chromophor combinations for biophotonic uses, use of these chromophores, and kit

专利摘要:
patent summary: "combinations of chromophores for biophotonic uses". The present disclosure presents biophotonic compositions and methods useful in phototherapy. specifically, the biophotonic compositions of the present disclosure contain at least two xanthene dyes. The biophotonic compositions and methods of the present disclosure are useful in stimulating wound healing and skin rejuvenation, as well as in treating acne and other skin conditions.
公开号:BR112015005382A2
申请号:R112015005382
申请日:2013-09-13
公开日:2019-11-26
发明作者:Loupis Nikolaos；Piergallini Remigio
申请人:Klox Tech Inc；
IPC主号:

专利说明:

Invention Patent Descriptive Report for COMBINATIONS OF CHROMOPHORES FOR BIOPHOTONIC USES, USE OF THESE CHROMOPHORES, AND KIT.
[001] BACKGROUND OF THE DESCRIPTION [002] Phototherapy was recently recognized as a therapy with a wide range of applications in medical, cosmetic and dental areas, being used in surgeries, therapies and exams. For example, phototherapy was developed to treat cancers and tumors, to treat skin problems, to disinfect specific sites as an antimicrobial treatment and to stimulate wound healing.
[003] Phototherapy techniques include photodynamic therapy, which involves a stage of systemic administration or the absorption of a photosensitive agent or chromophore in the diseased or injured tissue, followed by the application of specific activation light for the site. Other types of phototherapy include only the use of light at specific wavelengths, in order to reach the tissue using LED (light emitting diode) or fluorescent lamps, or lasers.
[004] The purpose of this description is to present new and improved compositions and methods, useful in phototherapy.
[005] SUMMARY OF DESCRIPTION [006] This description provides topical biophotonic compositions and methods of using biophotonic compositions for the biophotonic treatment of living tissues. Biophotonic treatment may include skin rejuvenation; tissue repair, including wound healing, scar removal and reduction; treatment of skin problems, such as acne; and treatment of periodontitis.
[007] The biophotonic composition of the present description consists of a gelling agent and at least two xanthene dyes, in which the main xanthene dye has an emission spectrum that overlaps at least 5%, 10%, 20%, 25%, 30 %, 40%, 50%, 60%, 70%
Petition 870160045479, of 23/08/2016, p. 5/12
2/82 with an absorption spectrum of a secondary xanthene dye. In some embodiments, the main xanthene dye has an emission spectrum that overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with absorption spectrum of the secondary xanthene dye.
[008] Among the particularly useful combinations of xanthene dyes are, without limitation: Fluorescein + eosin Y; Fluorescein + eosin Y + cane rose; Fluorescein + eosin Y + phloxin B; Eosin Y + cane rose; Eosin Y + phloxin B; Fluorescein + erythrosine B + eosin Y; Eosin Y + erythrosine; Eosin Y + erythrosine B + cane rose; Eosin Y + erythrosine B + phloxin B; Fluorescein + eosin Y + erythrosine B + cane rose; and Fluorescein + eosin Y + erythrosine B + phloxin B.
[009] The gelling agent can be formed by a hygroscopic substance. In addition, or as an alternative, the gelling agent can also be a hydrophilic polymer, a hydrated polymer or a lipid. In certain embodiments, the gelling agent is composed of one or more of the following options: glycerin, glycols such as propylene glycol, polymers of polyacrylic acid, hyaluronic acid, glucosamine sulfate or gelatin.
[010] In certain embodiments, the gelling agent is a cross-linked polyacrylic acid polymer, with high molecular weight, with viscosity in the range of approximately 20,000 to 80,000, from 20,000 to 100,000, from 25,000 to 90,000, from 30,000 to 80,000, from 30,000 to 70,000, from 30,000 to 60,000, from 25,000 to 40,000 cP. In certain embodiments, the cross-linked polyacrylic acid polymer is a carbomer selected from the group comprising, without limitation, Carbopol® 71G NF, 971P NF, 974P NF, 980 NF, 981 NF, 5984 EP, ETD 2020NF, Ultrez 10 NF, 934 NF, 934P NF, 940 NF, 941 NF or 1342 NF.
3/82 [011] In certain embodiments, the biophotonic composition is considerably translucent and / or transparent. In certain embodiments, the biophotonic composition has a translucency of at least 70% at 460 nm. In other embodiments, the composition has a translucency of at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 85%, 90%, 95% or 100% at 460 nm.
[012] In certain embodiments, the biophotonic composition is a liquid, a gel, a semi-solid, a cream, a foam, a lotion, an oil, an ointment, a paste, a suspension or an aerosol spray.
[013] In certain embodiments, the biophotonic composition is encapsulated in a transparent impermeable membrane, or in a permeable membrane that allows the permeation of gases, but not liquids. The membrane can be formed by a lipid.
[014] In certain modalities, the biophotonic composition is also formed by an oxygen generating agent. In some embodiments, the oxygen-generating agent is formed by hydrogen peroxide, carbamide peroxide, benzoyl peroxide, molecular oxygen or water. When the oxygen releasing agent is a peroxide, it may be present in values of less than 6% H ₂ O ₂ , from 0.5% by weight to 6 by weight of H ₂ O ₂ (or its equivalent), from 0 , 5% to 5.5%, 0.5% to 5.0%, 0.5% to 4.5%, 0.5% to 4.0%, 0.5% to 3, 5%, 0.5% to 3.0%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5% or 0.5% to 1.0%.
[015] In certain embodiments, the biophotonic composition does not generate a considerable amount of heat after illumination by light. In some modalities, the energy emitted by the biophotonic composition does not cause damage to the tissue.
[016] In certain embodiments, the main and secondary xanthene dyes are present in the composition in an amount of
4/82 approximately 0.001% to 0.5% by weight of the composition.
[017] In certain modalities, the biophotonic composition can be applied or impregnated in a material, such as a pillow, a covering, a woven or non-woven mesh or similar material. The impregnated material can be used as a mask (like a face mask) or a plaster.
[018] In certain modalities, the biophotonic composition is also formed by at least one waveguide within or adjacent to the composition. The waveguide can be a particle, a fiber or a fibrillar network, of a material capable of transmitting and / or emitting light.
[019] In certain embodiments, the composition does not contain silica, tanning agents or non-fluorescent dyes.
[020] The present description also provides uses of the compositions and methods present for the biophotonic treatment of living tissues.
[021] Therefore, in some respects, there is a method for applying biophotonic therapy to a wound, including: applying a biophotonic composition to a wound containing at least one major xanthene dye and a secondary xanthene dye, in which the dye Principal xanthene has an emission spectrum that overlaps at least 1% to 10%, from 5% to 15%, from 10% to 20%, from 15% to 25%, from 20% to 30%, from 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with an absorption spectrum of the secondary xanthene dye; and lighting the biophotonic composition with light and a wavelength that overlaps an absorption spectrum of the main xanthene dye.
[022] In some modalities of the method for applying biophotonic therapy to a wound, the method stimulates wound healing. In certain modalities of the method, the wound as described herein includes, for example, chronic or acute wounds, such as ulcers of
5/82 diabetic foot, bedsores, varicose ulcers or amputations. In some modalities of the method for applying therapy to a wound, the method encourages the reduction of scar tissue formation. In certain modalities, the treatment can be applied to the wound or on it, once, twice, three, four, five or six times a week, daily or with any other frequency. The total treatment time can be one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve weeks, or any other period of time that is appropriate.
[023] In other respects, there is a method for the biophotonic treatment of acne, including: applying to the skin a biophotonic composition containing at least one main xanthene dye and one secondary xanthene dye, in which the main xanthene dye has an emission spectrum which overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with an absorption spectrum of the secondary xanthene dye; and lighting the biophotonic composition with light and a wavelength that overlaps an absorption spectrum of the main xanthene dye. In certain modalities of the method for the biophotonic treatment of acne, the treatment can be applied on the skin, for example, on the face, once, twice, three, four, five or six times a week, daily or with any other frequency. The total treatment time can be one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve weeks, or any other period of time that is appropriate. In certain modalities, the face can be divided into different areas (cheeks, forehead) and each area can be treated independently. For example, the compound can be applied topically in a first part, that part can be illuminated and then the biophotonic composition can
6/82 be removed. Then the compound can be applied to a second area, lighted and removed. Finally, the compound is applied to a third area, lit and removed.
[024] The methods disclosed for the treatment of acne or wounds may also include, for example, the administration of a systemic or topical drug before, during or after biophotonic treatment. This drug can be an antibiotic, hormone treatment or any other pharmaceutical preparation that can help treat acne or wounds. The combination of a systematic treatment with a topical biophotonic treatment can reduce the duration of the systemic treatment time.
[025] In other respects, there is a method for the biophotonic treatment of skin diseases, including: applying to the skin a biophotonic composition containing at least one main xanthene dye and one secondary xanthene dye, in which the main xanthene dye has a spectrum emission overlapping at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30 % to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with an absorption spectrum of the secondary xanthene dye; and lighting the biophotonic composition with light and a wavelength that overlaps an absorption spectrum of the main xanthene dye.
[026] In other respects, there is a method to stimulate skin rejuvenation, including: applying to the skin a biophotonic composition containing at least one main xanthene dye and one secondary xanthene dye, in which the main xanthene dye has an emission spectrum which overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with an absorption spectrum of the xanthene dye
Secondary 7/82; and lighting the biophotonic composition with light and a wavelength that overlaps an absorption spectrum of the main xanthene dye.
[027] In other respects, the present description provides a method for the treatment of periodontal diseases, including: application in the periodontal pockets of a biophotonic composition containing at least one main xanthene dye and one secondary xanthene dye, in which the main xanthene dye has an emission spectrum that overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, from 30% to 40%, from 35% to 45%, from 50% to 60%, from 55% to 65% or from 60% to 70% with an absorption spectrum of the secondary xanthene dye; and lighting the biophotonic composition with light and a wavelength that overlaps an absorption spectrum of the main xanthene dye.
[028] In other respects, there is a method of using an energy transfer cascade between at least one main and one secondary fluorescent chromophore to absorb and / or emit light within the visible range of the electromagnetic spectrum for the treatment of skin, wound treatment, skin rejuvenation, periodontitis treatment. The present methods and compositions of the present description can also be used to treat viral and fungal infections.
[029] In certain modalities of any method of the present description, the biophotonic composition is illuminated for any period per treatment, in which the biophotonic composition is activated, for example, for 1 min. 30 minutes. The distance from the light source of the biophotonic composition can be any one capable of providing the appropriate light power density to the biophotonic composition and / or to the skin tissue, for example, 5 cm, 10 cm, 15 cm or 20 cm. The biophotonic composition is applied topically to any thickness
8/82 appropriate. Typically, the biophotonic composition is applied topically to the skin or wounds with a thickness of at least 2 mm, about 2 mm to about 10 mm.
[030] In certain embodiments, the method of the present description contains a stage of illumination of 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 illuminated for a period of at least 3 minutes.
[031] In certain modalities of the methods of the present description, the biophotonic composition is removed from the treatment site after the application of light. In this way, 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 illuminated for a period of at least 3 minutes. In some embodiments, the biophotonic composition is removed after a period of at least 3 minutes after applying the biophotonic composition to the treatment site.
[032] In other modalities, the biophotonic composition is maintained for one, two or three weeks, and illuminated with light, which can include ambient light at various intervals. In that case, the composition can be covered between exposures to light. For example, the biophotonic composition can be soaked in a plaster and placed inside or on a wound and left in place for an extended time (ie, more than a day).
[033] BRIEF DESCRIPTION OF THE DRAWINGS [034] Figure 1 shows the absorption of light in the different layers of the skin (Samson et al. Evidence Report / Technology Assessment 2004, 111, pages 1-97).
9/82 [035] Figure 2 illustrates Stokes' deviation.
[036] Figure 3 illustrates the absorption and emission spectra of the donor and recipient chromophores. The spectral overlap between ο the absorption spectrum of the recipient chromophore and the emission spectrum of the donor chromophore is also shown.
[037] Figure 4 is a schematic representation of a Jablonski diagram, which illustrates the transitions involved between a donor emission and the absorption of the recipient.
[038] Figures 5A and 5B are, respectively, absorption and emission spectra of (i) sodium salt of fluorescein at approximately 0.09 mg / mL, (ii) Eosin Y at approximately 0.305 mg / mL and (iii) a mixture of sodium salt of fluorescein at approximately 0.09 mg / ml and Eosin Y at approximately 0.305 mg / ml, all in a carbamide gel (Example 1).
[039] Figures 6A and 6B are, respectively, absorption and emission spectra of (i) sodium salt of fluorescein at a final concentration of 0.18 mg / mL, (ii) Eosin Y at approximately 0.305 mg / mL and (iii) a mixture of sodium salt of fluorescein at approximately 0.18 mg / mL and Eosin Y at approximately 0.305 mg / mL, all in an aqueous solution (Example 2).
[040] Figures 7A and 7B are, respectively, absorption and emission spectra of (i) phloxin B at a final concentration of 0.25 mg / mL, (ii) eosin Y at approximately 0.05 mg / mL and ( iii) a mixture of floxin B (0.25 mg / ml) and eosin Y (0.05 mg / ml), all in a 12% carbamide gel (Example 3).
[041] Figures 8A and 8B are, respectively, absorption and emission spectra of (i) phloxin B at a final concentration of 0.25 mg / mL, (ii) eosin Y at approximately 0.08 mg / mL and ( iii) a mixture of floxin B (0.25 mg / ml) and eosin Y (0.08 mg / ml), all in an aqueous solution (Example 4).
10/82 [042] Figures 9A and 9B are, respectively, absorption and emission spectra of (i) floxin B at 100 pg / g, (ii) fluorescein at approximately 100 pg / g and (iii) a mixture of floxin B (100 pg / g) and fluorescein (100 pg / g), all in a 12% carbamide gel (Example 5).
[043] Figures 10A and 10B are, respectively, absorption and emission spectra of (i) floxin B at 100 pg / g, (ii) fluorescein at approximately 100 pg / g and (iii) a mixture of floxin B (100 pg) / g) and fluorescein (100 pg / g), all in a 12% carbamide gel (Example 6).
[044] Figures 11A and 11B are, respectively, absorption and emission spectra of (i) eosin Y at a final concentration of 0.305 mg / mL, (ii) cane rose at approximately 0.085 mg / mL and (iii) a mixture eosin Y (0.305 mg / mL) and cane rose (0.085 mg / mL), all in a 12% carbamide gel (Example 7).
[045] Figure 12 shows that eosin Y and cane rose act synergistically (Example 8).
[046] Figures 13A and 13B show the fluorescence emission (power density) over time of compositions containing (i) fluorescein + eosin Y (Figure 11 A) and (ii) eosin Y + cane rose (Figure 11B ) (Example 9).
[047] Figures 14A and 14B are, respectively, absorption and emission spectra of (i) cane rose at approximately 0.085 mg / mL, (ii) fluorescein sodium salt at approximately 0.44 mg / mL and (ii ) eosin Y at approximately 0.305 mg / ml and iii a mixture of (i), (ii) and (iii) in a carbamide gel (Example 10).
[048] Figures 15A and 15B are, respectively, absorption and emission spectra of (i) cane rose at approximately 0.085 mg / mL, (ii) fluorescein sodium salt at a final concentration of approximately 0.44 mg / mL and (ii) eosin Y at approximately
11/82
0.305 mg / ml and (iii) a mixture of (i), (ii) and (iii) in an aqueous composition (Example 11).
[049] Figure 16 is an emission spectrum illustrating the intensity, over time, of the light emitted from the composition tested in Examples 12 and 13.
[050] Figures 17A and 17B show that the energy density of the fluorescence emitted from eosin (upper) and fluorescein (lower) in a composition increases rapidly with increasing chromophore concentration, but decreases to a stable point with , still more increase in concentration, while the activating light decreases with increasing concentration (Example 15).
[051] DETAILED DESCRIPTION [052] Overview [053] This description provides compositions, including at least two photoactive chromophores that can transfer energy from one to the other, and useful methods for treating fabrics with these compositions, for example, to promote tissue repairs, including wound healing, for cosmetic skin treatment, such as skin rejuvenation, for treating skin conditions like acne and for periodontal treatment.
[054] Definitions [055] Before proceeding with the description of this description in more detail, it should be understood that this description is not limited to specific compositions or stages of the process, as these may vary. It should be noted that, as used in this specification and the appended claims, the singular forms "one / one" and "one / a" include references in the plural, unless the context clearly suggests otherwise.
[056] As used here, the term “approximately” in the context of a given value or range, refers to a value or to
12/82 a range within 20%, preferably within 10%, and even more preferably within 5% of the reported value or range.
[057] It should be noted here that “and / or”, as used in this document, should be understood as a specific description of each of the specified resources or components, with or without the other. For example, “A and / or B” should be understood as a specific description of each (i) A, (ii) B and (iii) A and B, as if each case were defined individually in this document.
[058] "Biophotonic" represents the generation, manipulation, detection and application of photons in a biologically relevant context. In other words, biophotonic compositions exert their physiological effects mainly due to the generation and manipulation of photons. “Biophotonic composition” is a composition as described in this document, which can be activated by light to produce photons for biologically relevant applications.
[059] "Topical composition" means a composition applied to body surfaces, such as skin, mucous membranes, vagina, oral cavity, wounds and the like. A topical composition can be in the form of, without limitation, a cream, a gel, a gel, an ointment, a lotion, a smooth homogeneous mixture, a solution, a bioadhesive, an ointment, a milk. The topical composition can impregnate in materials such as a pillow, sheet, fabric or fibers, plasters, spray, suspension, foam or the like.
[060] The terms "chromophore", "photoactivating agent" and "photoactivating agent" are used interchangeably in this document. A chromophore means a chemical compound that, when reached by light irradiation, is able to absorb light, for example, a xanthene dye. The chromophore immediately goes into photoexcitation and can then transfer its energy to other molecules or emit it as light.
13/82 [061] Oxidizing agent ”,“ oxidizing agent ”or“ oxygen releasing agent ”, terms used interchangeably here, represent a chemical compound that readily transfers oxygen atoms and oxidizes other compounds. This includes molecular oxygen and oxygen containing compounds such as water, peroxide, etc.
[062] "Photodegradation" means the photochemical destruction of a chromophore.
[063] The term “actinic light” must be understood as light energy emitted from a specific light source (such as a lamp, LED or laser) and capable of being absorbed by matter (for example, the chromophore or photoactivator defined above). In a preferred embodiment, actinic light is visible light.
[064] “Wound” means an injury to any tissue, including, for example, acute, subacute, delayed or difficult to heal injuries and chronic injuries. Examples of wounds include both open and closed wounds. Wounds include, for example, burns, incisions, excisions, injuries, lacerations, abrasions, punctures or penetrating wounds, surgical wounds, bruises, bruises, crush injuries, ulcers (such as pressure ulcers, venous or diabetic), wounds caused by periodontitis (inflammation of the periodontium) and gunshot wounds.
[065] "Wound healing" means the promotion or acceleration of tissue repair, including wound closure, activation of a chronic wound or reduction in scar formation.
[066] "Skin rejuvenation" means a process of reducing, decreasing, delaying or reversing one or more signs of skin aging. For example, common signs of skin aging include, without limitation, the appearance of fine lines or wrinkles, thin or transparent skin, loss of underlying fat (leading to deep cheeks and eye sockets, as well as
14/82 noticeable loss of firmness in the hands and neck), bone loss (causing bones to shrink and move away from the skin due to bone loss, causing sagging skin), dry skin (which can cause itching), sweating insufficient to cool the skin, unwanted facial hair, freckles, age spots, microvarices, rough and hardened skin, fine wrinkles that disappear when stretched, flabby skin or blemished complexion. According to the present description, one or more of the signs indicated above can be reduced, decreased, delayed or even reversed by the compositions and methods of the present description.
[067] Biophotonic compositions [068] This description presents biophotonic compositions.
Biophotonic compositions are compositions that contain, in general terms, chromophores activated by light and that accelerate the dispersion of light energy, which makes the light have a therapeutic effect and / or causes the photochemical activation of other agents contained in the composition (for example, example, breakdown of an oxygen releasing agent in the presence of such a composition or at the treatment site, leading to the formation of oxygen radicals, such as singlet oxygen). The biophotonic compositions of the present description contain at least two xanthene dyes as chromophores.
[069] When a chromophore absorbs a photon of a certain wavelength, it becomes excited. This is an unstable condition, and the molecule tries to return to the ground state, releasing excess energy. For some chromophores, the emission of excessive energy as light is favorable, when transforming back to the ground state. This process is called fluorescence. The peak wavelength of the emitted fluorescence is shifted to longer wavelengths compared to the absorption wavelengths due to the loss of energy during the conversion process. That
15/82 is called Stokes' deviation and is illustrated in Figure 2. In an appropriate environment (for example, in a biophotonic composition), much of that energy is transferred to the other components of the composition or directly to the treatment site.
[070] Without adhering to the theory, it is believed that the fluorescent light emitted by photoactivated chromophores may have therapeutic properties, due to the properties of femto, peak or nanosecond emissions, which can be recognized by biological cells and tissues, leading to favorable biomodulation. In addition, the fluorescent light emitted has a longer wavelength and therefore a deeper penetration into the tissue than the activation light. The irradiation of tissue with this wide range of wavelengths, including in some modalities the activation light that passes through the composition, can generate different and complementary effects on cells and tissues. In addition, the inventors observed that the generation of oxygen species (eg singlet oxygen) by photoactivated chromophores causes microbubbles within the composition, which can have a physical impact on the tissue to which it is applied, for example, dislodging biofilms and the debridement of necrotic tissue or providing a pressure stimulus. The biofilm can also be pretreated with an oxygen releasing agent to weaken the biofilm prior to treatment with the composition of the present description.
[071] Furthermore, it is believed that the use of chromophores in a composition for emitting fluorescent light provides the ability to adjust the light emitted to a much greater degree than when using a light source such as an LED or a laser. . For example, depending on the therapy or treatment needed, chromophores can be chosen according to the wavelength of the emitted light and the appropriate concentrations used to control the power density of the emitted light.
16/82 [072] The biophotonic compositions of the present description are considerably transparent / translucent and / or have high light transmittance, in order to allow the dissipation of light in and through the composition. In this way, the tissue area under the composition can be treated both by the fluorescent light emitted by the composition, and by the light that is radiating the composition to activate it. The percentage of transmittance of the biophotonic composition can be measured in the wavelength range from 250 nm to 800 nm using, for example, a Perkin-Elmer Lambda 9500 series visible UV spectrometer. In some embodiments, the transmittance of the compositions disclosed here is measured at 460 nm.
[073] Since the transmittance depends on the thickness, the thickness of each sample can be measured with a caliper before loading the spectrometer. The transmittance values can be normalized to a thickness of 100 pm (or any thickness) according to:
Í2. ^r 2
FT- _C o _rr (A t ₂ ) = = [Fr-corÁA fi)] ^f i, in which, ti = actual specimen thickness, t ₂ = thickness at which transmittance measurements can be normalized.
[075] In some modalities, the biophotonic composition has transparency or translucency that exceeds 15%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85 % at 460 nm. In some embodiments, the transparency exceeds 70% at 460 nm, 86% at 460 nm, 87% at 460 nm, 88% at 460 nm, 89% at 460 nm, 90% at 460 nm, 91% at 460 nm, 92 % at 460 nm, 93% at 460 nm, 94% at 460 nm, 95% at 460 nm, 96% at 460 nm, 97% at 460 nm, 98% at 460 nm or 99% at 460 nm.
[076] The biophotonic compositions of the present description are for topical use. Such compositions can be described on the basis of the components that form them. Additionally or alternately
17/82, the compositions of the present description have functional and structural properties, and these properties can also be used to define and describe the compositions. The components of the composition of this description are detailed below, individually.
[077] Chromophores [078] The topical biophotonic compositions of the present description contain at least two xanthene dyes such as chromophores. Combined xanthene dyes can increase the photoabsorption of the combined dye molecules and increase the absorption and selectivity of photobiomodulation. This creates several possibilities to generate new photosensitive mixtures and / or selective xanthene dye mixtures.
[079] When these compositions with multiple xanthene dyes are illuminated using a light with an appropriate wavelength to activate at least one of the xanthene dyes, energy transfer can occur between the xanthene dyes. This process, known as resonance energy transfer, is a photophysical process by which an excited "donor" xanthene dye (also called the main xanthene dye in this document) transfers its excitation energy to a "recipient" xanthene dye ( also called the secondary xanthene dye in this document). The efficiency and direction of resonance energy transfer depends on the spectral characteristics of the donor and recipient xanthene dyes. In particular, the energy flow between the xanthene dyes depends on the spectral overlap that reflects the relative positioning and shapes of the absorption and emission spectrum. For energy transfer to occur, the emission spectrum of the donor xanthene dye should preferably overlap the absorption spectrum of the recipient xanthene dye (Figure 3).
18/82 [080] The transfer of energy manifests itself through the reduction or suppression of the donor's emission and a reduction of the lifetime of the state of excitation accompanied also by an increase in the intensity of the emission of the recipient. Figure 4 is a schematic representation of a Jablonski diagram that illustrates the transitions involved between a donor emission and the absorption of the recipient.
[081] To reinforce the efficiency of energy transfer, the donor xanthene dye must have good photon absorption and photon emission capacity. In addition, it is believed that the greater the overlap between the emission spectrum of the donor xanthene dye and the absorption spectrum of the recipient xanthene dye, the better the transfer between the donor xanthene dye and the recipient xanthene dye will be.
[082] In some embodiments, the main xanthene dye has an emission spectrum that overlaps at least approximately 80%, 50%, 40%, 30%, 20%, 10% with a chromophore absorption spectrum of the xanthene dye. In one embodiment, the main xanthene dye has an emission spectrum that overlaps at least approximately 20% with an absorption spectrum of the secondary xanthene dye. In some embodiments, the main xanthene dye has an emission spectrum that overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70%, with absorption spectrum of the secondary xanthene dye.
[083] The percentage of spectral overlap, as used in this document, means the percentage of overlap of the wavelength range of the emission of the donor xanthene dye with the absorption wavelength range of the recipient xanthene dye, measured with width a a quarter of the height (full width at quar
19/82 have maximum, FWQM). For example, Figure 3 shows the normalized spectra of absorption and emission of the donor and recipient xanthene dyes. The spectral FWQM of the absorption of the xanthene receptor dye is approximately 60 nm (515 nm to approximately 575 nm). The overlap of the spectrum of the donor xanthene dye with the absorption spectrum of the recipient xanthene dye is about 40 nm (from 515 nm to approximately 555 nm). Thus, the overlap can be calculated as 40 nm / 60 nm x 100 = 66.6%.
[084] In some embodiments, the secondary xanthene dye absorbs at a wavelength in the range of the visible spectrum. In certain embodiments, the secondary xanthene dye has a relatively longer absorption wavelength than that of the main xanthene dye, within the range of approximately 50 nm to 250 nm, 25 nm to 150 nm or 10 nm to 100 nm.
[085] As discussed earlier, the application of light over the compositions of the present description can result in a cascade of energy transfer between the xanthene dyes. In certain embodiments, such an energy transfer cascade provides photons that penetrate the epidermis, dermis and / or mucosa of the tissue under treatment, including, for example, the site of a wound or tissue with acne or other skin disease . In some modalities, such an energy transfer cascade is not accompanied by concomitant heat generation. In some embodiments, the energy transfer cascade does not result in tissue damage.
[086] In some embodiments, the main xanthene dye absorbs a wavelength in the visible spectrum range, such as between 380 nm to 800 nm, 380 nm to 700 nm or 380 nm to 600 nm. In other embodiments, the main xanthene dye absorbs at wavelengths of approximately 200 nm to 800 nm, 200 nm to 700 nm, 200 nm to 600 nm or 200 nm to 500 nm. In one mode, the coran
20/82 main xanthene absorbs at a wavelength of approximately 200 nm to 600 nm. In some embodiments, the main xanthene dye absorbs light with a wavelength of approximately 200 nm to 300 nm, 250 nm to 350 nm, 300 nm to 400 nm, 350 nm to 450 nm, 400 nm to 500 nm, 400 nm to 600 nm, 450 nm to 650 nm, 600 nm to 700 nm, 650 nm to 750 nm or 700 nm to 800 nm.
[087] It will be clear to those skilled in the art that the optical properties of a given xanthene dye may vary, depending on the medium surrounding the xanthene dye. Therefore, as used here, the wavelength (or spectrum) of the absorption and / or emission of a specific xanthene dye corresponds to the wavelengths (or spectra) measured in a biophotonic composition of the present description.
[088] Examples of xanthene dyes are, among others, eosin B (4 ', 5'-dibromo, 2', 7'-dinitr-o-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'-tetrabromofluorescein, dianion) methyl ester; eosin (2 ', 4', 5 ', 7'-tetrabromofluorescein, monoanion) p-isopropylbenzyl ester; eosin derivative (2 ', 7'-dibromo-fluorescein, dianion); eosin derivative (4 ', 5'-dibromofluorescein, dianion); eosin derivative (2 ', 7'-dichloro-fluorescein, dianion); eosin derivative (4 ', 5'-dichloro-fluorescein, dianion); eosin derivative (2 ', 7'-diiodo-fluorescein, dianion); eosin derivative (4 ', 5'-diiodo-fluorescein, dianion); eosin derivative (tribromofluorescein, dianion); eosin derivative (2 ', 4', 5 ', 7'-tetrachlorofluorescein, dianion); eosin; eosin dicetylpyridinium chloride ion pair; erythrosine B (2 ', 4', 5 ', 7'-tetraiodo-fluorescein, dianion); erythrosine; dianion erythrosine; erythrosine B; fluorescein; dianion fluorescein; phloxin B (2 ', 4', 5 ', 7'-tetrabromo-3,4,5,6-tetrachloro-fluorescein, dianion); phloxin B (tetrachloro-tetrabromo-fluorescein); phloxin B; rose
21/82 cane (3,4,5,6-tetrachlor-2 ', 4', 5 ', 7'-tetraiodo-fluorescein, dianion); pyronine G, pyronine J, pyronine Y; rhodamine dyes, such as rhodamine, include 4,5-dibromo-rhodamine methyl; 4,5-dibromo-rhodamine n-butyl ester; rhodamine 101 methyl ester; rhodamine 123; rhodamine 6G; rhodamine 6G hexyl ester; tetrabromo-rhodamine 123; and tetramethylrodamine ethyl ester.
[089] In certain embodiments, the main xanthene dye is present in an amount of approximately 0.01% to 40% by weight of the compound, and the secondary xanthene dye is present in an amount of approximately 0.001% to 40% by weight of the composition. In certain embodiments, the total percentage by weight of the xanthene dyes is present in an amount of 0.01% to 40.001% of the weight of the composition. In certain embodiments, the main xanthene dye is present in the amount of approximately 0.01% to 1%, 0.01% to 2%, 0.05% to 1%, 0.05% to 2%, 1% to 5 %, 2.5% to 7.5%, 5% to 10%, 7.5% to 12.5%, 10% to 15%, 12.5% to 17.5%, 15% to 20%, 17.5% to 22.5%, 20% to 25%, 22.5% to 27.5%, 25% to 30%, 27.5% to 32.5%, 30% to 35%, 32, 5% to 37.5% or 35% to 40% by weight of the composition. In certain embodiments, the secondary xanthene dye is present in the approximate amount of 0.001% to 1%, 0.001% to 2%, 0.001% to 0.01%, 0.01% to 0.1%, 0.1% to 1 , 0%, 1% to 2%, 1% to 5%, 2.5% to 7.5%, 5% to 10%, 7.5% to 12.5%, 10% to 15%, 12, 5% to 17.5%, 15% to 20%, 17.5% to 22.5%, 20% to 25%, 22.5% to 27.5%, 25% to 30%, 27.5% at 32.5%, 30% to 35%, 32.5% to 37.5% or 35% to 40% by weight of the composition. In certain embodiments, the total percentage by weight of the xanthene dyes is present in the approximate amount of less than 0.5%, less than 0.1%, 0.001% to 0.1%, 0.01% to 1%, 0.01 % to 2%, 0.05% to 2%, 0.001% to 0.5%, 0.5% to 1%, 0.5% to 2%, 1% to 5%, 2.5% to 7, 5%, 5% to 10%, 7.5% to 12.5%, 10% to 15%, 12.5% to 17.5%, 15% to 20%, 17.5% to 22.5% , 20% to 25%, 22.5% to 27.5%, 25%
22/82 to 30%, 27.5% to 32.5%, 30% to 35%, 32.5% to 37.5%, or 35% to 40.05% by weight of the composition. All amounts are given as weight percent by weight of the total concentration, and the equivalent weight or volume quantities.
[090] In certain embodiments, the proportion of the concentrations of the main and secondary xanthene dyes in the compound ranges from 1: 1 to 1: 1000. In certain embodiments, the relative concentration of eosin Y: Fluorescein may be present in such a way that there is less eosin Y than fluorescein, such as 1000: 1, 100: 1, 10: 1 or 60% to 80%: 20% at 40%. In certain embodiments, the ratio of eosin Y to cane rose is 1: 1 or 70% to 90%: 10% to 30%. In certain embodiments, the ratio of fluorescein to eosin Y to cane rose can be 20% to 40%: 30% to 60%: 10% to 20%. The proportion can be customized according to the desired emitted light spectrum for a given treatment or therapy.
[091] In some modalities, the combinations of xanthene dye are selected in such a way that their fluorescent lights emitted, in photoactivations, are within one or more parts of the green, yellow, orange, red and infrared of the electromagnetic spectrum, with, for example example, with a maximum wavelength in the range of approximately 490 nm to approximately 800 nm. In certain embodiments, the fluorescent light emitted has a power density of approximately 0.005 to approximately 10 mW / cm ² , approximately 0.5 to approximately 5 mW / cm ² or approximately 0.05 to approximately 2 mW / cm ² .
[092] Among the particularly useful combinations of xanthene dyes are, without limitation: fluorescein + eosin Y; fluorescein + eosin Y + cane rose; fluorescein + eosin Y + phloxin B; eosin Y + cane rose; eosin Y + phloxin B; eosin Y + erythrosine; fluorescein + erythrosine B + eosin Y; eosin Y + erythrosine B + cane rose;
23/82 eosin Y + erythrosine B + phloxin B; fluorescein + eosin Y + erythrosin B + cane rose; and fluorescein + eosin Y + erythrosine B + phloxin B.
[093] At least some of these combinations are believed to have a synergistic effect at certain proportions of concentration within the composition. For example, in certain proportions of concentration and with adequate activation light, eosin Y can transfer energy to cane rose, erythrosine B or phloxin B when activated. This transferred energy is then emitted as fluorescence and / or by the production of reactive oxygen species (such as singlet oxygen).
[094] The synergistic effect may be obvious from the fact that the composition has a light absorption spectrum that covers a wider range of wavelengths compared to an individual light absorption spectrum of one of the individual chromophores in the composition, when the individual chromophores and the compound are activated by the same activation light (when the light has substantially the same emission spectra). This can give the composition the ability to be activated by a wider range of wavelengths of activation light, for example, by white light, thus avoiding the need for a precise wavelength of the activation light.
[095] The synergistic effect may also be evident from the fact that the composition has a spectrum of light emission that covers a wider range of wavelengths compared to an individual light absorption spectrum of one of the individual chromophores in the composition, when the individual chromophores and the compound are activated by the same activation light. It is believed that this absorbed and re-emitted light is transmitted through the composition and that it is also transmitted into the treatment site. This spectrum emitted next will illuminate the target tissue with different
24/82 penetration depths (Figure 1), which can provide beneficial therapeutic effects to the target tissue. For example, green light has been reported to have wound healing properties. By emitting a wider range of wavelengths, a wider range of therapeutic effects can be achieved. The emitted wavelength can be perfectly adjusted using different combinations and concentrations of chromophores.
[096] The synergistic effect may also be evident from the fact that the composition has a higher absorption or light emission peak compared to an individual light emission / absorption peak of one of the individual chromophores in the composition, when the chromophores and the composition are activated by the same activation light. The ability to absorb and emit higher levels of photons can provide a therapeutic effect in certain applications. In addition, a lower concentration of an individual chromophore may be required in order to obtain a certain power density. Higher power densities can match shorter treatment times.
[097] This synergistic effect may also be evident from the fact that the composition produces more oxygen species in the presence of an oxygen releasing agent compared to the oxygen species produced by an individual chromophore in the composition, when the individual chromophores and the composition are activated by the same activation light. The ability to produce higher levels of oxygen species without the need to increase the treatment time or the power density of the activation light can be an advantage in certain situations.
[098] Through the synergistic effects of xanthene dye combinations in the compound, xanthene dyes that cannot be activated normally by an activation light (such as a blue light)
25/82 can be activated by transferring energy from the xanthene dyes that are activated by the activation light. In this way, the various properties of the photoactivated xanthene dyes can be used and shaped according to the necessary aesthetic or medical therapy.
[099] For example, the cane rose is capable of generating a high yield of atomic oxygen when photoactivated in the presence of molecular oxygen, but it has a low quantum yield in terms of emitted fluorescent light. Bengal rose has a maximum absorption of approximately 540 nm and is therefore normally activated by green light. Eosin Y has a high quantum fluorescence yield and can be activated by blue light. Combining cane rose and eosin Y, a composition is obtained that is capable of emitting therapeutic fluorescent light and generating atomic oxygen when activated by blue light. In this case, it is believed that the blue light makes the photoactivation of eosin Y, which transfers some of its energy to the cane pink, also emitting some energy as fluorescence.
[0100] Photobleaching of a chromophore or more may occur during lighting. This can be a visual confirmation of the dose application. As chromophores photobleach, they emit less fluorescence over time. At the same time, they also absorb less activation light over time, so tissues receive increasing amounts of activation light. In this way, chromophores modulate the exposure of the tissue to light, which can offer some protective effect.
[0101] (b) Additional chromophores [0102] In addition to the xanthene dye combination, the topical biophotonic compositions of the present description may also include, among others, the following:
26/82 [0103] Chlorophyll dyes [0104] Examples of chlorophyll dyes include, but are not limited to, chlorophyll a; chlorophyll b; oil-soluble chlorophyll; bacterochlorophyll a; bacterochlorophyll b; bacteriochlorophyll c; bacteriochlorophyll d; protochlorophyll; protochlorophyll a; antipathetic derivative of chlorophyll 1; antipathetic derivative of chlorophyll 2.
[0105] Methylene blue dyes [0106] Examples of methylene blue derivatives include, but are not limited to, 1-methyl methylene blue; 1,9-dimethyl methylene blue; methylene blue; methylene blue (16.mu.M); methylene blue (14.mu.M); methylene violet; bromo-methylene violet; 4-iodo-methylene violet; 1,9-dimethyl-3-dimethyl-amine-7-diethylamine-phenothiazine; and 1,9-di methyl-3dethylamine-7-dibutyl-amino phenothiazine.
[0107] Azo dyes [0108] Examples of azo (or diazo-) dyes include, but are not limited to, methyl violet, neutral red, para (to red) (pigment red 1), amaranth (azorubin S), crimson ( azorubin, food red 3, acid red 14), allura AC red (FD&C 40), tartrazine (FD&C yellow 5), orange G (acid orange 10), ponceau 4R (food red 7), methyl red (acid red 2) and ammonium purpurate murexide.
[0109] In some aspects of the description, the additional chromophores of the biophotonic composition disclosed in this document can be selected independently from any of the following: acid black 1, acid blue 22, acid blue 93, acid fuchsin, acid green, acid green 1, acid green 5, acid magenta, acid orange 10, acid red 26, acid red 29, acid red 44, acid red 51, acid red 66, acid red 87, acid red 91, acid red 92, acid red 94, acid red 101 , acid red 103, acid rosein, acid ruby, acid violet 19, acid yellow 1,
27/82 acid yellow 9, acid yellow 23, acid yellow 24, acid yellow 36, acid yellow 73, acid yellow S, acridine orange, acriflavin, alcian blue, alcian yellow, alcohol soluble eosin, alizarin, alizarin blue 2RC , alizarin carmine, alizarin cyanine BBS, alizarin R cyanine, alizarin red S, alizarin glitter, aluminon, starch black 10B, starch black, aniline blue WS, anthracene blue SWR, auramine O, azocanine B , azocarmin G, azoic diazo 5, azoic diazo 48, azure A, azure B, azure C, basic blue 8, basic blue 9, basic blue 12, basic blue 15, basic blue 17, basic blue 20, basic blue 26, brown basic 1, basic fuchsin, basic green
4, basic orange 14, basic red 2 (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, scarlet Biebrich, brown Bismarck Y, scarlet crystal shiny 6R, calcium red , carmine, carminic acid (acid red 4), sky blue B, China blue, cochineal, sky blue, CG chrome violet, chromotrope 2R, cyanine R chromoxane, Congo red, Congo red, cotton blue, cotton red, scarlet croceine, crocina, ponceau cristal 6R, violet cristal, dahlia, diamond green B, DiOC6, direct blue 14, direct blue 58, direct red, direct red 10, direct red 28, direct red 80, direct yellow 7, eosin B, bluish eosin, eosin, eosin Y, yellowish eosin, eosinol, Erie B garnet, erythromycin cyanine R, erythrosine B, ethyl eosin, ethyl green, ethyl violet, Evans blue, rapid blue B, rapid green B, rapid red B, rapid yellow, fluorescein food green 3, gallein, blue galamine, galocyanine, gentian violet, hemateine, hematin, hematoxylin, fast rubina Helio BBL, blue Helvetia, hemateine, hematin, hematoxylin, Hoffman's violet, imperial red, indocyanine green, blue ingraine, blue ingrain 1, yellow ingraína 1, INT, Kermes, kermésico acid, Kernechtrot, lacquer, lacquer acid, violet
28/82
Lauth, light green, Lissamine SF green, fast blue Luxol, magenta 0, magenta I, magenta II, magenta III, malachite green, Manchester brown, Martius yellow, merbromine, mercurochrome, methanyl yellow, methylene azure A, methylene azure B , methylene azure C, methylene blue, methyl blue, methyl green, methyl violet, methyl violet 2B, methyl violet 10B, nipple blue 3, nipple blue 10, nipple blue 14, nipple blue 23, nipple blue 32, blue jaw 45, red jaw 3, red jaw 11, violet jaw 25, violet jaw 39, bluish black Naftol, green Naftol B, yellow Naftol S, natural black 1, natural red, natural red 3, natural red 4, red natural 8, natural red 16, natural red 25, natural red 28, natural yellow 6, NBT, neutral red, new fuchsin, Niagara blue 3B, night blue, Nile blue, Nile A blue, Nile blue oxazone, sulfate Nile blue, Nile red, Nitro BT, N tetrazolium blue ilo, fast nuclear red, oil red O, orange G, orcein, pararosaniline, phoxin B, phycobilins, phycocyanins, phycoerythrins. Cyanine phycoerythrin (PEC), phthalocyanines, picric acid, ponceau 2R, ponceau 6R, ponceau B, ponceau xylidine, ponceau S, primrose, purpurin, pyronin B, pyronin G, pyronin Y, rhodamine B, rosaniline, bengal rose, saffron, saffron O, scarlet R, scarlet red, Scharlach R, shellac, red Syrian F3B, Solochrome cyanine R, soluble blue, black solvent 3, solvent blue 38, solvent red 23, solvent red 24, solvent red 27, solvent red 45, yellow solvent 94, alcohol soluble eosin, Sudan III, Sudan IV, Sudan B black, sulfur yellow S, Swiss blue, tartrazine, thioflavin S, thioflavin T, thionine, toluidine blue, toluiline red, tropeolin G, tripaflavin, blue trypan, uranine, Victoria 4R blue, Victoria B blue, Victoria B green, water blue I, water soluble eosin, xylidine ponceau or yellowish eosin.
[0110] In certain embodiments, the composition of the present description includes any of the additional chromophores listed above, in addition to the xanthene dyes, or a combination of these, in order to provide a biophotonic impact on the application site. This is a distinct application of these agents and differs from the use of chromophores as simple paints or as catalysts in photopolymerization.
[0111] Chromophores can be selected, for example, from the wavelength properties of their emissions, in the case of fluorophores, from their energy transfer potential, by their ability to generate reactive oxygen species or by antimicrobial effect. These needs may vary depending on the conditions required by the treatment. For example, chlorophyll can have an antimicrobial effect on bacteria found on the face.
[0112] (c) Gelling agent [0113] The composition may optionally contain a gelling agent. A gelling agent to be used in accordance with the present description can comprise any ingredient suitable for use in a topical biophotonic formulation, as described herein. The gelling agent can be an agent capable of forming a cross-linked matrix, including physical and / or chemical cross-links. The gelling agent is preferably biocompatible, and can be biodegradable. In some embodiments, the gelling agent is capable of forming a hydrogel or hydrocolloid. A suitable gelling agent is one capable of forming a viscous liquid or a semi-solid. In preferred embodiments, the gelling agent and / or the composition has appropriate light transmitting properties. It is also important to select a gelling agent, which will allow the biophotonic activity of the chromophores. For example, some chromophores require a hydrated environment to fluoresce. The gelling agent may be able to form a gel by itself, or in combination
30/82 tion with other ingredients, such as water or another gelling agent, or when applied to a treatment site, or when illuminated with light.
[0114] In some embodiments, the composition is in the form of a gel, a cream, an ointment, a lotion, a paste, a spray or a foam.
[0115] The gelling agent, according to various embodiments of the present description, may contain polyalkylene oxides, particularly copolymers of polyethylene glycol and poly (ethylene oxide) poly (propylene oxide), including block copolymers and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol replaced by one or more polyalkylene oxides, for example, mono-, bi- and tri-polyoxyethylated glycerol, mono- and bi-polyoxyethylated propylene glycol, and trimethylene glycol and bi-polyoxyethylated; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and their analogous copolymers, such as polyacrylic acid itself, polymethacrylic acid, poly (hydroxyethylmethacrylate), poly (hydroxyethylacrylate), poly (methylalkyl sulfoxide methacrylate), poly (methylalkyl sulfoxide acrylate) and any copolymers one of the above, and / or with additional acrylate species, such as aminoethyl acrylate and mono-2 (acryloxy) -ethyl succinate; polymalleic acid; poly (acrylamides) such as pure polyacrylamide, poly (methacrylamide), poly (dimethylacrylamide), and poly (N-isopropylacrylamide); polyolefinic alcohols such as polyvinyl alcohol; poly (N-vinyl lactams) such as poly (vinyl pyrrolidone), poly (N-vinyl-caprolactam) and their copolymers, polyoxazolines, including poly (methyloxazoline) and poly (ethyloxazoline); and polyvinylamines.
[0116] The gelling agent, according to certain modalities of the present description, may contain a polymer selected from synthetic or semi-synthetic polymeric materials, polyacrylic copolymers
31/82 cans, cellulose derivatives and copolymers of polymethyl vinyl ether / maleic anhydride. In some embodiments, the hydrophilic polymer comprises a polymer with a high molecular weight (i.e., molar masses greater than approximately 5,000 and, in some cases, greater than approximately 10,000, 100,000 or 1,000,000) and / or cross-linked polyacrylic acid polymer. In certain embodiments, the polymer is a polyacrylic acid polymer, with a viscosity in the range of approximately 15,000 to 100,000, 15,000 to 90,000, 15,000 to 80,000, 20,000 to 80,000, 20,000 to 70,000, 20,000 to 40,000 cP. In a certain embodiment, the polymer is a polymer of high molecular weight and / or cross-linked polyacrylic acid, in which the polyacrylic acid polymer has viscosity in the range of 15,000 to 80,000 cP.
[0117] It is possible to use carbomers. Carbomers are synthetic polymers of high molecular weight acrylic acid, cross-linked with allysaccharose or pentaerythritol alii ether, with a molecular weight of approximately 3 x 10 ⁶ . The gelling mechanism depends on the neutralization of the carboxylic acid portion to form a soluble salt. The polymer is hydrophilic and produces crystalline gels when neutralized. Carbomer gels have good thermal stability, and the viscosity and yield of the gel remain essentially unaffected by temperature. As topical products, carbomer gels have excellent rheological properties. The inherent pseudoplastic flow allows the immediate recovery of viscosity, when the shear is closed and the high yield and rapid breaking make it ideal for dispensing. The aqueous solution of Carbopol® has an acidic nature, due to the presence of carboxylic acid residues. The neutralization of this solution cross-links and gelatinizes the polymer, to form an integral viscous structure with the desired viscosity.
[0118] Carbomers are available as fine and white powders
32/82 cos, dispersible in water to form colloidal acid suspensions (a dispersion of 1% has approximately pH 3) of low viscosity. The neutralization of these suspensions using a base of, for example, sodium, potassium or ammonia hydroxides, low molecular weight amines and alkanolamines, results in the formation of translucent gels. Nicotine salts, such as nicotine chloride from stable water-soluble complexes, with carbomers with a pH of approximately 3.5, and are stabilized at an optimum pH of approximately 5.6.
[0119] In some embodiments of this description, the carbomer is Carbopol. Such polymers are commercially available from B.F. Goodrich or Lubrizol, identified as Carbopol® 71G NF, 420, 430, 475, 488, 493, 910, 934, 934P, 940, 971PNF, 974P NF, 980 NF, 981 NF and the like. Carbopol are versatile polymers with controlled release, as described by Brock (Pharmacotherapy, 14: 430-7, 1994) and Durrani (Pharmaceutical Res., Supp.) 8: S-135 (1991)), and belong to a family of synthetic carbomers, with high molecular weight, non-linear polymers of acrylic acid, cross-linked with a polyalkenyl polyether. In some embodiments, the carbomer is Carbopol® 974P NF, 980 NF, 5984 EP, ETD 2020NF, Ultrez 10 NF, 934 NF, 934P NF or 940 NF. In other modalities, the carbomer is Carbopol® 980 NF, ETD 2020 NF, Ultrez 10 NF, Ultrez 21 or 1382 Polymer, 1342 NF, 940 NF.
[0120] In certain embodiments, the gelling agent contains a hygroscopic material. A hygroscopic material is a substance capable of capturing water, for example, by means of absorption or adsorption, even with low relative humidity, such as 50% at room temperature (for example, 25 ° C). Hygroscopic material may include, without limitation, glucosamine, glycosaminoglycan, poly (vinyl alcohol), poly (2-hydroxyethyl methylacrylate), polyethylene oxide, collagen, chitosan
33/82 na, alginate, a hydrogel based on poly (acrylonitrile), a hydrogel of poly (ethylene glycol) / poly (acrylic acid) interpenetrating polymer network, a polybutylene terephthalate oxide, a polybutylene oxide, a hyaluronic acid, high molecular weight polyacrylic, poly (hydroxyethyl methacrylate), poly (ethylene glycol), tetraethylene glycol diacrylate, polyethylene glycol methacrylate and poly (methylacrylate-co-hydroxyethyl acrylate).
[0121] The biophotonic composition of the present description can be further encapsulated, for example, in a membrane. Such a membrane can be transparent and / or considerably or completely impermeable. The membrane may be impermeable to liquids, but permeable to gases, such as air. In certain embodiments, the composition can form a membrane that encapsulates the chromophores of the topical biophotonic compound, where the membrane can be considerably impermeable to liquids and / or gases.
[0122] The composition can include any other carrier.
[0123] (d) Oxygen releasing agents [0124] In accordance with certain embodiments, the compositions of the present description may optionally also contain an oxygen releasing agent, for example, as an oxygen source.
[0125] When a biophotonic composition of the present description, which contains an oxygen releasing agent, is illuminated with light, the xanthene dyes are excited to a higher energetic state. When the electrons in the xanthene dyes return to a lower energy state, they emit photons with a lower energy level, thus causing the emission of light with a longer wavelength (Stokes deviation). In the proper environment, a part of this energy release is transferred to oxygen or reactive hydrogen peroxide, and causes the formation of oxygen radicals, such as singlet oxygen. It is believed that singlet oxygen and other types of reactive oxygen, generated by the activation of the biophotonic composition,
34/82 operate on a hormone basis. That is, a beneficial health effect provided by the low exposure to a normally toxic stimulus (for example, reactive oxygen), by the stimulation and modulation of the stress response pathways in the cells of the tissues under treatment. The endogenous response to free radicals generated by exogenous (reactive oxygen type) is modulated in an increasing defensive capacity against exogenous free radicals, and induces the acceleration of healing and regeneration processes. In addition, the activation of the composition can also produce an antibacterial effect. The extreme sensitivity of bacteria to exposure to free radicals makes the composition of the present description a truly bactericidal composition.
[0126] As previously stated, the generation of oxygen types by the compound in some modalities is accompanied by microbubbling, which can contribute to the debridement or displacement of biofilms at the application site. This can allow better penetration of the activation light and / or fluorescent light at the treatment site, for example, to deactivate bacterial colonies, leading to a reduction in their number.
[0127] Among the oxygen releasing agents that may be included in the composition are, without limitation, peroxides, such as hydrogen peroxide, urea peroxide and benzoyl peroxide. Peroxide compounds are oxygen-releasing agents that contain the peroxide group (R-O-O-R), which is a chain structure that contains two oxygen atoms, both attached to each other and a radical and some element.
[0128] Hydrogen peroxide (H ₂ O ₂ ) is the starting material for the preparation of organic peroxides. OH ₂ O ₂ is a powerful oxygen-releasing agent, and the property of hydrogen peroxide is that it breaks down into water and oxygen and does not form persistent toxic waste compounds. The hydrogen peroxide to be used in this composition
35/82 can be used in gel form, for example, with 6% hydrogen peroxide. An appropriate concentration range over which hydrogen peroxide can be used in the present composition is approximately between 0.1% and 6%.
[0129] Hydrogen peroxide and urea (also known as urea peroxide, carbamide peroxide or percarbamide) is soluble in water and contains approximately 35% hydrogen peroxide. The carbamide peroxide to be used in this composition can be used as a gel, for example with 16% carbamide peroxide, which represents 5.6% hydrogen peroxide, or 12% carbamide peroxide. A suitable concentration range over which urea peroxide can be used in the present composition is approximately 0.3% to 16%. Urea peroxide breaks down into urea and hydrogen peroxide in slow release, which can be accelerated by heat or photochemical reactions. The released urea [carbamide, (NH ₂ ) CO ₂ )], is highly soluble in water and is a powerful protein denaturant. It increases the solubility of some proteins and increases the rehydration of the skin and mucous membranes.
[0130] Benzoyl peroxide consists of two benzoyl groups (benzoic acid with the H of the carboxylic acid removed) joined by a peroxide group. It is found in acne treatments, in concentrations ranging from 2.5% to 10%. The groups released from peroxide are effective in fighting bacteria. Benzoyl peroxide also stimulates the renewal of skin layers and the cleansing of pores, which further helps in reducing bacterial counts and reduces acne. Benzoyl peroxide breaks down into benzoic acid and oxygen in contact with the skin, none of which are toxic. A suitable concentration range over which benzoyl peroxide can be used in the present composition is approximately 2.5% to 5%.
36/82 [0131] Among the other oxygen-releasing agents are molecular oxygen, water, perbonates and carbonates. Oxygen releasing agents can be supplied as a powder, liquid or gel within the composition. The composition may include an amount of oxygen-releasing agent, which is increased by the independent application of oxygen-releasing agents to the treatment site. [0132] Alternatively, oxygen releasing agents can also be applied to the tissue separately from the composition.
[0133] (e) Healing factors [0134] The composition of the present description may contain healing factors. Healing factors comprise compounds that stimulate or increase the healing or tissue regeneration process at the site of application of the composition. During photoactivation of the composition of the present description, there is an increase in the absorption of the molecules at the treatment site, through the skin, wound or mucosa. An increase in blood flow at the treatment site was observed over longer periods of time. An increase in lymphatic drainage and a possible change in osmotic balance, due to the dynamic interaction of cascades of free radicals, can be reinforced or even intensified with the inclusion of healing factors. Suitable healing factors are, among others:
[0135] Hyaluronic acid (hyaluronan, hyaluronate): it is a non-sulfated glycosaminoglycan, widely distributed through connective, epithelial or neural tissues. It is one of the main components of the extracellular matrix and contributes considerably to the proliferation and migration of cells. Hyaluronan is an important component of the skin, involved in tissue repair. Although it is abundant in extracellular matrices, it contributes to tissue hydrodynamics, cell movement and proliferation and participates in a large amount of surface cell interactions, notably those in
37/82 mainly comprise the CD44 receptor. Hyaluronidase enzymes degrade hyaluronan. There are at least seven types of hyaluronidase-like enzymes in humans, many of which are tumor suppressors. The degradation products of hyaluronic acid, oligosaccharides and hyaluronic acid of very low molecular weight, have pro-angiogenic properties. In addition, recent studies show that hyaluronic fragments, but not the high molecular weight native to hyaluronic, can reduce inflammatory responses in macrophage and dentritic cells in wound tissues. Hyaluronic acid is very suitable for biological applications applied to the skin. Due to its high biocompatibility, it is used to stimulate tissue regeneration. Studies have shown that hyaluronic acid that appears in the early stages of healing creates space for white blood cells that mediate the immune response. It is used in the synthesis of biological structures in applications for wound healing and in the treatment of wrinkles. A suitable concentration range over which hyaluronic acid can be used in the present composition is approximately 0.001% to approximately 3%.
[0136] Glucosamine: it is one of the most abundant monosaccharides in human tissues and a precursor in the biological synthesis of proteins and glycosylated lipids. It is commonly used in the treatment of osteoarthritis. The common form of use of glucosamine is its sulfate salt. Glucosamine has several effects, including anti-inflammatory activity, stimulation of proteoglycan synthesis and the synthesis of proteolytic enzymes. A suitable concentration range over which glucosamine can be used in the present composition is approximately 0.01% to approximately 3%.
[0137] Allantoin: it is a glyoxylic acid diureide. Has keratolytic effect, increases the water content of the extracellular matrix,
38/82 increases the peeling of the upper layers of dead (apoptotic) skin cells and stimulates the proliferation of skin in wound healing.
[0138] (f) Antimicrobials [0139] The composition of this description may contain antimicrobial agents. Antimicrobials kill microbes or inhibit their growth or build-up. Examples of antimicrobials (or antimicrobial agents) are defined in U.S. patent application publications 20040009227 and 20110081530. Suitable antimicrobials for use in the methods of this description include, but are not limited to, dormant phenolic and phenolic compounds, resorcinol and its derivatives, bisphenol compounds, benzoic esters (parabens), halogenated carbonyls, polymeric antimicrobial agents, thiazolines, trichlorometilotimides, natural antimicrobial agents (also called natural essential oils), metal salts and broad spectrum antibiotics.
[0140] Among the specific dormant phenolic and phenolic antimicrobial agents that can be used in the description are, without limitation: phenol; 2-methylphenol; 3-methylphenol; 4-methylphenol; 4-ethylphenol; 2,4dimethylphenol; 2,5-dimethylphenol; 3,4-dimethylphenol; 2,6-dimethylphenol; 4-npropylphenol; 4-n-butylphenol; 4-n-amylphenol; 4-tert-amylphenol; 4-n-hexylphenol; 4-n-heptylphenol; aromatic and mono and polyalkyl halophenols; p-chlorophenyl; methyl p-chlorophenol; ethyl p-chlorophenol; n-propyl p-chlorophenol; n-butyl p-chlorophenol; n-amyl p-chlorophenol; sec-amyl p-chlorophenol; n-hexyl p-chlorophenol; cyclohexyl p-chlorophenol; n-heptyl p-chlorophenol; n-octyl; pchlorophenol; o-chlorophenol; methyl o-chlorophenol; ethyl o-chlorophenol; n-propylchlorophenol; n-butyl o-chlorophenol; n-amyl o-chlorophenol; tert-amylchlorophenol; n-hexyl o-chlorophenol; n-heptyl o-chlorophenol; o-benzyl p-chlorophenol; o-benxyl-m-methyl p-chlorophenol; o-benzyl-m, m-dimethyl-chlorophenol; o-phenylethyl p-chlorophenol; o-phenylethyl-m-methyl p-chlorophenol; 3
39/82 methyl p-chlorophenol 3,5-dimethyl p-chlorophenol, 6-ethyl-3-methyl p-chlorophenol, 6n-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-3,5dimethyl p-chlorophenol; 6-diethylmethyl-3-methyl p-chlorophenol; 6-isopropyl-2-ethyl3-methyl p-chlorophenol; 2-sec-amyl-3,5-dimethyl p-chlorophenol; 2-diethylmethyl-
3,5-dimethyl p-chlorophenol; 6-sec-octyl-3-methyl p-chlorophenol; p-chloro-mcresol p-bromophenol; methyl p-bromophenol; ethyl p-bromophenol; n-propyl pbromophenol; n-butyl p-bromophenol; n-amyl p-bromophenol; sec-amyl pbromophenol; n-hexyl p-bromophenol; cyclohexyl p-bromophenol; obromophenol; tert-amyl o-bromophenol; n-hexyl o-bromophenol; n-propylm, 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; 3,4,5,6tetabromo-2-methylphenol-; 5-methyl-2-pentylphenol; 4-isopropyl-3-methylphenol; para-chloro-metaxylenol (PCMX); chlorothymol; phenoxyethanol; phenoxyisopropanol; and 5-chloro-2-hydroxydiphenylmethane.
[0141] Resorcin and its derivatives can also be used as antimicrobial agents. Specific derivatives of resorcinol include, but are not limited to: resorcinol methyl; ethyl resorcinol; n-propyl resorcinol; n-butyl resorcinol; n-amyl resorcinol; n-hexyl resorcinol; n-heptyl resorcinol; n-octyl resorcinol; n-nonyl resorcinol; phenyl resorcinol; benzyl resorcinol; phenylethyl resorcinol; phenylpropyl resorcinol; p-chlorobenzyl resorcinol; 5-chloro-2,4-dihydroxy diphenyl methane; 4'-chloro-2,4-dihydroxy diphenyl methane; 5-bromo-2,4-dihydroxy diphenyl methane; and 4'-bromo-2,4-dihydroxydiphenyl methane.
[0142] Specific bisphenolic antimicrobial agents that can be used in the description include, among others: 2,2'-methylene bis (4-chlorophenol); 2,4,4'trichloro-2'-hydroxyl-diphenyl ether, marketed by Ciba Geigy, Florham Park, N.J., under the trade name Triclosan®; 2,2'-methylene bis- (3,4,6-trichlorophenol); 2,2'-methylene bis- (4-chloro-6bromophenol); bis- (2-hydroxy-3,5-dichlorophenyl) sulfide; and bis- (2-hydroxy-540/82 chlorobenzyl) sulfide.
[0143] Specific benzoyl esters (parabens) that can be used in the description include, among others: methylparaben; propylparaben; butylparaben; ethylparaben; isopropylparaben; isobutylparaben; benzylparaben; sodium methylparaben and sodium propylparaben.
[0144] Specific halogenated carbanilides that can be used in the description include, among others: 3,4,4'-trichloro carbanilides, such as 3- (4-chlorophenyl) -1- (3,4-dichlorophenyl) urea, sold under the registered trademark Triclocarban® of Ciba-Geigy, Florham Park, NJ; 3trifluoromethyl-4,4'-dichlorobarbanilide; and 3,3 ', 4-trichlorocarbanilide.
[0145] Specific polymeric antimicrobial agents that can be used in the description include, but are not limited to: polyhexamethylene biguanide hydrochloride; and poly (iminoimidocarbonyl iminoimidocarbonyl iminoexamethylene), sold under the registered trademark of Vantocil® IB.
[0146] Specific thiazolines that can be used in the description include, among others, those sold under the trade name MicroCheck®; and 2-n-octyl-4-isothiazolinone-3-one, sold under the trade name Vinyzene® IT-3000 DIDP.
[0147] Specific trichloromethyl thioamides that can be used in the description include, but are not limited to: N- (tricholomethylthio) phthalimide, sold under the brand name Fungitrol®; and N-trichloromethylthio-4-cyclohexene-1,2dicarboximide, sold under the brand name Vancide®.
[0148] Specific natural antimicrobial agents that can be used in the description include, among others, oils from: anise; lemon; orange; Rosemary; wintergreen; thyme; lavender; clove; hop; tea tree; citronella; wheat; barley; lemon grass; cedar leaf; cedar wood; cinnamon; fleagrass; geranium; sandalwood; Violet; Blackberry; eucalyptus; verbena; peppermint; basil; fennel; fir; balm;
41/82 menthol; ocan origanium; hydrastis; carradensis; berberidaceac daceae; Long Ratanhiae; and long turmeric. Also included in this class of natural antimicrobial agents are the basic chemical components of vegetable oils that have been found to provide antimicrobial benefits. These chemicals include, among others: anethole; catechol; camphene; thymol; eugenol; eucalyptol; ferulic acid; farnesol; inoquitiol; tropolene; limonene; menthol; methyl salicylate; coal; terpineol; verbenone; berberine; ratania extract; cariopelene oxide; citronellic acid; curcumin; nerolidol and geraniol.
[0149] Specific metal salts that can be used in the description include, but are not limited to, the metal salts of groups 3a-5a, 3b7b, and 8 of the periodic table. Specific examples of metal salts include, but are not limited to: aluminum; zirconium; zinc; silver; gold; copper; lanthanum; tin; Mercury; bismuth; selenium; strontium; scandium; yttrium; cerium; praseodymium; neodymium; promethium; samarium; europium; gadolinium; terbium; dysprosium; holmium; erbium; thallium; ytterbium; lutetium and combinations of these. An example of the metal-ion-based antimicrobial agent is sold under the brand name HealthShield®, and is manufactured by HealthShield Technology, of Wakefield, Mass, [give other examples here, for example: Silva and Sobrinho] [0150] Antimicrobial agents of broad Specific spectrum that can be used with the description include, but are not limited to, those listed in other categories of antimicrobial agents in this document.
[0151] Among the additional antimicrobial agents that can be used in the methods of the description are, without limitation: pyrithione and, particularly, zinc complexes containing pyrithione, such as the one sold under the trade name Octopirox®; dimethylol dimeyl hydantoin, sold under the trade name Glydant®; methylchlorisothiazolinone / methylisothiazolinone, sold under the trade name Kathon CG®;
42/82 sodium sulfite; sodium bisulfite; imidazolidinyl urea, sold under the brand name Germall 115®; diazolidinyl urea, sold under the brand name Germall 11®; benzyl alcohol v2-bromo-2-nitropropane-1,3diol, sold under the trade name Bronopol®; formalin or formaldehyde; iodopropynyl butylcarbamate, sold under the trade name Polyphase P100®; chloroacetamide; methanamine; methyldibromonitrile glutaronitrile (1,2-dibromo-2,4-dicianobutane), sold under the trade name Tektamer®; glutaraldehyde; 5-bromo-5-nitro-1,3-dioxane, sold under the trade name Bronidox®; phenethyl alcohol; ophenylphenol / sodium o-phenylphenol sodium hydroxymethylglycinate, sold under the trade name Suttocide A®; bicyclic polymethoxy oxazolidine; sold under the trade name Nuosept C®; dimethoxane; timersal; dichlorobenzene alcohol; captan; chlorphenesin; dichlorophen; chlorbutanol; glyceryl laurate; halogenated diphenyl ethers; 2,4,4'-trichloro-2'-hydroxydiphenyl ether, sold under the trade name Triclosan® and available from Ciba-Geigy, Florham Park, N.J .; and 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether. [0152] Additional antimicrobial agents that can be used in the methods of the description include those disclosed by U.S. patent numbers 3,141,321; 4,402,959; 4,430,381; 4,533,435; 4,625,026; 4,736,467; 4,855,139; 5,069,907; 5,091,102; 5,639,464; 5,853,883; 5,854,147; 5,894,042; and 5,919,554 U.S. patent application published under numbers 20040009227 and 20110081530.
[0153] (g) Collagens and agents that promote collagen synthesis [0154] The compositions of the present description may include collagens and agents that promote collagen synthesis. Collagen is a fibrous protein produced in dermal fibroblast cells that forms 70% of the dermis. Collagen is responsible for smoothing and firming the skin. So when collagen synthesis is reduced,
43/82 skin aging occurs and, thus, the firmness and smoothness of the skin is quickly reduced. As a result, the skin will be flabby and wrinkled. On the other hand, if collagen metabolism is activated by stimulating collagen synthesis in the skin, the components of the dermal matrices will be increased, leading to effects such as improved wrinkles, improved firmness and skin strengthening. Thus, collagens and agents that promote collagen synthesis can also be useful in the present description. Agents that promote collagen synthesis (ie, pro-collagen synthesis agents) include amino acids, peptides, proteins, lipids, small chemical molecules, natural products and extracts of natural products.
[0155] For example, it has been discovered that intake of vitamin C, iron and collagen can effectively increase the amount of collagen in the skin and bones. See U.S. patent application publication 20090069217. Examples of vitamin C include an ascorbic acid derivative, such as L-ascorbic acid or sodium L-ascorbate, an ascorbic acid preparation obtained by coating the ascorbic acid with an emulsifier, or the like , and a mixture containing two or more of these C vitamins, at an arbitrary rate. In addition, natural products containing vitamin C, such as acerola and lemon, can also be used. Examples of iron preparation include: an inorganic iron, such as iron sulphate, earthy sodium citrate or ferric pyrophosphate; an organic iron such as heme, ferritin iron or lactoferrin iron; and a mixture containing two or more of these irons, in any proportion. In addition, natural products containing iron, such as spinach or liver, can also be used. In addition, examples of collagen include: an extract obtained from treating bone, skin or the like of a bovine or porcine mammal, with an acid or alkali; a peptide obtained by hi
44/82 drolysis of the extract with a protease such as pepsin, trypsin or chymotrypsin; and a mixture containing two or more of these collagens in an arbitrary proportion. Collagen extracted from plant sources can also be used.
[0156] Additional pro-collagen synthesis agents are described, for example, in U.S. patents 7598291, 7722904, 6203805, 5529769, etc., and in U.S. patent application publications 20060247313, 20080108681, 20110130459, 20090325885,
20110086060, etc.
[0157] Methods of use [0158] The biophotonic compositions of the present description have several uses. Without sticking to the theory, the biophotonic compositions of the present description can stimulate wound healing or tissue repair. The biophotonic compositions of the present description can also be used to treat skin conditions. The biophotonic compositions of the present description can also be used to treat acne. The biophotonic compositions of the present description can also be used to rejuvenate the skin. The biophotonic compositions of the present description can also be used in the treatment of acute inflammation. Therefore, it is the aim of the present description to present a method for providing biophotonic therapy for a wound, in which the method will stimulate wound healing. It is also the aim of the present description to present a method for providing a biophotonic therapy for skin tissues attacked by acne, in which the method is used to treat acne. It is also an objective of the present description to present a method for providing a biophotonic therapy for skin tissues attacked by skin diseases, in which the method is used to treat skin disease. It is also the objective of the present description to present a method for providing a biophotonic therapy for skin tissues, in which the
45/82 method is used in skin rejuvenation.
[0159] In certain embodiments, the present description presents a method for offering biophotonic therapy on wounds, the method comprising: the application (for example, by means of topical application) of a biophotonic composition of the present description at the site of a wound, and illumination of the biophotonic composition using a wavelength light that overlaps an absorption spectrum of the main xanthene dye (eg donor xanthene dye) of the biophotonic composition.
[0160] In yet another aspect, the present description presents a method to stimulate skin rejuvenation. In certain embodiments, the present description presents a method for providing skin rejuvenation, the method comprising: applying (for example, by topical application) a biophotonic composition of the present description to the skin, and lighting the biophotonic composition using a wavelength light that overlaps the absorption spectrum of the main xanthene dye (eg donor xanthene dye) of the biophotonic composition.
[0161] In yet another aspect, the present description presents a method for providing a biophotonic therapy to the diseased skin tissue being treated. In certain embodiments, the present description presents a method for offering a biophotonic therapy for a target skin tissue, the method comprising: the application (for example, through topical application) of a biophotonic composition of the present description on the skin , and lighting the biophotonic composition using a wavelength light that overlaps the absorption spectrum of the main xanthene dye (eg donor xanthene dye) of the biophotonic composition.
[0162] In yet another aspect, the present description presents a method for providing biophotonic therapy to skin tissue
46/82 sick with acne. In certain embodiments, the present description presents a method for offering a biophotonic therapy for skin with acne, the method comprising: the application (for example, by means of topical application) of a biophotonic composition of the present description on the skin, and lighting the biophotonic composition using a wavelength light that overlaps the absorption spectrum of the main xanthene dye (eg donor xanthene dye) of the biophotonic composition.
[0163] In other embodiments, the present description presents a method for treating acute inflammation, the method comprising: topical application of a biophotonic composition of the present description to the skin tissue affected by acute inflammation, and illumination of the biophotonic composition using a wavelength light that overlaps the absorption spectrum of the main xanthene dye (eg donor xanthene dye) of the biophotonic composition.
[0164] The biophotonic compositions suitable for use with the methods of the present description can be selected from any of the modalities of the biophotonic compositions described here. For example, biophotonic compositions useful in the method of the present description can comprise a main xanthene dye, which is subjected to at least a partial photobleaching, under the application of light. The main xanthene dye can be absorbed at wavelengths of approximately 200 nm to 800 nm, 200 nm to 700 nm, 200 nm to 600 nm or 200 nm to 500 nm. In one embodiment, the main xanthene dye absorbs at a wavelength of approximately 200 nm to 600 nm. In some embodiments, the main xanthene dye absorbs light at a wavelength of approximately 200 nm to 300 nm, 250 nm to 350 nm, 300 nm to 400 nm, 350 nm to 450 nm, 400 nm to 500 nm, 450 nm to
47/82
650 nm, 600 nm at 700 nm, 650 nm at 750 nm or 700 nm at 800 nm. The absorption spectrum of the secondary xanthene dye should overlap at least approximately 80%, 50%, 40%, 30% or 20%, with an emission spectrum of the main xanthene dye. In some embodiments, the main xanthene dye has an emission spectrum that overlaps at least 1% to 10%, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70%, with absorption spectrum of the secondary xanthene dye.
[0165] Lighting the biophotonic composition with light can cause the transfer of energy from the primary xanthene dye to the secondary xanthene dye. Subsequently, the secondary xanthene dye can emit energy like fluorescence and / or generate reactive oxygen species. In certain embodiments of the present description, the transfer of energy caused by the application of light is not accompanied by the concomitant generation of heat, or does not result in tissue damage.
[0166] The biophotonic compositions useful for the present methods can be formulated with any carrier. In certain embodiments, the carrier is a gelling agent. The gelling agent may contain, among others, lipids, such as glycerin, glycols such as propylene glycol, hyaluronic acid, glucosamine sulfate, cellulose derivatives (hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose and the like), non-cellulosic polysaccharides (galactomannans, gum, guar gum, gum, guar gum locust bean, gum arabic, sterculia gum, agar, alginates and the like) and acrylic acid polymers.
[0167] In the methods of the present description, any actinic light source can be used. Any type of halogen lamp, LED or plasma or laser arc can be suitable. The main features
48/82 of the appropriate actinic light sources is that they should emit light with a wavelength (or wavelengths) suitable for the activation of one or more chromophores present in the composition. In one embodiment, an argon laser is used. In another embodiment, a phosphate-titanium-phosphate (KTP) laser is used (like a GreenLight ™ laser). In another mode, sunlight can be used. In yet another modality, an LED photocure device is the actinic light source. In yet another embodiment, the actinic light source is a light source with a wavelength between approximately 200 to approximately 800 nm. In yet another modality, the actinic light source is a visible light source with a wavelength between approximately 400 and 600 nm. In addition, the actinic light source must have adequate power density. The power density of non-collimated light sources (LED, halogen or plasma lamps) is in the range of approximately 1 mW / cm ² to approximately 200 mW / cm ² . The appropriate power density of laser light sources is in the range of approximately 0.5 mW / cm ² to approximately 0.8 mW / cm ² .
[0168] In some embodiments of the methods of the present description, light has an energy on the surface of the patient's skin, wound or mucosa, between approximately 1 mW / cm ² to approximately 500 mW / cm ² , 1-300 mW / cm ² , or 1-200 mW / cm ² , where the applied energy depends at least on the condition being treated, the wavelength of the light, the distance of the patient's skin from the light source and the thickness of the biophotonic composition. In certain embodiments, the light on the patient's skin is between approximately 1-40 mW / cm ² , or 20-60 mW / cm ² , or 40-80 mW / cm ² , or 60-100 mW / cm ² , or 80-120 mW / cm ² , or 100-140 mW / cm ² , or 120-160 mW / cm ² , or 140-180 mW / cm ² , or 160-200 mW / cm ² , or 110-240 mW / cm ² , or 110-150 mW / cm ² , or 190-240 mW / cm ² .
49/82 [0169] In some modalities, it is possible to use a mobile device to activate the modalities of the biophotonic composition of the present description, in which the mobile device must be able to emit light with an emission spectrum that overlaps a dye absorption spectrum donor xanthene present in the biophotonic composition. The mobile device can present a screen, through which the light will be emitted and / or the mobile device can emit the light from a flashlight, which can photoactivate the biophotonic composition.
[0170] In some modalities, it is possible to use a television screen or a computer monitor to activate the biophotonic composition, in which the screen can emit light with an emission spectrum that overlaps the absorption spectrum of the xanthene dye donating the biophotonic composition.
[0171] In certain modalities, the main and secondary xanthene dyes can be photoactivated by ambient light, which can be sunlight or other light sources. Ambient light can be considered as general lighting from all directions in a room with no visible light source. In certain embodiments, the main and / or secondary xanthene dyes can be photoactivated by light in the visible range of the electromagnetic spectrum. Exposure times to ambient light can be longer than to direct light.
[0172] In certain modalities, several light sources can be used to activate biophotonic compounds, such as a combination of ambient light and direct LED light.
[0173] The required duration of exposure to actinic light will depend on the surface of the area to be treated, the type of injury, trauma or wound being treated, the power density, the wavelength and the bandwidth of the source. light, the thickness of the biophotonic composition and the distance from the treated area of the light source. The illumination of the area treated by fluorescence can happen in
50/82 question of seconds, or even fractions of seconds, but a prolonged period of exposure is beneficial to explore the synergistic effects of the absorbed, reflected and re-emitted light in the compound of the present description and its interaction with the tissue being treated. In one embodiment, the time of exposure of the actinic light on the tissue, skin or wound in which the biophotonic composition was applied, is a period between 1 minute to 5 minutes. In another modality, the time of exposure of the actinic light on the tissue, skin or wound in which the biophotonic composition was applied, is a period between 1 minute to 5 minutes. In some embodiments, the biophotonic composition is illuminated for a period of between 1 minute and 3 minutes. In certain embodiments, the light is applied for a period of 1-30 seconds, 15-45 seconds, 30-60 seconds, 0.75-1.5 minutes, 1-2 minutes, 1.5-2.5 minutes, 2-3 minutes, 2.5-3.5 minutes, 3-4 minutes, 3.5-4.5 minutes, 4-5 minutes, 510 minutes, 10-15 minutes, 15-20 minutes, 20-25 minutes , or 20-30 minutes. In yet another modality, the actinic light source on the treated area remains in constant motion over the treated area for the appropriate exposure time. In yet another modality, several applications of biophotonic composition and actinic light are made. In some embodiments, the tissue, skin or wound is exposed to actinic light at least two, three, four, five or six times. In some modalities, a new application of the biophotonic composition is made before exposure to actinic light.
[0174] In the methods of the present description, the biophotonic composition can optionally be removed from the treatment site after the application of light. In certain modalities, the biophotonic composition is left on the treatment site for more than 30 minutes, more than an hour, more than 2 hours, more than 3 hours. Can be illuminated by ambient light. To prevent it from drying out, the composition can be covered with a transparent or translucent cover, such as
51/82 a polymer film or an opaque cover, which can be removed before lighting.
[0175] Wounds and wound healing [0176] The biophotonic compositions and methods of the present description can be used to treat and heal wounds. The wounds that can be treated by the biophotonic compositions and methods of the present description include, for example, injuries to the skin and subcutaneous tissues initiated in different ways (for example, bedsores caused by staying in bed for long periods, wounds induced by trauma, wounds induced by conditions such as periodontitis) and with varying characteristics. In certain embodiments, the present description presents biophotonic compositions and methods for the treatment and / or stimulation of the healing of, for example, burns, incisions, excisions, lacerations, abrasions, perforations or penetrating wounds, surgical wounds, bruises, bruises, damages crushing, gunshot wounds, wounds and ulcers.
[0177] The biophotonic compositions and methods of the present description can be used to treat or stimulate the healing of ulcers and chronic skin wounds, which are wounds that have failed to undergo an orderly and timely series of events to produce structural, functional and durable cosmetic. The vast majority of chronic wounds can be classified into three categories, based on aetiology: bedsores, neuropathic ulcers (diabetic foot) and vascular ulcers (venous or vascular).
[0178] In other specific modalities, the present description presents biophotonic compositions and methods for the treatment and / or stimulation of the healing of Grade l-IV ulcers. In certain modalities, the application presents compositions suitable for use in Grade II ulcers, particularly. Ulcers can be classified
52/82 in four degrees, depending on the depth of the wound: i) Grade I: wounds limited to the epithelium; ii) Grade II: wounds that extend into the dermis; iii) Grade III: wounds that extend to the subcutaneous tissue; and iv) Grade IV (or full thickness wounds): wounds to which the bones are exposed (for example, a point of bone pressure such as the greater trochanter or the sacrum).
[0179] For example, the present description presents biophotonic compositions and methods for the treatment and / or stimulation of the healing of diabetic ulcers. Diabetic patients are prone to foot ulcers and other ulcerations, due to both neurological and vascular complications. Peripheral neuropathy can cause alteration or total loss of sensation in the feet or legs. Diabetic patients with advanced neuropathy lose all ability to distinguish whether something is sharp or pointed. Any cuts or trauma to the feet can go completely unnoticed for days or weeks in patients with neuropathy. A patient with advanced neuropathy loses the ability to feel the wound under constant pressure and, consequently, ischemia and tissue necrosis can occur, which can lead to, for example, plantar ulcerations. Microvascular disease is one of the considerable complications in diabetics, which can also lead to ulcerations. In certain embodiments, compositions and methods for treating chronic wounds are presented in this document, in which the chronic wound is characterized by diabetic plantar ulcers and / or vascular complications of diabetes.
[0180] In other examples, the present description presents biophotonic compositions and methods for the treatment and / or stimulation of the healing of pressure ulcers. Pressure ulcers include bedsores, decubitus ulcers and ischial tuberous ulcers, and can cause severe pain and discomfort to the patient. A pressure ulcer
53/82 may occur as a result of long-term pressure applied to the skin. Thus, pressure can be exerted on the patient's skin due to the individual's weight or mass. A pressure ulcer can develop when the blood supply to an area of the skin is blocked or cut off for more than two or three hours. The affected skin area may be red, painful and may necrotize. If left untreated, the skin will open and you may become infected. A bed sore is, therefore, an ulcer that occurs in an area of the skin that is under pressure, for lying in bed, sitting in a wheelchair and / or wearing bandages for a long time. Pressure ulcers can occur when a person is bedridden, unconscious, unable to feel pain or immobile. Pressure ulcers usually occur on bony protrusions in the body, such as the buttock area (in the sacrum or iliac crest), or on the heels of a foot.
[0181] In other examples, the present description presents biophotonic compositions and methods for the treatment and / or stimulation of the healing of acute wounds.
[0182] Additional types of wounds that can be treated by the biophotonic compositions and methods of the present description, include those published by the US patent application published under ^Q 20090220450, incorporated herein for reference purposes.
[0183] Wound healing in adult tissues is a complex repair process. For example, the skin healing process involves recruiting a variety of specialized cells to the wound site, basement membrane deposition, angiogenesis, selective protease activity and reepithelization.
[0184] There are three distinct phases in the wound healing process. First, in the inflammatory phase, which usually occurs from the moment the wound occurs until the first two to five days, platelets are added to the deposit granules, promoting deposition
54/82 fibrin and stimulating the release of growth factors. Leukocytes migrate to the wound site and initiate digestion and transport debris away from the wound. During this inflammatory phase, monocytes are also converted into macrophages, which release growth factors to stimulate angiogenesis and the production of fibroblasts.
[0185] Second, in the proliferative phase, which normally occurs in two days to three weeks, granulation tissue is formed, and epithelialization and contraction begins. Fibroblasts, which are types of cells in this phase, proliferate and synthesize collagen to fill the wound and create a strong matrix in which epithelial cells develop. As fibroblasts reduce collagen, vascularization extends from nearby vessels, resulting in granulation tissue. Granulation tissue usually occurs from the base of the wound. Epithelialization involves the migration of epithelial cells from wound surfaces to seal the wound. Epithelial cells are moved by the need for contact with cells of similar types and are guided by a network of fibrin threads, which works as a grid, where these cells migrate. Contractile cells called myofibroblasts appear in wounds and help with wound closure. These cells present collagen synthesis and contractivity, and are common in granulation wounds.
[0186] Third, in the remodeling phase, the final phase of wound healing, which can occur from three weeks to several years, the collagen in the scar undergoes repeated degradations and resins. During this phase, the tensile strength of the newly formed skin increases.
[0187] However, as the rate of wound healing increases, there is often an associated increase in scar formation. Scarring is a consequence of the healing process in most adult animal and human tissues. Scar tissue
55/82 is not identical to the fabric it replaces, as it is usually of inferior functional quality. The types of scarring include, among others, atrophic, hypertrophic and keloids, as well as healing contractures. Atrophic scars are flat and have a depression under the surrounding skin, like a valley or a hole. Hypertrophic scars are raised scars that remain within the limits of the original lesion, and often contain excessive collagen organized in an abnormal pattern. Keloid scars are raised scars that spread beyond the margins of the original wound and invade the surrounding normal skin, in a specific way to the site, and often contain collagen spirals arranged abnormally.
[0188] In contrast, normal skin consists of collagen fibers arranged in a basket weave pattern, which contributes both to the resistance and the elasticity of the dermis. Thus, to achieve a smoother process in wound healing, a method is needed that not only simulates collagen production, but also does so in order to reduce the formation of scars.
[0189] The biophotonic compositions and methods of the present description stimulate wound healing through the formation of considerably uniform epithelization; collagen synthesis; controlled contraction; and / or reducing the formation of scar tissue. In certain embodiments, the biophotonic compositions and methods of the present description can stimulate wound healing through the formation of considerably uniform epithelization. In some embodiments, the biophotonic compositions and methods described in the present description stimulate collagen synthesis. In some other embodiments, the biophotonic compositions and methods described in the present description encourage controlled contraction. In certain embodiments, the biophotonic compositions and methods described in the present description stimulate wound healing, for example.
56/82 example, by reducing the formation of scar tissue or by accelerating the wound closure process. In certain embodiments, the biophotonic compositions and methods described in the present description stimulate wound healing, for example, by reducing inflammation. In some modalities, the biophotonic composition can be used right after the wound closes to optimize the scar revision. In this case, the biophotonic composition can be applied, at irregular intervals, such as once a week or at intervals considered appropriate by the doctor.
[0190] The biophotonic composition can be soaked in a woven or non-woven material, or in a sponge, and applied as a dressing. A light source, such as LEDs or waveguides, can be placed inside or adjacent to the wound dressing, or the composition, to illuminate the composition. The waveguides can be optical fibers capable of transmitting light, not only from their ends, but also from their bodies. For example, made with polycarbonate or polymethylmethacrylate.
[0191] Auxiliary therapies, which can be topical or systemic, such as antibiotic treatments, can also be employed. Negative pressure assisted wound closure can also be used to assist in wound closure and / or to remove the composition.
[0192] Acne and acne scars [0193] The biophotonic compositions and methods of the present description can also 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 description can be used in the treatment of acne in the pre-emergent or later stages, when the acne lesions are visible. Bland acne, mode
57/82 can be treated with biophotonic compositions and methods. Normally, the initial preemergent states of acne begin with an excessive secretion of sebum or oil from the sebaceous glands, located in the pilosebaceous apparatus. The sebum reaches the surface of the skin through the duct of the hair follicle. The presence of excessive amounts of sebum in the duct and in the skin tends to obstruct or stagnate the normal flow of sebum in the follicular duct, thereby causing thickening and solidification of the sebum, creating a solid plug known as blackhead. In the normal sequence of developing acne, hyperkeratinization of the follicular opening is stimulated, thereby completing the duct block. The usual results are papules, pustules or cysts, often contaminated with bacteria, which cause secondary infections. Acne is particularly characterized by the presence of blackheads, inflammatory papules or cysts. The appearance of acne can vary from mild skin irritation to corrosion and even the development of disfiguring scars. Thus, the biophotonic compositions and methods of the present description can be used for the treatment of irritation, corrosion, development of scars, blackheads, inflammatory papules, cysts, hyperkeratinization and thickening and hardening of the sebum, associated with acne.
[0194] The composition can be soaked or applied to a non-woven material, or to a sponge, and applied as a mask to parts of the body, such as face, body, arms, legs, etc. A light source, such as LEDs or waveguides, can be placed inside or adjacent to the mask or compound, to illuminate the composition. The waveguides can be optical fibers capable of transmitting light, not only from their ends, but also from their bodies. For example, made with polycarbonate or polymethylmethacrylate.
58/82 [0195] The biophotonic compositions and methods of the present description can also be used to treat various types of acne. Some types of acne are, for example, acne vulgaris, cystic acne, atrophic acne, bromide acne, chloracne, acne conglobata, cosmetic acne, detergent acne, epidermal acne, acne aestivalis, acne fulminans, halogenic acne, indurate acne, acne by iodine, keloid acne, mechanical acne, papular acne, ointment acne, premenstrual acne, pustular acne, scurvy acne, scrofulosorum acne, urticated acne, varioliformis acne, venerate acne, propionic acne, acne excoriee, negative acne, acne by steroid and nudolocystic acne.
[0196] Aging and skin rejuvenation [0197] The dermis is the second layer of the skin, containing the structural elements of the skin, the connective tissue. There are different types of connective tissues, with different functions. The elastin fibers give the skin its elasticity and the collagen gives the skin its resistance. [0198] The junction between the dermis and the epidermis is an important structure. The dermoepidermal junction interconnects to form finger-like epidermal ridges. The cells of the epidermis receive their nutrients from the blood vessels present in the dermis. Epidermal ridges increase the surface area of the epidermis that is exposed to these blood vessels and the necessary nutrients.
[0199] Skin aging brings about considerable physiological changes to the skin. The generation of new skin cells is reduced, and the epidermal ridges of the dermoepidermal junction flatten out. Although the number of elastin fibers increases, their structure and consistency are reduced. In addition, the amount of collagen and the thickness of the dermis are reduced as the skin ages.
[0200] Collagen is the main component of the skin's extracellular matrix, providing a structural base. During the aging process, reduced collagen synthesis and insolubilization
59/82 of collagen fibers, contribute to the reduction of the thickness of the dermis and the loss of the biochemical properties of the skin.
[0201] Physiological changes in the skin result in visible symptoms of aging, often called chronological, intrinsic aging and photoaging. The skin becomes dry, the roughness and flaking increase, the appearance becomes less attractive and, most obviously, fine lines and wrinkles appear. Other symptoms or signs of skin aging include, but are not limited to, thin or transparent skin, loss of underlying fat (leading to deep cheeks and eye sockets, as well as noticeable loss of firmness in the hands and neck), bone loss (causing bones shrink and move away from the skin, causing sagging skin), dry skin (which can cause itching), insufficient perspiration to cool the skin, unwanted facial hair, freckles, age spots, spider veins, rough and hardened skin, fine wrinkles that disappear when stretched, loose skin or blemished complexion.
[0202] The dermoepidermal junction is a basement membrane that separates the keratinocytes from the epidermis of the extracellular matrix, which is below the dermis. This membrane consists of two layers: the basal lamina in contact with the keratinocytes and the underlying reticular lamina, in contact with the extracellular matrix. The basal lamina is rich in type IV collagen and laminin, molecules that play a role in providing the structural base and bioadhesive properties for cell fixation.
[0203] Laminin is a glycoprotein that exists only in the basement membranes. It is formed by three polypeptide chains (alpha, beta and gamma) organized in the shape of an asymmetric cross and held together by disulfide bonds. The three chains exist in several subtypes, which result in twelve different isoforms for laminin, including Laminin-1 and Laminin-5.
60/82 [0204] The dermis is anchored in hemidesmosomes, specific points of junction located in the keratinocytes, which consist of aintegrins and other proteins, in the keratinocytes of the basement membrane by type VII collagen fibrils. Laminins, and particularly laminin-5, are the true anchor point between the hemidesmosome transmembrane proteins in the basal keratinocytes and type VII collagen.
[0205] The synthesis of laminin-5 and the expression of collagen VII have been shown to reduce aging skin. This causes the loss of contact between the dermis and the epidermis, and results in the loss of skin elasticity, which becomes flabby.
[0206] Recently another type of wrinkle, usually called expression wrinkle, has been recognized. These wrinkles involve loss of resistance, particularly of the dermis, which makes the skin no longer able to return to its original state when the facial muscles, which produce facial expressions, exert tension on the skin, resulting in the expression wrinkles. .
[0207] The compositions and methods of the present description stimulate skin rejuvenation. In some embodiments, the compositions and methods of the present description stimulate collagen synthesis. In other certain embodiments, the compositions and methods of the present description may reduce, attenuate, delay or even reverse one or more of the signs of skin aging, including, among others, the appearance of fine lines or wrinkles, thin or transparent skin, loss underlying fat (leading to deep cheeks and eye sockets, as well as noticeable loss of firmness in the hands and neck), bone loss (causing bones to shrink and move away from the skin, causing sagging skin), dry skin (which may cause itching), insufficient perspiration to cool the skin, unwanted facial hair, freckles, age spots, spider veins, skin
61/82 rough and hardened, fine wrinkles that disappear when stretched, loose skin or mottled complexion. In some embodiments, the compositions and methods described in the present description can induce the reduction of pore size, increase the modeling of skin subsections and / or increase the translucency of the skin.
[0208] Skin diseases [0209] The biophotonic compositions and methods of the present description can be used to treat skin diseases that include, but are not limited to, erythema, telangiectasia, actinic telangiectasia, psoriasis, skin cancer, pemphigus, sunburn, dermatitis , eczema, skin rashes, impetigo, chronic lichen simplex, rhinophyma, perioral dermatitis, pseudofolliculitis barbae, drug eruptions, erythema multiforme, erythema nodosum, granuloma annulare, actinic keratosis, purpura, alopecia areata, stomatitis, mouth ache, rheumatoid arthritis, rash , ichthyosis vulgaris, yeast infections, parasitic infections, viral infections, herpes simplex, intertrigo, keloids, keratoses, milia, molluscum contagiosum, pityriasis rosea, pruritus, urticaria, vascular tumors and malformations. Dermatitis includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, generalized exfoliative dermatitis and stasis dermatitis. Skin cancer includes melanoma, basal cell carcinoma and squamous cell carcinoma.
[0210] Some skin diseases have various symptoms, including redness, redness, burning, peeling, pimples, papules, pustules, blackheads, macules, nodules, vesicles, blisters, telangiectasia, spider veins, ulcerations, irritations or pains on the surface, itching , inflammation, red, purple or blue spots or discolorations, nevus and / or tumors. Thus, the biophotonic compositions and methods of the present description can be used to treat redness, redness, burning, peeling, pimples, papules, pustules, blackheads, macules, nodules, vesicles, blisters, telan
62/82 giectasia, spider veins, ulcerations, irritations or pains on the surface, itching, inflammation, red, purple or blue spots or discolorations, warts and / or tumors. Acute inflammation can present as pain, heat, redness, sweat and loss of function. It includes the symptoms seen in allergic reactions, such as insect bites, for example, mosquitoes, bees, wasps, reactions to poison ivy, after ablative therapy.
[0211] The composition can be soaked or applied to a non-woven material, or to a sponge, and applied as a mask to treat skin conditions. A light source, such as LEDs or waveguides, can be placed inside or adjacent to the mask or compound, to illuminate the compound. The waveguides can be optical fibers capable of transmitting light, not only from their ends, but also from their bodies. For example, made with polycarbonate or polymethylmethacrylate.
[0212] Kits [0213] The present description also presents kits for the preparation and application of any of the compositions of the present description. The kit may include a topical biophotonic composition of the present description. The composition can include an oxygen releasing agent, present in the approximate amount of 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. The main xanthene dye can be present in an amount of approximately 0.01% to 40% by weight of the composition, and the secondary xanthene dye can be present in an amount of approximately 0.01% to 40% by weight of the composition. In certain embodiments, the main xanthene dye is present in an amount of approximately 0.001% to 0.1%, 0.05% to 1%, 0.5% to 2%, 1% to 5%, 2.5% to 7.5%, 5% to 10%, 7.5% to 12.5%,
63/82
10% to 15%, 12.5% to 17.5%, 15% to 20%, 17.5% to 22.5%, 20% to 25%, 22.5% to 27.5%, 25% 30%, 27.5% to 32.5%, 30% to 35%, 32.5% to 37.5% or 35% to 40% by weight of the composition. In certain embodiments, the secondary xanthene dye is present in the approximate amount of 0.001% to 0.1%, 0.05% to 1%, 0.5% to 2%, 1% to 5%, 2.5% to 7 , 5%, 5% to 10%, 7.5% to 12.5%, 10% to 15%, 12.5% to 17.5%, 15% to 20%, 17.5% to 22.5 %, 20% to 25%, 22.5% to 27.5%, 25% to 30%, 27.5% to 32.5%, 30% to 35%, 32.5% to 37.5% or 35% to 40% by weight of the composition. In certain embodiments, the amount of xanthene dyes can be in the amount of approximately 0.05% to 40.05% by weight of the composition. In certain embodiments, the amount of xanthene dyes can be present in the approximate amount of 0.001% to 0.1%, 0.05% to 1%, 0.5% to 2%, 1% to 5%, 2.5% 7.5%, 5% to 10%, 7.5% to 12.5%, 10% to 15%, 12.5% to 17.5%, 15% to 20%, 17.5% to 22 , 5%, 20% to 25%, 22.5% to 27.5%, 25% to 30%, 27.5% to 32.5%, 30% to 35%, 32.5% to 37.5 % or 35% to 40.05% by weight of the composition.
[0214] In some embodiments, the kit contains more than one composition, for example, a first and a second composition. The main composition may contain the oxygen releasing agent and a secondary composition may contain the xanthene dyes in liquid or powder form. In some embodiments, the kit contains containers comprising the compositions of the present description.
[0215] Compositions can be stored in containers. Containers may be impermeable to light, hermetically sealed and / or leak-resistant. Examples of containers are, among others, syringes, small vials or bags. For example, the container can be a double-chamber syringe, where the contents of the chambers are mixed to expel the compounds from the chambers. In another example, the bag can contain two chambers, separated by a
64/82 fragile membrane. In another example, a component may be in a syringe and may be injected into a container that will contain the secondary component. The container can be a spray can, pressurized or not. The composition can be in liquid or gaseous form.
[0216] The biophotonic composition can also be supplied in a container containing one or more chambers for storing one or more components of the biophotonic composition, and an outlet in communication with the chamber (s) for the discharge of the biophotonic composition a from the container.
[0217] In other modalities, the kit comprises a systemic or topical drug to expand the treatment of the composition. For example, the kit may contain a systemic or topical antibiotic, or a hormone treatment for acne or crack healing.
[0218] Written instructions on how to use the biophotonic composition, according to the present description, can be included in the kit, or can be included in or associated with the containers that comprise the compositions of the present description.
[0219] In certain modalities, the kit may also comprise another component, a plaster. The plaster can be a porous or semi-porous structure, to receive the biophotonic omposition. The plaster may comprise fibrous woven or non-woven materials.
[0220] In certain modalities of the kit, the kit may also comprise a light source, such as a portable light with an appropriate wavelength to activate the chromophore of the biophotonic composition. The portable light can be powered by batteries or rechargeable.
[0221] In some modalities, the kit may also contain one or more waveguides.
[0222] The identification of the equivalent compositions, methods and kits are common knowledge and do not require more than
65/82 what a routine experience, given the explanations of this description. The practice of the description will also be better understood from the following examples, presented here for purposes of illustration, and should not be interpreted as any form of limitation of the description.
[0223] EXAMPLES [0224] The examples below are presented to illustrate the practice of several modalities of the present description. They are not intended to limit or define the entire scope of this description.
[0225] Example 1 - Absorption / emission spectra of fluorescein and eosin Y in a gel [0226] The photodynamic properties of (i) sodium salt of fluorescein at approximately 0.09 mg / ml, (ii) eosin were evaluated Y at approximately 0.305 mg / ml and (iii) a mixture of sodium salt of fluorescein at approximately 0.09 mg / ml and eosin Y at approximately 0.305 mg / ml, all in a gel (containing approximately 12% carbamide peroxide ). A Flexstation 384 II spectrophotometer with the following parameters was used to measure the emitted fluorescence: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0227] The absorption and emission spectra are described in Figures 5A and 5B, which indicate an energy transfer between the chromophores in the combination. In particular, broader absorption and emission spectra were obtained with eosin Y and the combination of chromophores, compared to individual chromophores. This means that the composition with multiple chromophores can be activated with a wider bandwidth of light and that light with multiple chromophores can emit a wider bandwidth of
66/82 light after lighting. In other words, the emission of the composition with multiple chromophores occurred in a wider range of wavelengths, compared to individual chromophores. In this example, the composition emitted light at the green, yellow and blue wavelengths of the visible spectra. Photobleaching of eosin Y was observed during lighting. Furthermore, the results (not shown) indicate that the presence of peroxide in the gel did not affect the absorption and emission spectra. Peroxide is optional in the compositions and methods of the present description.
[0228] Example 2 - Absorption / emission spectra of fluorescein and eosin Y in an aqueous solution [0229] The photodynamic properties of the (i) sodium salt of fluorescein at a final concentration of 0.18 mg / mL, (ii ) eosin Y at approximately 0.305 mg / mL and (iii) a mixture of sodium salt of fluorescein at approximately 0.18 mg / mL and eosin Y at approximately 0.305 mg / mL in an aqueous solution. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0230] The absorption and emission spectra are described in Figures 6A and 6B, which indicate an energy transfer between the chromophores in the combination. In addition, as shown in Figures 5A and 5B, broader emission spectra were obtained with the combination of chromophores and eosin Y, compared to individual chromophores. The composition emitted light at the green, yellow and blue wavelengths of the visible spectra. The difference in the absorption and emission spectra between Examples 1 and 2 can be explained by the optical difference of the medium (gel in Example 1 and solution
67/82 aqueous in this example), as well as possibly the effect of doubling the fluorescein concentration. It can be seen that the addition of fluorescein to eosin Y expands the bandwidth of the peaks of absorption and emission of eosin Y. This makes the combination of several chromophores capable of absorbing a wider range of wavelengths for photoactivation and to emit a wider range of wavelengths, which can provide, at the same time, different therapeutic effects. Photobleaching of eosin Y was observed during lighting.
[0231] Example 3 - Absorption / emission spectra of floxin B and eosin Y in a gel [0232] The photodynamic properties of: (i) floxin B at a final concentration of 0.25 mg / mL, (ii) eosin Y at about 0.05 mg / ml and (iii) a mixture of floxin B (0.25 mg / ml) and eosin Y (0.05 mg / ml), all in a 12% carbamide gel. A Flexstation 384 II spectrophotometer with the following parameters was used to measure the emitted fluorescence: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0233] The absorption and emission spectra are described in Figures 7A and 7B, which indicate an energy transfer between the chromophores in the combination. As before, broader absorption and emission spectra were obtained with the combination of chromophores floxin B and eosin Y, compared to individual chromophores. The compound emitted light at the green, yellow, orange and red wavelengths of the visible spectra.
[0234] Example 4 - Absorption / emission spectra of an aqueous solution of phloxin B and eosin Y [0235] The photodynamic properties of: (i)
68/82 floxin B at a final concentration of 0.25 mg / ml, (ii) eosin Y at about 0.08 mg / ml and (iii) a mixture of floxin B (0.25 mg / ml) and eosin Y (0.08 mg / mL), all in an aqueous solution. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0236] The absorption and emission spectra are described in Figures 8A and 8B, which indicate an energy transfer between the chromophores of the combination. Broader absorption and emission spectra were obtained with the combination of chromophores floxin B and eosin Y, compared to individual chromophores. The composition emitted light at the green, yellow, orange and red wavelengths of the visible spectra.
[0237] Example 5 - Absorption / emission spectra of phloxin B and fluorescein in a gel [0238] The photodynamic properties of: (i) fluorescein at a final concentration of 100 pg / g, (ii) phloxin B at about 100 pg / g and (iii) a mixture of fluorescein (100 pg / g) and phloxin B (100 pg / g), all in a 12% carbamide gel. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0239] The absorption and emission spectra are described in Figures 9A and 9B, which indicate an energy transfer between the chromophores of the combination. In this particular combination of chromophores and at that concentration, two peaks were observed that
69/82 correspond to the emission of fluorescein and phloxin B, in this combination of chromophores, with the highest peak at about an absorption of 577 nm, compared to individual chromophores.
[0240] Example 6 - Absorption / emission spectra of fluorescein and cane rose in a gel [0241] The photodynamic properties of: (i) fluorescein at a final concentration of 100 pg / g, (ii) cane rose at about 100 pg / g and (iii) a mixture of fluorescein (100 pg / g) and phloxin B (100 pg / g), all in a 12% carbamide gel. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0242] The absorption and emission spectra are described in Figures 10A and 10B, which indicate an energy transfer between the chromophores of the combination. In this combination of chromophores in particular and at this concentration, two emission peaks were observed in the combined chromophor composition; the combined compound showed a higher peak at about 580 nm, compared to individual chromophores.
[0243] Example 7 - Absorption / emission spectra of cane rose and eosin Y in a gel [0244] The photodynamic properties of: (i) eosin Y at a final concentration of 0.305 mg / mL, (ii) rose cane at about 0.085 mg / ml and (iii) a mixture of eosin Y (0.305 mg / ml) and cane rose (0.085 mg / ml), all in a 12% carbamide gel. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The ab
70/82 sorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0245] The absorption and emission spectra are described in Figures 11A and 11B, which indicate an energy transfer between the chromophores of the combination. In this particular combination of chromophores and at this concentration, greater absorption was obtained with the combination of chromophores, compared to individual chromophores. The emission spectra of this specific combination have a lower power density than that of eosin Y alone. In the absence of a temperature rise in the compound during or after lighting, this apparent loss of energy can be attributed to the generation of reactive oxygen species (see Example 8 below).
[0246] Example 8 - Eosin and cane rose generate oxygen species [0247] The synergy between the two components, according to the various modalities of this description, was investigated with the preparation of the following:
[0248] 1 - Eosin Y (0.035%) + Bengal rose (0.085%) in 12% carbamide gel.
[0249] 2 - Bengal rose (0.085%) in 12% carbamide gel.
[0250] Rosa cane is known to have high quantum yield in terms of singlet oxygen production in the presence of oxygen releasing agents when photoactivated by green light (the quantum yield of singlet oxygen is approximately 75% in water [Murasecco-Suardi et al, Helvetica Chimica Acta, Vol. 70, pp. 1760-73, 1987 ). Eosin Y is known for its high performance, in terms of fluorescent light emission, when photoactivated, and it can be at least partially activated by blue light, when in a gel. Photoactivated eosin Y has a very low quantum yield
71/82 higher in terms of singlet oxygen production in the presence of oxygen-releasing agents (the quantum yield of singlet oxygen when fully activated is approximately 4% [Gandin et al, Photochemistry and Photobiology, Vol.37, pp.271- 8, 1983 ).
[0251] When eosin Y and cane rose are combined, apparently both chromophores are activated by the same blue light, as evidenced by Figure 12.
[0252] Figure 12, on the left panel, shows a photograph of the composition when viewed under an optical microscope (x250) before exposure to a blue activation light. Very few bubbles were seen in both compositions. After illumination with blue light, there was a dramatic increase in bubbles in the composition that contained a combination of eosin Y and cane rose, but not in the composition that contained only cane rose or only eosin Y (not shown). This suggests that there is a transfer of energy from eosin Y to the cane rose, leading to the formation of oxygen species. Eosin Y alone in a carbamide gel showed properties similar to cane rose. A similar effect was seen with fluorescein and cane rose.
[0253] Example 9 - Variation in the proportions of chromophore concentration [0254] The effect of varying the concentrations of individual chromophores in compounds with multiple chromophores, according to the modalities of the present description, was investigated. The fluorescence emission over time of compositions containing (i) fluorescein - eosin Y and (ii) eosin Y - cane rose is shown in Figures 13A and 13B respectively.
[0255] As can be seen in Figure 13A, the emission properties of the following compositions were investigated: (i) 109 pg / g eosin Y + 10 pg / g fluorescein, (ii) 109 pg / g eosin Y + 100
72/82 pg / g of fluorescein, (iii) 109 pg / g of eosin Y, (iv) 10 pg / g of fluorescein, (v) 100 pg / g of fluorescein, all in a carbamide peroxide gel. A SP-100 spectroradiometer was used to measure the power density spectrum (mW / cm ² versus wavelength) of a photonic signal detected in the various compounds when illuminated by blue light (wavelength approximately 440 nm to 480 nm at a power density of less than 150 mW / cm ² for approximately 5 minutes). Fluorescence is measured as light within the range of 519 nm to 700 nm.
[0256] As can be seen, the fluorescence emitted from all concentrations decreases with time. This decrease is often accompanied by a photobleaching of one or more chromophores in the composition. A higher concentration of fluorescence in a composition with multiple chromophores provides a higher initial emitted fluorescence and that also lasts longer, that is, it has a longer lifetime. For the composition with eosin Y (109 pg / g) and fluorescein (100 pg / g), the initial emitted fluorescence is slightly lower than the composition containing 100 pg / g of fluorescein alone. This can be attributed to the use of energy to form oxygen species (as described in Example 6 above). Therefore, the relative concentrations of chromophores within a composition with multiple chromophores can be varied in order to customize the properties of fluorescence and the resulting oxygen species.
[0257] In Figure 13B, the following compositions were evaluated (i) 109 pg / g of eosin Y + 1 pg / g of cane rose (about 10: 1 ratio), (ii) 109 pg / g of eosin Y + 100 pg / g of cane rose (about 1: 1 ratio), (iii) 109 pg / g of eosin Y, (iv) 1 pg / g of cane rose, (v) 100 pg / g of cane rose , all in a carbamide peroxide gel. The same downward trend observed in Figure 13A was also observed for eosin Y only, eosin Y-1 pg / g pink
73/82 cane, and also eosin Y-10 pg / g cane rose (not shown). It is also possible to observe the very low levels of fluorescence for the two concentrations of cane rose only when activated by blue light. Surprisingly, for the composition of 109 pg / g of eosin Y + 100 pg / g of cane rose constant fluorescence was observed, albeit at a lower level than that of eosin Y alone, and eosin Y + 1 pg / g of cane rose. In this composition, no photobleaching of eosin Y was observed. Without wishing to be bound by theory, it is believed that eosin Y is not photobleaching as in this proportion of eosin Y / cane rose, eosin Y is able to transfer all its absorbed energy to the cane rose, which then emits energy and prevents photodegradation of eosin Y molecules. The peak emission wavelength of the composition 109 pg / g eosin Y + 100 pg / g cane rose is closer to the peak emission wavelength of the cane rose than of eosin y.
[0258] A similar effect of constant fluorescence was observed for a composition containing fluorescein, eosin Y and cane rose in proportions of relative concentration of about 1:10:10 (not shown).
[0259] Example 10 - Absorption / emission spectra of fluorescein, eosin Y and cane rose in a gel [0260] The photodynamic properties of (i) cane rose at approximately 0.085 mg / ml, (ii) sodium salt of fluorescein at approximately 0.44 mg / ml final concentration, (ii) eosin Y at approximately 0.305 mg / ml and (iii) a mixture of (i), (ii) and (iii) in a gel containing approximately 12% carbamide peroxide, according to an embodiment of the present description. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, excitation
74/82 at 460 nm and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0261] The absorption and emission spectra are described in Figures 14A and 14B, which indicate an energy transfer between the chromophores of the combination. As you can see in Figure 14B, the bandwidth of the combination of fluorescein, eosin Y and cane rose is greater than just eosin Y.
[0262] Example 11 - Absorption / emission spectra of fluorescein, eosin Y and cane rose in an aqueous solution [0263] The photodynamic properties of (i) cane rose 0.085 mg / ml, (ii) sodium salt of fluorescein at approximately 0.44 mg / ml in final concentration, (ii) eosin Y at approximately 0.305 mg / ml and (iii) a mixture of (i), (ii) and (iii) in aqueous solution according to one embodiment of this description. A Flexstation 384 II spectrophotometer was used to measure the emitted fluorescence, with the following parameters: fluorescence mode, 460 nm excitation and emission spectra from 465 nm to 750 nm. The absorbance was read using a Synergy HT microplate reader: absorbance mode, spectra between 300 nm and 650 nm.
[0264] The absorption and emission spectra are described in Figures 15A and 15B, which indicate an energy transfer between the chromophores of the combination, in the absence of a peroxide, but in the presence of other oxygen releasing agents (for example, water) .
[0265] Regarding the absorption and emission spectra of the compositions of the present description in a carbamide peroxide gel, the same spectra were obtained for the same chromophores in a gel without the peroxide.
[0266] Example 12 - Angiogenic potential of a composition of
75/82 description [0267] A human skin model was developed to assess the angiogenic potential of the compositions of the present description. Briefly described, a composition containing eosin Y and erythrosine was applied to a human skin model containing fibroblasts and keratinocytes. The skin model and composition were separated by a nylon screen with a pore size of 20 microns. The composition was then irradiated with blue light ("activation light") for 5 minutes at a distance of 5 cm from the light source. The activation light consisted of light emitted from an LED-type lamp, with an average maximum wavelength of approximately 400-470 nm, and a power intensity measured at 10 cm from 7.7 J / cm ² to 11.5 J / cm ² . With the illumination of the activation light, the composition emitted fluorescent light. As the composition was in limited contact with the cells, fibroblasts and keratinocytes were exposed mainly to activation light and fluorescent light emitted from the composition. The conditioned medium from the treated 3D human skin model was then applied to human aortic endothelial cells pre-inserted in Matrigel®. The formation of tubes by endothelial cells was observed and monitored by microscopy and image analysis after 24 hours. The conditioned medium of 3D skin models treated with light illumination induced the formation of endothelial tubes in vitro, suggesting an indirect effect of light treatment (blue light and fluorescence) in angiogenesis through the production of factors by fibroblasts and keratinocytes. Normal and conditioned media from untreated skin samples were used as a control, and did not induce the formation of endothelial tubes.
[0268] Figure 16 is an emission spectrum illustrating the intensity, over time, of the light emitted from the biophotonic composition, measured using the spectroradiometer of Example 9. It is possible
76/82 reasonably infer that other combinations of chromophores that have a comparable emission spectrum also induced angiogenesis. As you can see in Figure 16, the fluorescence light emitted had a wavelength of approximately 520 nm to 620 nm with a peak of approximately 560 nm. A similar emission spectrum was observed using eosin Y and fluorescein (Figure 5B); eosin Y and phloxin B (Figure 7B, Figure 8B); eosin Y and cane rose (Figure 11B); fluorescein, eosin Y and cane rose (Figure 14B, Figure 15B). There are also other possible combinations of chromophores with a similar emission spectrum, and it is reasonable to expect angiogenic properties from these combinations.
[0269] Example 13 - Protein secretion and gene expression profiles [0270] Wounded and non-wounded 3D human skin models (EpiDermFT, MatTek Corporation) were used to assess the potential for triggering distinct protein secretion and expression profiles of a compound of the present description. In summary, a compound containing eosin and erythrosine was applied to 3D models of human skin, with and without wounds, under different conditions (with growth factors [1X], 50% growth factors [0.5X] and no growth factor [0X]). The different conditions produced an uncommitted cure, semi-starvation conditions and starvation conditions, respectively. The skin models and the composition were separated by a nylon screen with a pore size of 20 microns. Each model-composition combination was then irradiated with blue light ("activation light") for 5 minutes at a distance of 5 cm from the light source. The activation light consisted of light emitted from an LED-type lamp, with an average maximum wavelength of approximately 440-470 nm, and a power intensity of 60150mW / cm ² to 5 cm, and a total energy intensity after 5 minutes
77/82 approximately 18-39 J / cm ² . The registered controls consisted of 3D models of skin not illuminated by light.
[0271] Gene expression and protein secretion profiles were measured 24 hours after exposure to light. Cytokine secretion was analyzed by antibody arrays (human antibody array RayBio Human Cytokine), gene expression was analyzed by PCR matrix (PAHS-013A, SABioscience) and cytotoxicity was determined by GAPDH and LDH release. The results (Tables 1 and 2) showed that treatment with light is able to raise the level of secreted protein and gene expression involved in the initial inflammatory phase of wound healing in wounded skin insertions and in non-starvation conditions. In starvation conditions reproducing chronic wounds, there was no increase in the level of secreted inflammatory proteins compared to the control. Interestingly, the effect of light treatment on skin models without wounds had a much less impact on the cellular level than on skin with inserted wounds, which suggests an effect on the cellular level of light treatment. It appears to accelerate the inflammatory phase of the wound healing process. Due to the lack of other types of cells, such as macrophages, in the 3D skin model, the anti-inflammatory response is absent and may explain the delay in wound closure. Cytotoxicity was not observed in light treatments. The eosin y and erythrosin b composition had the same emission properties, as shown in Figure 16. As indicated above, it is reasonable to infer that other combinations of chromophores that have a comparable emission spectrum would also induce protein secretion or expression gene, as shown in this Example.
[0272] Table 1 - List of proteins with statistically considerable differences in the proportions of secretion between groups of
78/82 treated and untreated control on day 3. Two arrows indicate that the rate was more than double.
Medium 1X 0.5X Medium Medium 0X IncreaseENA78 p = 0.04 ΐΐII-1R4 / ST2 p = 0.02 ΐΐMMP3 p = 0.01 ΠMCP-2 p = 0.04 ΐΐ Angiogenin p = 0.03 ΐ CXCL16 p = 0.04 Reduction BMP6 p = 0.01;TNFa p = 0.005 J, BMP6 p = 0.02;
[0273] Table 8 - List of genes with statistically significant difference in the proportion of expression between the treated and untreated control groups, during the first 24 hours. Two arrows indicate that the rate was more than double.
Medium 1X 0.5X Medium Medium 0X Increase CTGF p = 0.02 ΐ ITGB3 p = 0.03 ΐ MMP1 p = 0.03 ΐ MMP3 p = 0.01 ΐ THBS1 P = 0.02 ΐ CTGF P = 0.04 ΐITGB3 p = 0.05 ΐMMP1 p = 0.02 ΐΐMMP10 p = 0.003ΐΐMMP3 p = 0.007 ΐΐMMP8 p = 0.02 ΐΐTHBS1 p = 0.03 ΐ MMP3 p = 0.007 ΐΐLAMA1 p = 0.03 ΐITGA2 p = 0.03ΐ Reduction SAH1 p = 0.009ΠNCAM1 p = 0.05ΠVCAM1 p = 0.03 NCAM1 p = 0.02 U VCAN p = 0.02;LAMC1 p = 0.002 J, COL6A1 p = 0.007 J, MMP7 p = 0.003;
79/82
Π
C0L7A1 ρ = 0.04 ί
CTNNA1 ρ = 0.03 ί
[0274] Example 14 - Eosin Υ and fluorescein induce collagen formation [0275] A composition, according to one embodiment of the present invention, containing 0.01% eosin and 0.01% fluorescein in a carrier matrix (gel 1.8% carbopol), was evaluated for its potential to induce collagen formation. Human dermal fibroblasts were placed in glass bottom plates with wells (MatTek®). There were about 4000 cells per well. After 48 hours, the glass bottom plates were inverted, and the cells were treated by the glass bottom with (i) no light (control), (ii) exposure to sunlight for about 13 minutes at noon (control), (iii) the compound applied to the bottom of the glass well on the other side of the cells (without exposure to light), (iv) the compound applied to the bottom of the glass well on the other side of the cells (exposure to sunlight for about 13 minutes at noon), and (v) the compound applied to the bottom of the glass well on the other side of the cells (exposure to blue light for about 5 minutes). In cases (iii), (iv) and (v), there was no direct contact between the cells and the composition. In cases (iv) and (v), the cells were exposed to the light emitted by the compound of eosin Y and fluorescein, when exposed to sunlight and blue light respectively. At least partial photobleaching was observed in cases (iv) and (v). After treatment, the cells were washed and incubated in a regular medium for 48 hours. A collagen assay was then carried out on the supernatant using the Picrosirius Red method. This method involves adding Syrian red dye solution (Sirius Red)
80/82 in picric acid to the supernatant, incubate with light agitation for 30 minutes and then centrifuge to form a pellet. The pellet was washed, first, with 0.1N HCI and then with 0.5N NaOH to remove the loose dye. After centrifugation, the suspension was read at 540 nm for type I collagen. The results are shown in Table 1.
[0276] Table 1 - Qualitative comparison of type I collagen concentration in human dermal fibroblast supernatant exposed to (i) no light (control), (ii) sunlight for about 13 minutes at noon (control), ( iii) any light emitted from a glass-separated eosin Y and fluorescein compound (no light exposure), (iv) any light emitted from the glass-separated eosin Y and fluorescein compound (exposure to sunlight for about 13 minutes at noon) and (v) the compound applied to the bottom of the glass well, on the other side of the cells (exposure to blue light for about 5 minutes). ++ indicates collagen levels about twice as high as +, and +++ indicates collagen levels about three times as high as +.
No light (control) Sunlight (control) Eosin Y + fluorescein - no light Eosin Y and fluorescein sunlight Eosin Y + fluorescein - light blue Collagen concentration + + Ό277] There was a d statistical difference between collagen levels
no induced by the compound with eosin Y and fluorescein exposed to sunlight and blue light, compared to controls: exposed to sunlight and not exposed to any light.
[0278] Collagen generation is an indicator of a potential for tissue repair, including granule tissue stabilization
81/82 tion and reduction of wound size. It is also related to reducing fine lines, pore sizes, improving texture and tensile strength of intact skin. The emission spectrum of the compound with eosin Y and fluorescein in this example had a single peak emission with a wavelength that varied between about 480 nm and 620 nm. After illumination with sunlight, the peak power density decreased, indicating at least partial photobleaching in 13 minutes, which was also observed by the color change of the compound. The fluorescence / photobleach emission rate was slower when illuminated by sunlight (white light), as compared to compounds with eosin Y and fluorescein (e.g., compounds of Examples 5 and 6) when activated by blue light.
[0279] Example 15 - Selection of the chromophore concentration in the biophotonic composition [0280] The fluorescence spectrum of the compositions with different concentrations of chromophores was investigated by means of a spectroradiometer and a blue activation light (according to Example 9). The example of fluorescence spectrum of eosin Y and fluorescein was shown in Figures 17A and 17B. It has been found that the fluorescence emitted from the chromophore increases rapidly in greater concentration, but decreases to a baseline value, with even more increase in concentration. The activation light that passes through the compound reduces with the increase in the chromophore compound, since more is absorbed by the chromophores. Therefore, the concentration of chromophores in the compounds of the present description can be selected according to a necessary proportion and a level of light activation and tissue fluorescence treatment, from this example. In some modalities, it will be after the rapid increase zone, that is, between 0.5 mg / mL and 1 mg / mL for eosin Y (Figure 17A).
82/82 [0281] Therefore, the concentration can be selected according to the required activation light and fluorescence. In some modalities, it will be after the rapid increase zone, that is, between 0.5 mg / mL and 1 mg / mL for eosin Y (Figure 17A).
[0282] Compositions with a cane rose behave a little differently and become more opaque with increased concentration, which may be due to the formation of bubbles.
[0283] Similarly, the relationship between the power density of the light received by the tissues and the illumination time was investigated. The power density of the activation light was found to be initially low and increased over time. This fact is correlated to the photobleaching of the light-absorbing chromophores and the more activation light passing through the compound in order to reach the tissues. Similarly, the fluorescent light emitted by the composition decreased with time as photobleaching of one or more chromophores occurred. In general, the power density of the light that treats the fabrics gradually increased with the time of illumination.
[0284] It should be considered that the invention is not limited to the modalities particularly described and illustrated in this document, but includes all modifications and variations that fall within the scope of the description as defined in the attached claims.

权利要求:
Claims (16)
[1]
1. Biophotonic composition for topical application in a target tissue, characterized by the fact that it comprises at least a first xanthene dye and a second xanthene dye, in which the first xanthene dye has an emission spectrum that overlaps at least 1% to 10% %, 5% to 15%, 10% to 20%, 15% to 25%, 20% to 30%, 25% to 35%, 30% to 40%, 35% to 45%, 50% to 60%, 55% to 65% or 60% to 70% with an absorption spectrum of the second xanthene dye; and wherein the first and second xanthene dyes are present in the composition at a concentration of approximately 0.001% to 0.5% by weight of the composition.
[2]
2. Biophotonic composition, according to claim 1, characterized by the fact that the emission spectrum covers portions of the visible spectrum selected between: green and yellow; yellow and orange; green, yellow and orange; yellow and red; or orange, yellow and red.
[3]
3. Biophotonic composition, according to claim 1, characterized by the fact that the first and second dyes are Eosin Y and Fluorescein; Eosina Y and Rosa Bengal; Eosin Y and Floxin B; or Fluorescein and Bengal Rose.
[4]
4. Biophotonic composition, according to claim 1, characterized by the fact that the first xanthene dye is Eosin
Y and the second xanthene dye is Fluorescein, in which the biophotonic composition further comprises a third xanthene dye, which is Bengal Rose.
[5]
5. Biophotonic composition, according to claim 1, characterized by the fact that the first xanthene dye is Eosin
Y and the second xanthene dye is Fluorescein, in which the biophotonic composition further comprises a third xanthene dye, which is Erythrosine B.
Petition 870160045479, of 23/08/2016, p. 6/12
2/3
[6]
6. Biophotonic composition according to any one of claims 1 to 5, characterized by the fact that activation by light results in a cascade of energy transfer between the first and second xanthene dyes.
[7]
Biophotonic composition according to any one of claims 1 to 6, characterized by the fact that the first and / or the second xanthene dye absorbs at a wavelength in the visible spectrum range.
[8]
Biophotonic composition according to any one of claims 1 to 7, characterized by the fact that the first xanthene dye absorbs at a wavelength between approximately 400 nm to 500 nm.
[9]
Biophotonic composition according to any one of claims 1 to 8, characterized in that the second xanthene dye absorbs at a relatively longer wavelength than that of the first xanthene dye within the range between approximately 10 nm to 100 nm .
[10]
Biophotonic composition according to any one of claims 1 to 9, characterized by the fact that it further comprises an oxidizing agent.
[11]
11. Biophotonic composition according to any one of claims 1 to 10, characterized by the fact that the first and second xanthene dyes are present in the composition at a concentration between approximately 0.001% to 0.1% or between approximately 0.001% to 0 , 01% by weight of the composition.
[12]
12. Biophotonic composition according to any one of claims 1 to 11, characterized by the fact that it is for use in a method to promote collagen formation or to promote angiogenesis.
[13]
13. Biophotonic composition, according to any one
Petition 870160045479, of 23/08/2016, p. 7/12
3/3 of claims 1 to 12, characterized in that it is for use in a method for modulating the expression of MMP1, MMP3, MMP8, MMP10, MCP-2, IL-1R4 / ST2, ENA78 and TNFa in order to promote tissue repair.
[14]
14. Kit, characterized by the fact that it comprises:
a first component comprising a biophotonic composition, as defined in any one of claims 1 to 13; and optionally a second component comprising an oxidizing agent.
[15]
15. Use of a first chromophore and a second chromophore, where the first and second chromophores are the first and second xanthene dyes, characterized by the fact that it is for the manufacture of a biophotonic composition for the treatment of a skin disease, for the treatment of a wound, or for skin rejuvenation, where the composition is for topical application to a target skin tissue, and the composition has a light absorption spectrum or a light emission spectrum covering a broader range of wavelengths compared to a light absorption spectrum of at least one of the individual chromophores, first and second, when the individual composition and chromophores are illuminated with the same activation light.
[16]
16. Invention, in any form of its embodiments or in any applicable category of claim, for example, product or process or use encompassed by the material initially described, revealed or illustrated in the patent application.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4320140A|1980-10-09|1982-03-16|Sterling Drug Inc.|Synergistic insecticidal compositions|

---

US4647578A|1983-12-02|1987-03-03|Sterling Drug Inc.|Phototoxic insecticidal compositions and method of use thereof|

---

US8974363B2|1997-12-11|2015-03-10|Provectus Pharmatech, Inc.|Topical medicaments and methods for photodynamic treatment of disease|

---

KR20000070747A|1997-02-03|2000-11-25|에프. 아. 프라저, 에른스트 알테르 , 한스 페터 비틀린 , 피. 랍 보프, 브이. 스펜글러, 페. 아에글러|Process for the preparation of fluorescent compositions, fluorescent compositions and their use|

---

US6676655B2|1998-11-30|2004-01-13|Light Bioscience L.L.C.|Low intensity light therapy for the manipulation of fibroblast, and fibroblast-derived mammalian cells and collagen|

---

WO2001012181A1|1999-08-13|2001-02-22|Photogen, Inc.|Improved topical medicaments and methods for photodynamic treatment of disease|

---

US20050008892A1|2002-02-01|2005-01-13|Hiroshi Yamamoto|Fluorescent compositions comprising diketopyrrolopyrroles|

---

US20050059731A1|2003-09-16|2005-03-17|Ceramoptec Industries, Inc.|Erythrosin-based antimicrobial photodynamic therapy compound and its use|

---

US7344701B2|2004-02-03|2008-03-18|Biosearch Technologies, Inc.|Xanthene dyes|

---

US20100266989A1|2006-11-09|2010-10-21|Klox Technologies Inc.|Teeth whitening compositions and methods|

---

EP2338465A1|2005-11-09|2011-06-29|Klox Technologies Inc.|Teeth whitening compositions and methods|

---

CN104707143B|2008-11-07|2018-04-27|克洛克斯科技公司|For the oxidant of wound healing and the composition of light activating agent|

---

PT2453922T|2009-07-17|2017-12-19|Klox Tech Inc|Antibacterial oral composition|

---

GB201200490D0|2012-01-12|2012-02-22|Univ Bath|Wound dressing|

---

US20130281913A1|2012-04-20|2013-10-24|Klox Technologies Inc.|Biophotonic compositions and methods for providing biophotonic treatment|CN104707143B|2008-11-07|2018-04-27|克洛克斯科技公司|For the oxidant of wound healing and the composition of light activating agent|

---

PT2453922T|2009-07-17|2017-12-19|Klox Tech Inc|Antibacterial oral composition|

---

US20130281913A1|2012-04-20|2013-10-24|Klox Technologies Inc.|Biophotonic compositions and methods for providing biophotonic treatment|

---

US11116841B2|2012-04-20|2021-09-14|Klox Technologies Inc.|Biophotonic compositions, kits and methods|

---

CN108310672A|2012-09-14|2018-07-24|克洛克斯科技公司|Beauty bio-photon composition|

---

US20140276354A1|2013-03-14|2014-09-18|Klox Technologies Inc.|Biophotonic materials and uses thereof|

---

KR20160029795A|2013-07-03|2016-03-15|클록스 테크놀로지스 인크.|Biophotonic Compositions Comprising a Chromophore and a Gelling Agent for Treating Wounds|

---

EP3125963B1|2014-04-01|2019-11-20|Klox Technologies Inc.|Tissue filler compositions and methods of use|

---

EP3152250A4|2014-06-04|2018-01-03|Klox Technologies Inc.|Biophotonic hydrogels|

---

AU2015273123A1|2014-06-09|2016-12-22|Klox Technologies Inc.|Silicone-based biophotonic compositions and uses thereof|

---

WO2016041067A1|2014-09-15|2016-03-24|Klox Technologies Inc.|Emissive polymeric matrices|

---

US20170362744A1|2014-10-31|2017-12-21|Klox Technologies Inc.|Photoactivatable fibers and fabric media|

---

JP2016172705A|2015-03-17|2016-09-29|国立大学法人 東京大学|Mint3 inhibitor|

---

BR112018014161A2|2016-01-11|2018-12-11|Klox Tech Limited|biophotonic compositions for treating skin and soft tissue injury having one or both resistant and non-resistant infections|

---

CN109073557A|2016-05-20|2018-12-21|霍华德休斯医学研究所|Photolytic activity fluorogen and internal labeling method|

---

EP3515496A4|2016-09-23|2020-05-20|Klox Technologies Inc.|Biophotonic compositions and methods for reducing scarring|

---

US11207408B2|2016-09-23|2021-12-28|Klox Technologies Inc.|Biophotonic compositions, methods, and kits for inhibiting and disrupting biofilms|

---

AU2018212954A1|2017-01-27|2019-09-12|FB Dermatology Limited|Methods for photobiomodulation of biological processes using fluorescence generated and emitted from a biophotonic composition or a biophotonic system|

---

US20210170027A1|2017-11-17|2021-06-10|Klox Technologies Limited|Biophotonic compositions, methods and kits for enhancing hair growth|

---

EP3710108A4|2017-11-17|2021-08-18|Klox Technologies Limited|Modulation of biophotonic regimens|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-04-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-09| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-04-28| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-09-15| B09B| Patent application refused [chapter 9.2 patent gazette]|

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2020-12-01| B09B| Patent application refused [chapter 9.2 patent gazette]|Free format text: MANTIDO O INDEFERIMENTO UMA VEZ QUE NAO FOI APRESENTADO RECURSO DENTRO DO PRAZO LEGAL |

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201261701502P| true| 2012-09-14|2012-09-14|

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US201261701513P| true| 2012-09-14|2012-09-14|

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US201261701510P| true| 2012-09-14|2012-09-14|

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US201361766611P| true| 2013-02-19|2013-02-19|

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US13/830,488|US20130281913A1|2012-04-20|2013-03-14|Biophotonic compositions and methods for providing biophotonic treatment|

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GB1307157.6A|GB2499921B|2012-04-20|2013-04-19|Biophotonic compositions, kits and methods|

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PCT/CA2013/000395|WO2013155620A1|2012-04-20|2013-04-19|Biophotonic compositions, kits and methods|

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US201361873791P| true| 2013-09-04|2013-09-04|

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PCT/CA2013/000786|WO2014040176A1|2012-09-14|2013-09-13|Chromophore combinations for biophotonic uses|

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