustulosa, acne scurvosa, acne tuberculosa, acne urticaria, acne vulgaris, acne toxicans, acne propionate, acne artifically, acne gramnegativum, acne steroids, and acne nodularis.