Pharmaceutical delivery compositions and uses thereof

专利摘要:
In some aspects, the disclosure relates to compositions and methods for skin repair and regeneration. In some embodiments, compositions described by the disclosure comprise natural products (e.g., extracts) combined with biotechnological excipient systems, such as bio surfactants, suitable for the repair of compromised skin, such as mucosal tissue (e.g., oral mucosal tissue).
公开号:ES2850277A2
申请号:ES202190041
申请日:2020-01-10
公开日:2021-08-26
发明作者:Marcelo Buzzi
申请人:Innovacorium Inc；
IPC主号:

专利说明:

[0002] Pharmaceutical Administration Compositions and Uses Thereof
[0004] Related requests
[0006] This application claims the benefit provided under 35 USC 119 (e) from the filing date of the US provisional application serial number 62 / 791,005, filed on January 10, 2019, entitled "DRUG DELIVERY COMPOSITIONS AND USES THEREOF ' (COMPOSITIONS FOR THE ADMINISTRATION OF DRUGS AND THE USES OF THEM), the full content of which is incorporated herein by reference.
[0008] Background
[0010] Treatments for damaged tissue, such as mucous membranes or skin, often include topical or systemic administration of therapeutic agents (eg, antibacterial drugs) combined with wound dressing and mechanical or enzymatic debridement. Although these treatments are typically sufficient to promote the healing of small cuts and infections, more severely damaged tissues, such as chronic wounds, infected skin, etc., are not usually adequately cared for by these modalities. A major challenge of current methods is to provide a microenvironment for tissue that is refractory for microbial growth and creates molecular conditions that promote tissue healing and regeneration.
[0012] Summary
[0014] Aspects of the disclosure relate to compositions and methods useful for treating damaged skin. The disclosure is based, in part, on drug delivery compositions (systems) comprising one or more of each of the following: a surface activating agent (eg, a surfactant), a hydrating agent (eg, a hygroscopic agent) and a carbonate-based buffer that maintains the pH of the composition between about 7.5 and 9.5. Without wishing to be bound by any specific theory, when administered to the damaged tissue (eg, skin, mucous tissue, etc.) of an individual (eg, a human individual), the compositions disclosed by the disclosure provide a microenvironment that promotes tissue healing and regeneration by simultaneously providing: 1) molecular debridement; 2) adequate hydration; and 3) anti-inflammatory and antimicrobial activity (eg, removal of bacterial biofilm as a result of breakdown of the exopolymeric polysaccharide support structure). In some embodiments, the properties and / or activities of the compositions disclosed by the disclosure are surprising in light of currently available wound healing compositions, which typically have pH values in the neutral range (e.g., pH about 7.0 ) to acidic (eg, pH about 5.0-6.0).
[0016] As a consequence, in some aspects, the disclosure provides a composition comprising a drug delivery system comprising a carbonate buffer solution, at least two different bio-surfactants, at least one hygroscopic agent, and at least one antioxidant; and at least one bioactive agent, wherein the composition has a pH ranging from about 7.5 to about 9.5.
[0018] In some embodiments, a carbonate buffer solution comprises one of the following ions: sodium, potassium, calcium, and magnesium. In some embodiments, a carbonate buffer solution is a sodium bicarbonate buffer solution.
[0020] In some embodiments, the biosurfactants in the composition are selected from a polymeric glycolipid, lipopeptide, and biosurfactant.
[0022] In some embodiments, a glycolipid is selected from a rhamnolipid, sophoolipid, trehalolipid, cellobiolipid, mannosylerythritol lipid, and any combination thereof. In some embodiments, the biosurfactants comprise at least one rhamnolipid and at least one sophoolipid.
[0024] In some embodiments, a lipopeptide is selected from a surfactin, plipastatin, bazillomycin, fengicin, subtilisin, gramicidin, polymyxin, and any combination thereof.
[0026] In some embodiments, a polymeric biosurfactant is selected from emulsane, biodispersan, liposan, mannan-lipid-protein complex, carbohydrate-lipid-protein complex, and any combination thereof.
[0027] In some embodiments, the total amount of the biosurfactants in a composition ranges from about 1.5% (w / w) to 10% (w / w). In some embodiments, the ratio of rhamnolipid to sophoolipid in a composition ranges from about 1: 9 (eg, 1% (w / w) to 99% (w / w)) to about 9: 1 (eg , 99% (w / w) to 1% (w / w)). In some embodiments, the ratio is about 50% to 50% (eg, 1: 1).
[0029] In some embodiments, a hygroscopic agent comprises an agent selected from a glycol polymer, glycosoaminoglycan, and a cellulosic polymer. In some embodiments, a glycol polymer comprises a polyethylene glycol glycol polymer wherein, optionally, the polyethylene glycol glycol polymer comprises between 2 polymer subunits and about 50,000 polymer subunits. In some embodiments, a glycosaminoglycan is hyaluronic acid. In some embodiments, a cellulosic polymer comprises carboxymethyl cellulose or hydroxyethyl cellulose. In some embodiments, the amount of the hygroscopic agent in the composition ranges from about 1% (w / w) to about 10% (w / w).
[0031] In some embodiments, at least one antioxidant in the composition is a lipophilic antioxidant. In some embodiments, a lipophilic antioxidant is butylated hydroxytoluene (BHT), butylated hydroxybutylanisol (BHA), and / or a tocopherol. In some embodiments, a tocopherol is alpha-tocopherol.
[0033] In some embodiments, a composition comprises at least one bioactive agent. In some embodiments, a bioactive agent is a bioactive small molecule, protein, nucleic acid, or extract.
[0035] In some embodiments, a bioactive extract is made (eg, extracted) from one or more types of propolis (eg, a mixture of propolis). In some embodiments, a propolis (eg, propolis mixture) comprises green propolis, brown propolis, red propolis, or a combination thereof (eg, green and brown propolis, red, green and brown propolis, etc.). In some embodiments, a natural bioactive extract (eg, a propolis extract) comprises one or more of the following: a flavonoid, artepilin C, triterpenoid, isoflavone, and aromatic acid. In some embodiments, the ratio of green propolis to brown propolis in a composition ranges from about 1: 9 to about 9: 1. In some embodiments, the total amount of bioactive extract of Propolis in a composition ranges from about 5% (w / w) to about 20% (w / w).
[0037] In some embodiments, a natural bioactive extract is obtained (eg, extracted) from one or more types of seaweed (eg, a mixture of seaweed). In some embodiments, one or more types of seaweed are selected from the genera Enteromorpha, Ulva, Monostroma, Codium, Caulerpa, Bryopsis, Porphyra, and Laminaria. In some embodiments, a natural bioactive extract (eg, seaweed extract) comprises one or more sulfated polysaccharides. In some embodiments, one or more sulfated polysaccharides are selected from carrageenan, galactan, ulvan, and fucoidan. In some embodiments, the bioactive extract further comprises Aloe vera extract. In some embodiments, the total amount of bioactive seaweed extract in a composition ranges from about 5% (w / w) to about 20% (w / w).
[0039] In some embodiments, a natural bioactive extract comprises one or more carotenoids and / or vitamin A (or a derivative thereof). In some embodiments, a bioactive extract comprising carotenoids is obtained (eg, extracted) from carrot oil. In some embodiments, a natural bioactive extract of carrot oil comprises one or more complexes of vitamin B. In some embodiments, one or more complexes of vitamin B are a derivative of pantothenic acid or a derivative or analog thereof. In some embodiments, a vitamin B complex comprises dexpanthenol. In some embodiments, the total amount of natural bioactive carrot oil extract in a composition ranges from about 1% (w / w) to about 5% (w / w).
[0041] In some embodiments, a composition further comprises one or more proteins (eg, animal proteins, extracellular matrix proteins, etc.). In some embodiments, the protein comprises collagen, albumin, or a combination thereof.
[0043] In some embodiments, a natural bioactive extract is obtained (eg, extracted) from a plant. In some embodiments, a natural bioactive extract is obtained (eg, extracted) from Melissa officinalis. In some embodiments, a natural bioactive extract of Melissa officinalis comprises one or more vitamin B complexes. In some embodiments, one or more vitamin B complexes comprise methylcobalamin and / or cyanocobalamin. In some embodiments, the one or more vitamin B complexes are a derivative of pantothenic acid or a derivative or analog thereof, where optionally the vitamin B complex comprises dexapanthenol. In some embodiments, the total amount of natural bioactive extract of Melissa officinalis in a composition ranges from about 1% (w / w) to about 5% (w / w).
[0045] In some embodiments, a composition as described by the disclosure is formulated as a solid (eg, powder, such as lyophilized powder), liquid, gel (eg, a hydrogel), or foam. In some embodiments, a liquid is a mouthwash. In some embodiments, a gel or foam is formulated as an aerosolized spray or a hydrogel. In some embodiments, a composition as described by the disclosure is presented on or on a solid substrate. In some embodiments, a solid substrate comprises cotton fibers. In some embodiments, a solid substrate is a cotton bandage or mask.
[0047] In some embodiments, the disclosure provides a solid substrate comprising a composition as described herein. In some embodiments, a kit further comprises one or more elastic bandages. In some embodiments, the composition is formulated as a foam, gel, or liquid.
[0049] In some embodiments, a solid substrate comprises cotton fibers. In some embodiments, a solid substrate is a bandage (eg, a non-adhesive bandage) or a mask (eg, a cotton face mask).
[0051] In some aspects, the disclosure provides a kit comprising a composition as described herein and a non-adherent wound dressing. In some embodiments, a non-adherent wound dressing comprises cotton fibers.
[0053] In some aspects, the disclosure provides a kit comprising a composition as described herein and one or more antiviral agents effective to treat a herpes simplex virus.
[0055] In some embodiments, one or more antiviral agents are selected from acyclovir, valacyclovir, and famciclovir. In some embodiments, the herpes simplex virus is cold sore (HSL). In some embodiments, the composition, the antiviral agent, or a combination thereof are formulated for topical administration.
[0057] In some aspects, the disclosure provides a method of treating lesions in the oral cavity of an individual (eg, a human individual), the method comprising administering a composition as described herein to an individual with one or more more lesions in the oral cavity.
[0059] In some embodiments, an individual has, or is suspected of having, mucositis. In some embodiments, an individual was previously administered chemotherapy, radiation therapy, or a combination of chemotherapy and radiation therapy. In some embodiments, an individual has undergone oro-maxillofacial surgery.
[0061] In some embodiments, the composition is administered directly into the individual's oral cavity. In some embodiments, administration is via oral spray or mouthwash. In some embodiments, an individual is administered the composition more than once per day (eg, 2, 3, 4, or more times per day). In some embodiments, the composition is administered to the individual before a meal, after a meal, or before and after a meal. In some embodiments, administration of the composition inhibits the formation and / or development of the bacterial biofilm.
[0063] In some aspects, the disclosure provides a method comprising administering a composition as described herein to the skin of an individual in need thereof.
[0065] In some embodiments, the individual's skin has undergone a cosmetic procedure. In some embodiments, the cosmetic procedure is a laser skin peel.
[0067] In some embodiments, the individual's skin is damaged. In some embodiments, the damaged skin is a wound (eg, surgical incision, etc.), ulcer, or blister.
[0069] In some embodiments, administration comprises contacting the individual's skin with a solid substrate that comprises the composition. In some embodiments, the solid substrate is a non-adhesive bandage or a cotton face mask.
[0070] In some embodiments, the composition is administered topically. In some embodiments, administration occurs at least 1,2,3,4,5,6,7,8,9 or 10 times per day. In some embodiments, administration occurs at least 1,2,3,4,5,6,7,8,9 or 10 times per week.
[0072] In some embodiments, an individual has, or is suspected of having, diabetes (eg, type 1 diabetes or type II diabetes). In some embodiments, the individual has a chronic wound resulting from diabetes or impaired skin resulting from insufficient blood flow, for example, varicose veins or a pressure sore. In some embodiments, the individual has, or is suspected of having, a diabetic ulcer, eg, a diabetic foot ulcer.
[0074] In some embodiments, an individual is infected or suspected of being infected with a herpes simplex virus. In some embodiments, the virus is cold sore.
[0076] In some aspects, the disclosure provides a method of regenerating a peripheral nerve ending in an individual in need thereof, the method comprising administering to the individual: a first composition comprising a bioactive extract of Melissa officinalis ; and a second composition comprising methylcobalamin and / or cyanocobalamin.
[0078] In some embodiments, the first and second compositions are administered as a single composition. In some embodiments, the first and / or second composition is administered topically.
[0080] In some embodiments, the individual's skin is damaged. In some embodiments, the damaged skin is a wound, ulcer, or blister. In some embodiments, the individual is infected or suspected of being infected with a herpes simplex virus. In some embodiments, the herpes simplex virus is cold sore.
[0082] Brief description of the drawings
[0084] Figure 1 shows representative data for the efficacy of tissue repair formulations against 3-day S. aureus MRSA biofilms. Both daily and single applications were evaluated. Note that the data are presented as microbial survivors. Ex = excipient.
[0085] Figure 2 shows representative data for the efficacy of formulations for tissue repair against 3-day P. aeruginosa biofilms. Both daily and single applications were evaluated. Note that the data are presented as microbial survivors. Ex = excipient.
[0087] Figure 3 shows representative data for the efficacy of formulations for tissue repair against 3-day C. albicans biofilms. Both daily and single applications were evaluated. Note that the data are presented as microbial survivors. Ex = excipient.
[0089] Figure 4 shows a schematic diagram depicting wound sites in the dorsal region of randomly selected pigs for each treatment.
[0091] Figure 5A-5H are photographs depicting the full thickness excisional wound healing process in pig skin with various treatment and control. Figure 5A shows data for formulation A. Figure 5B shows data for formulation B. Figure 5C shows data for formulation C. Figure 5D shows data for formulation D. Figure 5E shows data for saline control (SALT). Figure 5F shows data for PluroGel. Figure 5G shows data for Medihoney. Figure 5H shows data for Amerigel.
[0093] Figure 6 shows the percent reduction in wound area from the wound healing compositions and saline control treatments. A, formulation A; B, formulation B; C, formulation C; D, formulation D; PG, Plurogel; MH, Medihoney; AMG; Amerigel; SAL, saline control.
[0095] Detailed description
[0097] Chronic wounds that do not heal through the normal wound healing pattern and remain in a state of chronic inflammation are often a hostile microenvironment rich in protease and pro-oxidant. Such a microenvironment tends to promote the degradation of developmental factors and the overproduction of reactive oxygen species (ROS), resulting in more tissue damage and slower tissue repair. Microbes present in the wound also contribute to the repair of damaged tissue.
[0098] The disclosure relates to drug delivery systems and drug compositions for promoting wound healing and tissue generation. The disclosure is based, in part, on drug delivery compositions (systems) comprising one or more of each of the following: a surface activating agent (eg, a surfactant), a hydrating agent (eg, a hygroscopic agent) and a carbonate-based buffer that maintains the pH of the composition between about 8.0 and 9.5. In some embodiments, a composition further comprises one or more at least one bioactive agent.
[0100] Without wishing to be bound by any particular theory, when administered to impaired tissue (eg, skin, mucous tissue, etc.) of an individual, the compositions disclosed by the disclosure provide a microenvironment that promotes tissue healing and regeneration while simultaneously providing : 1) molecular debridement; 2) adequate hydration; and 3) anti-inflammatory and antimicrobial activity. For example, in some embodiments, the compositions disclosed by the disclosure promote the removal of bacterial biofilm as a result of disruption of the exopolymeric polysaccharide support structure. In some embodiments, the properties and / or activities of the compositions disclosed by the disclosure are surprising in light of currently available wound healing compositions, which typically have pH values in the range of neutral (eg, about pH 7) to acidic (eg, pH about 5.0-6.0).
[0102] As a consequence, in some aspects, the disclosure provides a composition comprising a drug delivery system comprising a carbonate buffer solution, at least two different bio-surfactants, at least one hygroscopic agent, and at least one antioxidant; and at least one bioactive agent, wherein the composition has a pH ranging from about 8.0 to about 9.5.
[0104] Surface tension regulating agents
[0106] The disclosure relates, in part, to compositions comprising one or more surface tension regulating agents. In some embodiments, a surface tension regulating agent is a surfactant.
[0108] Generally, a composition as described herein may comprise one or more surfactants (eg, 1,2,3, 4, 5, 6, 7, 8, 9, 10, or more than 10 surfactants). In some embodiments, each surfactant in a composition is selected from a bio-surfactant, anionic surfactant, zwitterionic surfactant, or nonionic surfactant. In some embodiments, a composition as described herein lacks (eg, does not comprise) a surfactant.
[0110] In some embodiments, at least one surfactant is a bio-surfactant. As used herein, a "biosurfactant" refers to surfactant biomolecules produced by microorganisms (eg, certain bacterial cells) that reduce cell surface tension (eg, the surface tension of cell membranes, such as cell membranes). mammalian cells).
[0112] Examples of biosurfactants include, but are not limited to, glycolipids (eg, rhamnolipids, sophoolipids, trehalolipids, celobiolipids, mannosyrythritol lipids, etc.), lipopeptides (eg, surfactin, plipastatin, bacillomycin, phengicin, subtilisin, gramycin, phengicin, subtilisin, gramycin. polymyxins etc.) and polymeric biosurfactants (eg emulsan, biodispersan, liposan, mannan-lipid-protein, carbohydrate-lipid-protein, etc.). In some embodiments, a biosurfactant is selected from a glycolipid, lipopeptide, and polymeric biosurfactant.
[0114] In some embodiments, the biosurfactants in the present disclosure herein are one or more biosurfactants selected from glycolipids. Glycolipids are carbohydrates linked to long-chain aliphatic acids or hydroxyaliphatic acids by an ester group. Examples of glycolipids include, but are not limited to, rhamnolipids, trehalolipids, and sopho-lipids. In some embodiments, the glycolipids are produced by Pseudomonas aeruginosa bacterial cells.
[0116] As used herein, "rhamnolipid" refers to glycolipids, in which one or two molecules of rhamnose are attached to one or two molecules of hydroxydecanoic acid. In some embodiments, a rhamnolipid is 3- [3 - [(2R, 3R, 4R, 5R, 6S) -3,4,5-trihydroxy-6-methyloxane-2-yl] oxydecanoyloxy] decanoic acid, also referred to as " Ramnolipid R1 "herein.
[0118] As used herein, "soporolipid" refers to glycolipids that are produced by yeast and consists of a carbohydrate dimeric soporose linked to a long chain hydroxyl fatty acid via glycosidic linkages. Sophoolipids can comprise a mixture of at least six to nine sophoolipids different hydrophobic. In some embodiments, a sophoolipid is a lactone form of the sophoolipid. In some embodiments, a sophorolipid is the acid (E) -17 - [(2R, 3R, 4S, 5S, 6R) -6- (acetyloxymethyl) -3 - [(2S, 3R, 4S, 5S, 6R) -6 - (acetyloxymethyl) -3,4,5-trihydroxyoxan-2-yl] oxy-4,5-dihydroxyoxan-2-yl] oxyoctadec-9-enoic.
[0120] In some embodiments, a composition comprises a combination of surfactants, such as a rhamnolipid and a sophoolipid (eg, at least one rhamnolipid and at least one sophoolipid). The relative amounts (eg, ratio) of surfactants (eg, a rhamnolipid and a soforo-lipid) in a composition can vary. In some embodiments, the ratio of a rhamnolipid to a sophorolipid ranges from about 1: 9 to about 9: 1 (eg, any ratio between 1: 9 and 9: 1, eg, 1: 1,2: 8 , 8: 2, 7: 3, 3: 7, 6: 4, 4: 6, etc.).
[0122] The ratio or amount of biosurfactants in a composition (for example, ratio of rhamnolipid to sophoolipid) can be measured, for example, by weight% (w / w), volume% (v / v), concentration molar, etc. in relation to the total composition.
[0124] The total amount of biosurfactants in a composition can vary. In some embodiments, the total amount of biosurfactants in a composition ranges from about 0.1% (w / w) to about 8% (w / w). In some embodiments, the total amount of bio-surfactants in a composition is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7% , 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7% , 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7% , 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7% , 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7% , 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7% , 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7% , 7.8%, 7.9% or approximately 8.0%. In some embodiments, a composition as described herein does not contain a biosurfactant.
[0126] In solution, depending on the concentration and the temperature, the surfactants structurally form a spherical micelle called a "unimer". The structure of the micelle changes over time, breaking and expanding to form a multimer. In some embodiments, the unimers are configured to continuously trap wound debris, creating a rinsing action. As the surfactant reduces the surface tension between the wound bed and a cleansing liquid, the cleansing liquid comes into intimate contact with the wound bed. This facilitates the removal of non-viable loose tissue and microbial particles from the viable wound bed, thereby inhibiting (eg, preventing) biofilm formation and aiding in the eradication of older, recalcitrant biofilms. In some embodiments, surfactants break down and prevent biofilm reformation after debridement. In some embodiments, the presence of high tensile strength biomolecules, such as the rhamnolipid and sopho-lipid biotensurfactants described herein, promotes biochemical microdebridement that causes effective disruption in the polysaccharide matrix of the bacterial biofilm and removal of devitalized and necrotic tissues resulting from cell damage.
[0128] In some embodiments, the compositions described by the disclosure comprise one or more anionic surfactants. Examples of anionic surfactants include soaps, alkylbenzene sulfonates, alkyl sulfonates, alkyl sulfates, fluorinated fatty acid salts, silicones, fatty alcohol sulfates, polyoxyethylene fatty alcohol ether sulfates, alpha-olefin sulfonate, phosphate ether of polyoxyethylene fatty alcohol, alkyl alcohol amide, alkylsulfonic acid acetamide, alkylsuccinate sulfonate salts, amino alcohol alkylbenzene sulfonates, naphthenates, alkylphenol sulfonate, and polyoxyethylene monolaurate.
[0130] The total amount of anionic surfactants in a composition can vary. In some embodiments, the total amount of anionic surfactant in a composition ranges from about 0.1% (w / w) to about 8% (w / w). In some embodiments, the total amount of bio-surfactants in a composition is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7% , 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7% , 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7% , 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7% , 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7% , 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7% , 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7% , 7.8%, 7.9% or approximately 8.0%. In some embodiments, a composition as described herein lacks (eg, does not comprise) an anionic surfactant.
[0132] In some embodiments, the compositions described by the disclosure comprise one or more nonionic surfactants. Examples of nonionic surfactants include polyethylene glycol alkyl ethers (Brij), octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, polypropylene glycol alkyl ethers, alkyl glucoside ethers, decylglucoside, polyethylene glycol ethers, octylenglycol ethers, polyalkylenglycoside ethers, polyalkylenglycoside ethers , glycerol alkyl esters, glyceryl laurate, polyoxyethylene glycol sorbitan alkyl esters, sorbitan alkyl esters, cocamide MEA, cocamide DEA, polyethylene glycol and polypropylene glycol block copolymer: poloxamers, tallowamine POethoxylateEA.
[0134] The total amount of nonionic surfactants in a composition can vary. In some embodiments, the total amount of nonionic surfactants in a composition ranges from about 0.1% (w / w) to about 8% (w / w). In some embodiments, the total amount of nonionic surfactants in a composition is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0, 7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1, 7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2, 7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3, 7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4, 7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5, 7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6, 7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7, 7%, 7.8%, 7.9%, or approximately 8.0%. In some embodiments, a composition as described herein lacks (eg, does not comprise) a nonionic surfactant.
[0136] A composition can also include one or more zwitterionic surfactants. Examples of zwitterionic surfactants include, but are not limited to, synthetic zwitterionic surfactants (eg, one or more hydroxysultaines) and / or naturally occurring zwitterionic surfactants (eg, one or more betaines, phosphatidylcholines, and / or components lecithin). In some embodiments, the zwitterionic surfactant is cocamidopropyl betaine.
[0138] The total amount of zwitterionic surfactants in a composition can vary. In some embodiments, the total amount of zwitterionic surfactants in a composition ranges from about 0.1% (w / w) to about 8% (w / w). In some embodiments, the total amount of zwitterionic surfactants in a composition is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7 %, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7 %, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,, 6%, 2.7%, 2.8%, 2.9%, 3.0%,, 1%, 3, 2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%,, 0%, 4.1%, 4.2 %, 4.3%, 4.4%,, 5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2% , 5.3%,, 4%, 5.5%, 5.6%, 5.7%, 5.8%,, 9%, 6.0%, 6.1%, 6.2%, 6 , 3%, 6.4%, 6.5%, 6.6%, 6.7%,, 8%, 6.9%, 7.0%, 7.1%, 7.2%,, 3 %, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, or approximately 8.0%. In some embodiments, a composition as described herein lacks (eg, does not comprise) a zwitterionic surfactant.
[0140] Buffer / pH systems
[0142] Currently used skin care compositions typically have a pH close to the natural pH of human skin (e.g. pH 6.8-7.0) or slightly more acidic than the pH of human skin (e.g. pH 5.0-7.0). The disclosure is based, in part, on compositions that have a pH greater than 7 (eg, more basic or alkaline than neutral), which provides a microenvironment that promotes tissue healing and regeneration. In some embodiments, the healing and / or regeneration activity of compositions described by the disclosure is surprising in view of the more basic pH of the compositions compared to typical wound care products.
[0144] The pH of a composition as described by the disclosure ranges from about 7.5 to about 10.0. In some embodiments, the pH of a composition described by the disclosure ranges from about 8.0 to about 9.5. In some embodiments, the pH of a composition disclosed by the disclosure is about 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8, 3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0). Methods for measuring the pH of a composition are known, for example, by means of pH-meter, measurement on the basis of electrodes (for example, glass electrodes, reference electrodes, combination electrodes, etc.), colorimetric measurement, etc. Generally, pH is measured at room temperature (for example, between 18 ° C and 24 ° C). However, it should be recognized that pH can be measured at other temperatures (eg, less than 10 ° C, greater than 25 ° C, etc.).
[0146] The pH of a composition can be maintained by means of a buffering system. Examples of buffering systems include, but are not limited to, carbonate buffering systems, phosphate buffering systems, protein buffering systems, etc. In some embodiments, a composition may comprise 1,2,3,4,5,6,7,8,9,10 or more buffering systems.
[0148] The disclosure is based, in part, on compositions comprising a carbonate buffering system. Generally, a "carbonate buffering system" refers to a solution comprising a weak acid (eg, carbonic acid) and its conjugate base (eg, bicarbonate anion), which buffers changes in the pH of the solution. . The conjugate base (eg bicarbonate anion) can be provided by any conjugated salt of carbonic acid, eg sodium bicarbonate (NaHCO ^s ), potassium bicarbonate (KHCO ³ ), cesium bicarbonate (CsHCO ^s ), magnesium bicarbonate (Mg (HCO ³ ) ² ), calcium bicarbonate (Ca (HCO ³ ) ² ) and ammonium bicarbonate (NH ⁵ CO ³ ). In some embodiments, a carbonate buffer system comprises sodium bicarbonate (NaHCO ³ ). In some embodiments, a carbonate buffer system comprises ammonium bicarbonate (NH ⁵ CO ³ ).
[0150] In addition to the pH buffer, certain buffering systems (for example, Na-based and NH ^4- based buffering systems) increase the concentration of Na ⁺ or NH ⁴⁺ ions in a composition or in a microenvironment created when the composition it comes into contact with damaged tissue (eg, a wound, blister, ulcer, etc.). Without wishing to be bound by any particular theory, large ions (for example, sodium ions) bind to certain molecules on the surface of mammalian cells, such as heparin sulfate (HS), and prevent pathogens from entering. cells, for example, as described in Rabenstein et al. (2002) Nat. Prod. Rep. 19: 312-331. In some embodiments, binding large ions to the cell membrane also influences the signal transduction of growth factors, such as FGF and EGF, which are important for skin regeneration.
[0152] In some embodiments, the compositions described by the disclosure contain (or provide) an amount of ions (eg, Na ⁺ or NH ⁴ ions) in a wound microenvironment that is sufficient to break the attachment of microbes, such as bacteria. and viruses, to proteoglycans (eg, HS, etc.) on the surface of target cells.
[0154] In some embodiments, a composition described by the disclosure comprises between about 0.5% (w / w) and about 10% (w / w) bicarbonate salt (eg, sodium bicarbonate). In some embodiments, a composition comprises between about 2% and about 5% (w / w) bicarbonate salt (eg, sodium bicarbonate), eg, about 2%, 2.1%, 2, 2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3, 2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4, 2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or 5% (w / w) of sodium bicarbonate. In some embodiments, a composition as described herein lacks (eg, does not comprise) a carbonate buffering system.
[0156] Hydration agents
[0158] Compositions of the disclosure may comprise one or more hydration agents (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). A "hydration agent" or "hygroscopic agent" usually refers to a molecule or molecules that attract and / or hold water molecules from the surrounding environment, by absorption or adsorption. Examples of hygroscopic agents include polymers, such as cellulosic polymers, glycol polymers, glycosoaminoglycans, mucopolysaccharides, etc.
[0160] In some embodiments, a hygroscopic agent is not a deliquescent agent (eg, a molecule that absorbs enough water from its environment to form an aqueous solution). Examples of deliquescent agents include salts (eg, calcium chloride, magnesium chloride, zinc chloride, ferric chloride, carnallite, potassium carbonate, potassium phosphate, ferric ammonium citrate, ammonium nitrate, potassium hydroxide, and hydroxide. of sodium).
[0162] In some embodiments a composition comprises one or more cellulosic polymers, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cellulosic polymers. In some embodiments, a composition lacks (eg, does not comprise) a hydrating agent. Generally, cellulosic polymers comprise two or more repeating subunits (eg, polymer subunits) of glucose. Examples of cellulosic polymers include methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, and carboxymethylcellulose (CMC). In some embodiments, at least one of the cellulosic polymers is hydroxyethyl cellulose or carboxymethyl cellulose.
[0163] The total amount of the one or more cellulosic polymers in a composition can vary. In some embodiments, a composition comprises between about 0.1% (w / w) and about 5% (w / w) cellulosic polymer. In some embodiments, a composition comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0 , 9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1 , 9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2 , 9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3 , 9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4 , 9% or 5.0% (w / w) of cellulosic polymer.
[0165] In some embodiments, a composition comprises one or more glycol polymers, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more glycol polymers. Generally, glycol polymers comprise two or more repeating subunits (eg, polymer subunits) of a polyether, such as ethylene oxide. In some embodiments, the glycol polymer is polyethylene glycol (PEG, also referred to as PEO and POE). Additional examples of glycol polymers include methoxypoly (ethylene glycol) and polypropylene glycol (PPG). In some embodiments, at least one of the glycol polymers is a PEG.
[0167] The number of polymer subunits in a glycolic polymer (eg, PEG) can vary. In some embodiments, a glycolic polymer (eg, PEG) comprises between about 2 and 10,000,000 polymer subunits (eg, any integer between 2 and 10,000,000, inclusive). In some embodiments, a glycolic polymer (eg, PEG) comprises more than 10,000,000 subunits.
[0169] In some embodiments, a glycol polymer, such as a PEG polymer, is described by its molecular weight (eg, as measured in g / mol). In some embodiments, a glycol polymer is PEG 400 (for example, PEG polymer having an average molecular weight of 400 Dalton), PEG 500 (for example, PEG polymer having an average molecular weight of 500 Dalton), PEG 1000 (for example, PEG polymer that has an average molecular weight of 1000 Dalton), PEG 3500 (for example, PEG polymer that has an average molecular weight of 3500 Dalton), PEG 4000 (for example, PEG polymer that has an average molecular weight of 4000 Dalton), PEG 10,000 (for example, PEG polymer having an average molecular weight of 10,000 Dalton), PEG 50,000 (for example, PEG polymer having an average molecular weight of 50,000 Dalton), PEG 100,000 (for example, PEG polymer that has an average molecular weight 100,000 Dalton) or 1,000,000 PEG (eg, PEG polymer having an average molecular weight of 1,000,000 Dalton).
[0171] The geometry (eg, structure) of a glycol polymer, such as PEG, can vary. In some embodiments, a glycol polymer is a linear polymer (eg, linear PEG). In some embodiments, a glycol polymer is a branched polymer (eg, branched PEG, such as a "star PEG"). In some embodiments, a glycol polymer is a combined PEG (eg, multiple PEG chains grafted onto a polymer backbone).
[0173] The amount of the one or more glycol polymers (eg, PEG) in a composition can vary. In some embodiments, a composition comprises between about 0.1% (w / w) and about 15% (w / w) glycol polymer. In some embodiments, a composition comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0 , 9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1 , 9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2 , 9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3 , 9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4 , 9% or 5.0% (w / w) of glycol polymer. In some embodiments, a composition comprises about 10%, 11%, 12%, 13%, 14%, or 15% (w / w) glycol polymer. In some embodiments, a composition comprises no more than 15% -20% (w / w) (eg, no more than 15%, 16%, 17%, 18%, 19%, or 20% (w / w)) of glycolic polymer.
[0175] In some embodiments, a composition comprises one or more glycosaminoglycan, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more glycosaminoglycans. Typically, glycosaminoglycans are long polysaccharides that comprise two or more repeating disaccharide subunits (eg, polymer subunits), such as an amino sugar and a uronic sugar (eg, glucuronic acid, iduronic acid) or galactose. Examples of glycosaminoglycans include heparin (Hep) / heparan sulfate (HS), chondroitin sulfate (CS) / dermatan sulfate (DS), and hyaluronic acid (HA), etc. In some embodiments, at least one of the glycosaminoglycans is a hyaluronic acid (HA).
[0177] The number of polymer subunits and, consequently, the molecular weight (eg average molecular weight) of hyaluronic acid (HA) can vary. In some embodiments, a hyaluronic acid (HA) comprises a molecular weight between approximately 5,000 to 20,000,000 Daltons. In some embodiments, the number of disaccharide polymer subunits in HA ranges from about 2 polymer subunits to about 50,000 polymer subunits (eg, any integer between 2 and 50,000, inclusive).
[0179] The total amount of the one or more glycosaminoglycans in a composition can vary. In some embodiments, a composition comprises between about 0.1% (w / w) and about 5% (w / w) glycosaminoglycans. In some embodiments, a composition comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0 , 9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1 , 9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2 , 9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3 , 9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4 , 9% or 5.0% (w / w) of glycosaminoglycans.
[0181] In some embodiments, a drug delivery composition described by the disclosure comprises water. The amount of water in a composition can vary. In some embodiments, a composition comprises at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% ( w / w) of water.
[0183] Bioactive agents
[0185] The compositions described by the disclosure comprise one or more bioactive agents. Examples of bioactive agents include antimicrobial agents (eg, antibacterial agents, antiviral agents, antiparasitic agents, etc.), cytotoxic agents, anticancer agents, free radical scavengers, antioxidants, receptor ligands (eg, molecules that induce or inhibit cell signaling, etc.) etc. A bioactive agent can be a small molecule (eg, chemical), peptide, protein, polypeptide, nucleic acid (eg, DNA, RNA, etc.) or a bioactive extract. In some embodiments, a composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 bioactive agents. In some embodiments, a composition comprises more than 20 bioactive agents.
[0187] In some embodiments, a bioactive agent is an antimicrobial agent, such as an antibacterial, antiviral, or antiparasitic agent. Typically, an antimicrobial agent can be a small molecule (e.g. chemical), peptide, protein, polypeptide or nucleic acid (eg, DNA, RNA, etc.). Examples of antimicrobial agents include, but are not limited to, small molecules derived from bacteria and fungi (eg, amoxicillin, doxycycline, cephalexin, ciprofloxacin, metronidazole, etc.), small molecules derived from plants (eg, tannins, flavones , phenolics, alkaloids, etc.) and antimicrobial peptides (eg maximin, dermicidin, mecropin, andropin, etc.). In some embodiments, a bioactive agent is a plant-derived antimicrobial agent, such as baicalin (eg, extracted from Scutellaría baicalensis or Scutellaría lateríflora) or andrographolide (eg, extracted from Andrographis paniculata). In some embodiments, a composition as described herein lacks a chemical or elemental antimicrobial agent, for example, silver (for example, silver-based compounds, such as silver sulfadiazine) or zinc (for example, zinc-based compounds, such as zinc oxide).
[0189] In some embodiments, a bioactive agent is a cytotoxic agent. Examples of cytotoxic agents include, but are not limited to, alkylating agents (eg, cyclophosphamide, nitrosurea, etc.), anthracyclines (eg, doxorubicin, daunorubicin, etc.), taxanes (eg, taxol, paclitaxel, etc. .), HDAC (histone deacetylase) inhibitors, nucleotide analogs (eg, gemcitabine, etc.), platinum-based compounds (eg, cisplatin, etc.), and vinca alkaloids (eg, vinblastine, etc. .).
[0191] In some embodiments, a bioactive agent is an oxidant or free radical scavengers. Examples of antioxidants and free radical scavengers include, but are not limited to, certain enzymes (eg, superoxide dismutase, glutathione peroxidase, glucose oxidase-catalase, etc.), carotenoids (eg, astaxanthin, beta-carotene, tocopherol, etc. ), phenolic compounds (for example, plant-derived polyphenols, such as anthocyanins, flavan-3-ols (catechin), flavanols (for example, quercetin and rutin), cinnamates (for example, S-glutathionylcaphtharic acid), phenethyl ester caffeic acid (CAPE), chalcones, isoflavonoids (for example, 7-O-methylvestitol, medicarpine and tetrahydrochalcone 3, 4, 2 ', 3'), etc.
[0193] In some embodiments, a bioactive agent is a cell signaling molecule, such as a receptor ligand. Examples of cell signaling molecules include, but are not limited to, neurotransmitters (eg, GABA, glutamate, acetylcholine, serotonin, dopamine, etc.), cytokines (eg, IL-4, IL-15, TNFa, IFNy , etc.), hormones (eg, estrogen, etc.), small molecules (eg, nitric oxide, etc.), certain peptides (eg, neuropeptides, growth factors, etc.), etc.
[0195] As used herein, a "bioactive extract" refers to a composition comprising one or more bioactive agents that have been extracted (eg, isolated) from an organic source, eg, one or more plants. or plant, animal or animal products, insects or insect products, microorganisms or microbial products, etc. Generally, bioactive extracts can be produced by any appropriate method, for example, solvent-based extraction methods (for example, alcoholic extraction, hydrocarbon extraction etc.), maceration extraction methods, ultrasound extraction (for example, sonication ), microwave assisted extraction (MAE), etc. However, the person skilled in the art will appreciate that an appropriate extraction method depends on the type of material from which it is intended to isolate the bioactive agents and will select an extraction method as appropriate.
[0197] The amount of bioactive agent or extract in a composition can vary. In some embodiments, the concentration of a bioactive agent or bioactive extract in a composition ranges from about 0% w / w (absent) to about 20% w / w (eg, about 1%, 2%, 3% , 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or the 20%) of the total weight of the composition.
[0199] Bioactive extracts of propolis
[0201] In some embodiments, a composition comprises a bioactive extract derived from propolis. "Propolis" typically refers to a resinous material produced by honey bees (eg, Apis and other species) that comprises a variety of chemicals and molecules, including waxes, fatty acids, pollen, aromatic oils, and certain bioactive molecules (eg, flavonoids, isoflavinoids, chalcones, pterocarpans, etc.). Propolis can be found in various areas of the world, including North and Central America (for example, the United States, Canada, Mexico, Cuba, etc.), South America (for example, Brazil, Colombia, Chile, etc. ), Asia (for example, China) and New Zealand. In some embodiments, a bioactive propolis extract is made from a blend (eg, a blend) comprising at least a variety of Brazilian propolis. A bioactive propolis extract can be produced by any suitable extraction method, for example ethanol / glycol extraction or supercritical CO2 extraction.
[0203] The characterization of the sources of propolis can vary. For example, Brazilian propolis has originally been classified by geographic origin and / or physicochemical properties, and at least 12 sources of propolis were identified, including, but not limited to, five in the southern Brazilian group (group 3), one in the group from southeastern Brazil (group 12) and six in the group from northeast Brazil (group 6). However, when classified by botanical origin, three sources of Brazilian propolis were identified for the same varieties of propolis: poplars (for example, Populus sp.), Bacaris (for example, Baccharís sp., Such as Baccharís dracunculifolia, etc. .) and hyptis (eg, Hyptis sp., such as Hyptis divaricata). Additional sources of propolis are known, for example, as described by Park et al. (2002) J. Agric. Food Chem 50: 2502-2506, and Dezmirean et al. (2017) J. Apicultural Res 56 (5): 588-597. In some embodiments, the propolis is characterized by its color, for example, red propolis, green propolis, brown propolis, etc.
[0205] "Red propolis" refers to a propolis botanically derived from plants such as Dalbergia ecastophyllum ( D. ecastophyllum) (L) Taub. (Fabaceae), which are popularly known in Brazil as “rabo-de-bugio”. In some embodiments, red propolis is obtained from a selected region of Brazil, Cuba, Mexico, China, and Nigeria. Sources of red propolis are described, for example, by Corbellini Rufatto et al. (2017) Asian Pacific Journal of Tropical Biomedicine KTy. 591-598.
[0207] "Green propolis" refers to a propolis botanically derived from plants such as Baccharis dracunculifolia DC (Asteraceae), for example, as described by Lopes Machado et al. (2012) Evid Based Complement Alternat Med. 2012: 157652. In some embodiments, the green propolis is obtained from Brazil (for example, southeastern Brazil, for example, the state of Bahia, the state of Minas Gerais, the state of Sao Paulo, or the state of Paraná).
[0209] "Brown propolis" refers to a propolis botanically derived from plants such as Populus species ( P. alba, P. nigra, P. tremula) or Clusia species. In some embodiments, brown propolis is obtained from a selected region of Brazil, Venezuela, Cuba, and Europe.
[0210] The ratio of each type of propolis in a mixture from which a bioactive propolis extract is produced can vary. For example, in some embodiments, a propolis mixture comprises green and brown propolis in a ratio ranging from about 9: 1 to about 1: 9 (eg, 1: 1, 1: 2, 1: 3, 1: 4 , 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 2: 1, 2: 3, 2: 4, 2: 5, 2: 6, 2: 7, 2: 8, 2 : 9, 3: 1, 3: 2, 3: 4, 3: 5, 3: 6, 3: 7, 3: 8, 3: 9, 4: 1, 4: 2, 4: 3, 4: 5 , 4: 6, 4: 7, 4: 8, 4: 9, 5: 1, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9, 6 : 1, 6: 2, 6: 3, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 7: 1, 7: 2, 7: 3, 7: 4, 7: 5 , 7: 6, 7: 8, 7: 9, 8: 1, 8: 2, 8: 3, 8: 4, 8: 5, 8: 6, 8: 7, 8: 9, 9: 8, 9 : 7, 9: 6, 9: 5, 9: 4, 9: 3, 9: 2, 9: 1, etc.). In some embodiments, a propolis mixture comprises green and red propolis in a ratio ranging from about 9: 1 to about 1: 9 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 2: 1,2: 3, 2: 4, 2: 5, 2: 6, 2: 7, 2: 8, 2: 9, 3: 1, 3: 2, 3: 4, 3: 5, 3: 6, 3: 7, 3: 8, 3: 9, 4: 1, 4: 2, 4: 3, 4: 5, 4: 6, 4: 7, 4: 8, 4: 9, 5: 1, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9, 6: 1, 6: 2, 6: 3, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 7: 1, 7: 2, 7: 3, 7: 4, 7: 5, 7: 6, 7: 8, 7: 9, 8: 1, 8: 2, 8: 3, 8: 4, 8: 5, 8: 6, 8: 7, 8: 9, 9: 8, 9: 7, 9: 6, 9: 5, 9: 4, 9: 3, 9: 2, 9: 1, etc.). In some embodiments, a propolis mixture comprises brown and red propolis in a ratio ranging from about 9: 1 to about 1: 9 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 2: 1,2: 3, 2: 4, 2: 5, 2: 6, 2: 7, 2: 8, 2: 9, 3: 1, 3: 2, 3: 4, 3: 5, 3: 6, 3: 7, 3: 8, 3: 9, 4: 1, 4: 2, 4: 3, 4: 5, 4: 6, 4: 7, 4: 8, 4: 9, 5: 1, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9, 6: 1, 6: 2, 6: 3, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 7: 1,7: 2, 7: 3, 7: 4, 7: 5, 7: 6, 7: 8, 7: 9, 8: 1, 8: 2, 8: 3, 8: 4, 8: 5, 8: 6, 8: 7, 8: 9, 9: 8, 9: 7, 9: 6, 9: 5, 9: 4, 9: 3, 9: 2, 9: 1, etc.) In some embodiments, a propolis mixture comprises green, brown, and red propolis in a ratio ranging from about 9 : 1: 1 and approximately 1: 9: 1, and approximately 1: 1: 9 (for example, 1: 1: 1, 1: 2: 1,2: 1: 1, 1: 1: 2, etc.) .
[0212] The amount of bioactive propolis extract in a composition of the disclosure can vary. In some embodiments, a composition as described herein (eg, a drug delivery composition) comprises between about 0.1% w / w and about 20% w / w of a bioactive propolis extract. In some embodiments, a composition comprises between about 0.1% w / w and about 4% w / w of bioactive propolis extract. In some embodiments, a composition comprises between about 1% and about 5% w / w bioactive propolis extract. In some embodiments, a composition comprises between about 3% and about 7% w / w bioactive propolis extract. In some embodiments, a composition comprises between about 5% and about 20% w / w bioactive propolis extract.
[0213] Extracts obtained from propolis (for example, one or more types of propolis, such as a mixture of brown propolis, green propolis, red propolis, or any combination thereof) can comprise a variety of bioactive agents. In some embodiments, a bioactive extract derived from propolis comprises at least one of the following: fatty and phenolic acids and esters, substituted phenolic esters, flavonoids (eg, flavones, flavanones, flavonols, dihydroflavonols, chalcones, etc.), mono- , sesqui-, di- and triterpenes, steroids, aldehydes and aromatic alcohols, derivatives of naphthalene and stilbene, derivatives of caffeoylquinic acid, lignans, coumarins, prenylated and coumarin derivatives. Bioactive molecules derived from propolis are known in the art, for example, as described by Schindler Machado et al. (2016) Evid Based Complement Alternat Med. 2016: 6057650, and Trusheva et al. ( 2006) Evid Based Complement Alternat Med. 3 (2): 249-254, and Huang et al. (2014) Molecules 19: 19610-19632.
[0215] The disclosure is based, in part, on bioactive extracts of propolis comprising one or more (eg, 1, 2, 3, 4, 5, 6, etc.) antioxidants. In some embodiments, the one or more antioxidants are flavonoids (eg, isoflavones, etc.). In some embodiments, the flavonoid bioactives in a bioactive propolis extract promote a sequestration of reactive oxygen species (ROS) generated by DNA damage of the cellular elements subjected to radiation, causing a reduction in the degradation of the extracellular matrix of the oral mucosa. In some embodiments, the flavonoids are presented in a bioactive extract of propolis in a concentration ranging from about 100 µg / ml to about 500 µg / ml (eg, about 100 µg / ml, about 150 µg / ml , about 200 | jg / ml, about 250 | jg / ml, about 300 | jg / ml, about 350 | jg / ml, about 400 | jg / ml, about 450 | jg / ml, etc.), as shown measured gravimetrically. In some embodiments, the flavonoids are presented in a bioactive propolis extract in a concentration ranging from about 100 µg / ml to about 200 µg / ml, as measured gravimetrically. In some embodiments, the flavonoids are presented in a bioactive propolis extract in a concentration ranging from about 150 µg / ml to about 300 µg / ml, as measured gravimetrically. In some embodiments, the flavonoids are presented in a bioactive propolis extract at a concentration ranging from about 250 µg / ml to about 400 µg / ml, as measured gravimetrically.
[0216] In some embodiments, a bioactive propolis extract comprises one or more lipids, one or more waxes, or a combination of one or more lipids and one or more waxes. In some embodiments, the total lipid and wax concentration of a bioactive propolis extract ranges from about 25 | jg / ml to about 750 | jg / ml (eg, about 25 | jg / ml, 50 | jg / ml, 75 | jg / ml, 100 | jg / ml, 150 | jg / ml, 200 | jg / ml, 300 | jg / ml, 350 | jg / ml, 500 | jg / ml, 650 | jg / ml, etc.) , as measured gravimetrically. In some embodiments, the total lipid and wax concentration of a bioactive propolis extract ranges from about 25 µg / ml to about 100 µg / ml, as measured gravimetrically. In some embodiments, the total lipid and wax concentration of a bioactive propolis extract ranges from about 75 µg / ml to about 250 µg / ml, as measured gravimetrically. In some embodiments, the total lipid and wax concentration of a bioactive propolis extract ranges from about 300 µg / ml to about 550 µg / ml, as measured gravimetrically.
[0218] Bioactive seaweed extracts
[0220] In some embodiments, a composition comprises a bioactive extract obtained from a seaweed. In some embodiments, the bioactive extract is a powder produced by drying and grinding seaweed. Methods for producing seaweed extracts (eg powders) are known, eg as described by Costa et al. (2010) Biomedicine and Pharmacology 64: 21-28.
[0222] Seaweeds are generally classified into four families: Rhodium (red algae), Phaeophyceae (brown algae), Cyanophyceae (blue-green algae) and Chlorophyceae (green algae). The identification and classification of seaweed is described, for example, in AlgaeBase (Guiry, M.D. & Guiry, G.M. 2018. AlgaeBase. Worldwide electronic journal, National University of Ireland, Galway; www.algaebase.org).
[0224] In some embodiments, a bioactive seaweed extract comprises one or more types of red algae. Examples of red algae include, but are not limited to, Rhodophyta species (for example, Rhodophyta graciliara caudata, etc.), Porphyra species (for example, Porphyra haitanensis, etc.), Pterocladiella species (for example, Pterocladiella capillacea, etc. .), Osmundaria species (for example, Osmundaria obtusiloba, etc.), Gelidium species (for example, Gelidium cartilagenium, etc.), Chondrococcus species (for example, Chondrococcus hornemannii, etc.) and Hypnea species (for example, Hypnea musciformi, etc.). In some embodiments, a bioactive seaweed extract comprises Porphyra haitanensis.
[0226] In some embodiments, a bioactive seaweed extract comprises one or more types of brown algae. Examples of brown algae include, but are not limited to, Laminaria species (eg, Laminaria japonica, etc.), Sargassum species (eg, Sargassum wightii, Sargassumfilipendula, etc.), Spatoglossum species (eg, Spatoglossum schroderi, etc.), Padina species (eg Padina tetrastromatica, etc.), Dictyota species (eg Dictyota cervicornis, Dictyota menstrualis, Dictyota myrtensii, etc.), Dictyopteris species (eg Dictyopteris delicatula, etc.). In some embodiments, a bioactive seaweed extract comprises Laminaria japonica .
[0228] In some embodiments, a bioactive seaweed extract comprises one or more types of green algae. Examples of green algae include, but are not limited to, Ulva species (e.g. Ulva latuca, Ulva arasakii, Ulva armoricana, Ulva clathrata, Ulva conglobate, Ulva fasciata, Ulva pertusa, Ulva reticulate, Ulva rigida, Ulva rotundata, etc. .), Enteromorpha species (for example, Enteromorpha linza, Enteromorpha clathrata, Enteromorpha compressa, Enteromorpha intestinalis, Enteromorphaprolifera, etc.), Monostroma species (for example, Monostroma latissimum, Monostroma nitidum, Monostroma angicava, etc.), Codium species (for Example,), Caulerpa species (for example, Caulerpa brachyous, Caulerpa cupressoides, Caulerpa lentillifera, Caulerpaprolifera, Caulerpa racemosa, Caulerpa sertularioides, etc.), Bryopsis species (for example, Bryopsisplumose, etc.), Elalimeda species (for example, Elalimeda monile, etc.), Capsosiphon species (eg, Capsosiphon fulvescens, etc.), and Chaetomorpha species (eg, Chaetomorpha antennenina, etc.). In some embodiments, a bioactive seaweed extract comprises Ulva lactuca. In some embodiments, a bioactive seaweed extract comprises Enteromorpha linza. In some embodiments, a bioactive seaweed extract comprises Ulva latuca and Enteromorpha linza.
[0230] In some embodiments, a bioactive seaweed extract comprises one or more types of blue-green algae. Examples of blue-green algae include, but are not limited to, Microcystis species (for example, Microcystis aeruginosa, etc.), Nostoc species (for example, Nostoc linckia, Nostoc spongiaeform, etc.), Lyngbya species (for example, Lyngbya majuscule , Lyngbya bouillonii, Lyngbya sordida, etc.), Symploca species, Calothrix species, etc.
[0232] A bioactive extract may comprise a combination of seaweed species, for example, at least one species of green seaweed (for example 2, 3, 4, 5 or more species of green algae), at least one species of red seaweed (eg 2, 3, 4, 5 or more species of red algae) and / or at least one species of brown seaweed (eg 2, 3,4,5 or more species of brown algae). For example, a bioactive extract from seaweed can comprise the following species: Enteromorpha linza, Ulva lactula, Porphyra haitanensis, and Laminaria japonica. In some embodiments, a seaweed extract does not comprise (eg, it lacks one or more classes of seaweed species, such as red algae, green algae, brown algae, and blue-green algae). In some embodiments, a seaweed extract is devoid of blue-green algae.
[0234] The ratio of each type of seaweed species in a mixture from which a bioactive seaweed extract is produced can vary. For example, in some embodiments, a mixture comprises green and brown seaweed in a ratio ranging from about 5: 1 to about 1: 5 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 2: 1, 2: 3, 2: 4, 2: 5, 3: 1, 3: 2, 3: 4, 3: 5, 4: 1, 4: 2, 4: 3, 4: 5, 5: 1, 5: 2, 5: 3, 5: 4, etc.). In some embodiments, a mixture comprises green and red algae in a ratio ranging from about 5: 1 to about 1: 5 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 2: 1, 2: 3, 2: 4, 2: 5, 3: 1, 3: 2, 3: 4, 3: 5, 4: 1, 4: 2, 4: 3, 4: 5, 5: 1, 5: 2, 5: 3, 5: 4, etc.). In some embodiments, a mixture comprises brown and red algae in a ratio ranging from about 5: 1 to about 1: 5 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 2: 1, 2: 3, 2: 4, 2: 5, 3: 1, 3: 2, 3: 4, 3: 5, 4: 1, 4: 2, 4: 3, 4: 5, 5: 1, 5: 2, 5: 3, 5: 4, etc.). In some embodiments, a propolis blend comprises green, brown, and red algae in a ratio ranging from about 5: 1: 1 to about 1: 5: 1, and about 1: 1: 5 (eg, 1: 1: 1, 1: 2: 1,2: 1: 1, 1: 1: 2, etc.).
[0236] The amount of bioactive seaweed extract in a composition of the disclosure can vary. In some embodiments, a composition as described herein (eg, a drug delivery composition) comprises between about 0.1% w / w and about 20% w / w bioactive seaweed extract. The amount of seaweed extract can be expressed as a percentage by weight of each seaweed species extract in the composition, or as the total amount of bioactive seaweed extract in the composition. composition. For example, a composition may comprise 20% w / w of the total bioactive seaweed extract, of which four different types of extracts from seaweed species contribute 5% w / w.
[0238] In some embodiments, a composition comprises between about 0.1% w / w and about 5% w / w of a bioactive seaweed extract. In some embodiments, a composition comprises about 1%, about 2%, about 3%, about 4%, or about 5% w / w of bioactive seaweed extract. In some embodiments, a composition comprises between about 3% and about 7% w / w of bioactive seaweed extract. In some embodiments, a composition comprises between about 5% and about 20% w / w of bioactive seaweed extract.
[0240] Extracts obtained from seaweed (eg, one or more species of seaweed, such as a mixture of two, three, four or more species of seaweed) can comprise a variety of bioactive agents. In some embodiments, a bioactive seaweed extract comprises one or more of the following: sulfated polysaccharides, phorolotannins, xanthines (eg, fucoxanthin, astaxanthin, etc.), phloroglycinols, polyphenols, carotenoids, and sesquiterpenes.
[0242] The description is based, in part, on bioactive seaweed extracts comprising sulfated polysaccharides (eg, non-animal sulfated polysaccharides). Sulfated polysaccharides are anionic carbohydrate polymers that are generally classified according to the class of seaweed (eg, brown, green, red) from which they are derived. Typically, brown seaweeds (eg, pheophytes) produce sulfated fucans or fucoidans, which may comprise fucose, xylose, urinuco acid, and / or galactose sugars. Red marine algae (eg, rhodium) generally produce galactans and carrageenans, which may comprise sulfated galactose and 3,6-anhydrogalactose sugars. Green seaweeds produce ulvans, which include sulfated rhamnose bound to glucuronic acid, iduronic acid, or xylose. The classification of sulfated polysaccharides from seaweed is known, for example, as described by Pater (2012) 3 Biotech 2 (3): 171-185.
[0244] The bioactive characteristics of sulfated polysaccharides can vary. In some embodiments, a bioactive seaweed extract comprises one or more polysaccharides. sulfates that have antioxidant activity. Examples of antioxidant sulfated polysaccharides include, but are not limited to, ulvan extracted from Codia, Ulva, and Enteromorpha, galactans extracted from Caulerpa, fucans and fucodans extracted from Laminaria japonicum, and galactans and carrageenans from Porphyra haitanensis. In some embodiments, a bioactive seaweed extract comprises one or more sulfated polysaccharides having a bioactivity selected from anticoagulant activity, immunomodulatory activity, antitumor activity, antiviral activity, and antinociceptive activity. Methods for the extraction and functional characterization of sulfated polysaccharides from marine algae are known, for example, as described by Costa et al. (2010 Biomedicine and Pharmacotherapy 64: 21-28; Zhang et al. (2010) Carbohydrate Polymers ( 2010) 82: 118-121; and Wang et al. (2014) Mar. Drugs 12: 4984-5020, the full content of each of which is incorporated herein by reference.
[0246] In some embodiments, a bioactive seaweed extract comprises one or more sulfated polysaccharides selected from ulvan, carrageenan, and fucan, or a combination of the foregoing. In some embodiments, a bioactive extract comprises one or more ulvans, for example ulvans obtained from Ulva latuca and / or Enteromorpha linza. In some embodiments, a bioactive extract comprises one or more galactans and / or one or more carrageenans, for example, galactans and / or carrageenans obtained from Porphyra haitanensis. In some embodiments, a bioactive extract comprises one or more fucans and / or fucoidans, for example, one or more fucans and / or fucoidans obtained from Laminaria japonica.
[0248] Bioactive carrot extracts
[0250] In some embodiments, the disclosure relates to bioactive extracts comprising combinations of molecules that are useful for promoting tissue regeneration (eg, a bioactive tissue regeneration extract). In some embodiments, a tissue regenerating bioactive extract comprises one or more bioactive molecules derived from carrots (eg, carotenoids, etc.), one or more vitamin A derivatives, one or more scaffold molecules, or a combination of any of the above.
[0252] In some embodiments, the one or more bioactive agents are derived (eg, extracted) from carrots (eg, Dacus carota, or a cultivar or variant thereof).
[0253] Generally, carrots comprise a variety of bioactive molecules, for example carotenoids and phenolic compounds. Examples of extractable carotenoids from carrots include, but are not limited to, a-carotene and p-carotene. Examples of phenolic compounds extractable from carrots include chlorogenic acid, derivatives of hydroxycinnamic acid, ferulic acid, dicapheoylquinic acid, and anthocyanins. In some embodiments, one or more bioactive molecules are extracted from a carrot in the form of "carrot oil", which is typically produced by a solvent-based or pressure-based extraction method, for example, lipids and biomolecules by pressing into cold of carrot seeds and / or taproot; neutral oil-based extraction (eg mineral oil) of carrot seed and / or taproot compounds; alcohol-based extraction of biomolecules from carrot seeds and / or taproot; supercritical carbon dioxide extraction methods, etc. Methods for extracting bioactive molecules are also described, for example, in US Patent No. 7,141,083, US Publication No. 2008-0233238, and Japanese Patent No. JPH0676591.
[0255] In some embodiments, a bioactive tissue regeneration extract comprises one or more vitamin B complexes (eg, one or more members of a vitamin B complex). Vitamin B complex generally refers to a complex comprising all essential water soluble vitamins except vitamin C. In some embodiments, the vitamin B complex comprises thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin, folic acid, and cobalamins (vitamin B12). In some embodiments, a bioactive tissue regeneration extract comprises pantothenic acid or a derivative, analog, or salt thereof. Examples of pantothenic acid derivatives and analogs include pantothenol and dexpanthenol. In some embodiments, one or more vitamin B complexes is a derivative of pantothenic acid or a derivative or analog thereof. In some embodiments, a vitamin B complex comprises dexpanthenol.
[0257] The total amount of bioactive extract derived from carrot in a composition can vary. In some embodiments, the amount of bioactive extract obtained from carrot (eg, carrot oil extract) ranges from about 1% (w / w) to about 5% (w / w), for example, about 1%. %, about 2%, about 3%, about 4%, or about 5% w / w. In some embodiments, a bioactive tissue regeneration extract does not comprise (for example, it lacks) bioactive extract derived from carrot. In some embodiments, a bioactive tissue regeneration extract further comprises Aloe vera, for example, Aloe vera extract.
[0259] The disclosure is based, in part, on bioactive extracts for tissue regeneration comprising one or more scaffold molecules. As used herein, a "scaffold molecule" is a molecule, such as a protein or polymer, that provides a substrate to which cells (eg, stem cells, such as mesenchymal stem cells) can adhere and promote cell attachment, growth, and differentiation. In some embodiments, the one or more scaffold molecules is a protein (eg, an animal protein, extracellular matrix protein (ECM), etc.). In some embodiments, the protein comprises collagen, albumin, or a combination thereof. In some embodiments, the protein comprises one or more whey proteins, eg, albumin (eg, bovine serum albumin), fish whey proteins, pork whey proteins, etc. In some embodiments, a composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more scaffold molecules.
[0261] In some embodiments, a scaffold molecule is a polymer, eg, a polysaccharide polymer, eg, hyaluronic acid, chitosan, or alginate. In some embodiments, the polysaccharide polymer is hyaluronic acid. Hyaluronic acid is a glycosaminoglycan polymer that comprises repeating subunits of glucuronic acid and N-acetyl-D-glucosamine. Hyaluronic acid is normally classified according to its molecular weight. Low molecular weight hyaluronic acid (MWHA) generally has a molecular weight of less than 100 kDa. The average MWHA generally has a molecular weight between 100 and 300 kDa. High MWHA generally has a molecular weight greater than 300 kDa. In some embodiments, the scaffold molecule comprises medium MWHA.
[0263] The total number of scaffold molecules in a composition can vary. In some embodiments, the amount of scaffold molecules ranges from about 0.1% (w / w) to about 10% (w / w), eg, about 0.1%, about 0.5%. , about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% , about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% p / p.
[0265] The ratio of bioactive molecules to scaffold molecules in a tissue regenerating bioactive extract can vary. For example, in some embodiments, a composition comprises bioactive molecules and scaffold molecules in a ratio ranging from about 10: 1 to about 1:10 (eg, 1: 1, 1: 2, 1: 3, 1: 4 , 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 102: 1,2: 3, 2: 4, 2: 5, 2: 6, 2: 7, 2: 8 , 2: 9, 3: 1, 3: 2, 3: 4, 3: 5, 3: 6, 3: 7, 3: 8, 3: 9, 4: 1, 4: 2, 4: 3, 4 : 5, 4: 6, 4: 7, 4: 8, 4: 9, 5: 1, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9 , 6: 1, 6: 2, 6: 3, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 7: 1, 7: 2, 7: 3, 7: 4, 7 : 5, 7: 6, 7: 8, 7: 9, 8: 1, 8: 2, 8: 3, 8: 4, 8: 5, 8: 6, 8: 7, 8: 9, 9: 8 , 9: 7, 9: 6, 9: 5, 9: 4, 9: 3, 9: 2, 9: 1, 10: 1, etc.).
[0267] Bioactive lemon balm extracts
[0269] In some respects, the disclosure relates to bioactive extracts obtained from Melissa officinalis, also referred to as lemon balm. Melissa is a member of the mint family, Lamiaceae. Melissa is native to Europe and Central Asia, but can generally be grown around the world. Cultivars of M. officinalis include M. officinalis citronella, M. officinalis lemonella, M. officinalis Quedlinburger, M. officinalis lime, M. officinalis variegata, M. officinalis aurea, and M. officinalis Quedlinburger Niederliegende.
[0271] Bioactive molecules produced by lemon balm include, but are not limited to, polyphenolic compounds, eugenol, tannins, and terpenes (eg, monoterpenes, triterpenes, terpenoids, etc.), eg, (+) - citronellal, 1-octen- 3-ol, 10-a-cadinol, 3-octanol, 3-octanone, a-cubebene, a-humulene, p-bourbonen, caffeic acid, caryophyllene, caryophyllene oxide, catechin, chlorogenic acid, cis-3-hexenol, cis-ocimene, citral A, citral B, copaene, 5-cadinene, eugenyl acetate, Y-cadinene, geranial, geraniol, geranyl acetate, germacrene D, isogeranial, linalol, luteolin-7-glucoside, methylheptenone, neral, nerol , octyl benzoate, oleanolic acid, pomolic acid ((1R) -hydroxyursolic), protocatechuic acid, rhamnazine, rosmarinic acid, stachyose, succinic acid, thymol, trans-ocimene, ursolic acid and amine.
[0273] In some embodiments, the bioactive molecules are produced in the leaves and stems of lemon balm. Normally, bioactive molecules are isolated (for example, extracted) from lemon balm leaves in the form of an "essential oil", also called "volatile oil." Methods for extracting bioactive compounds from lemon balm are known in the art, for example, by aqueous extraction (for example, as described by Nolkemper et al. (2006) Planta Med. 72 (15): 1378-1382) or by pressure-based extraction (eg, as described by Dastmalchi et al. (2008) LWT - Food Science and Technology, 41 ( 3): 391-400).
[0275] In some embodiments, a bioactive extract obtained from Melissa officinalis comprises one or more monoterpenes or monoterpenoids, eg, citronellal, neral, and / or geranial. In some embodiments, a bioactive extract obtained from Melissa officinalis comprises rosmarinic acid. In some embodiments, the terpenes and rosmarinic acid present in the bioactive extracts of Melissa officinalis have antiviral (eg, antiretroviral, such as anti-herpes or anti-HIV) activity. The antiviral activity of the bioactive extracts obtained from Melissa officinalis are described, for example, in Allahverdiyev et al. (2004) Phytomedicine 11 (7-8): 657-61, and Geuenich et al. ( 2008) Retrovirology 5:27.
[0277] In some embodiments, a composition as described by the disclosure comprises a bioactive extract obtained from Melissa officinalis and one or more antiviral agents, eg, acyclovir, valacyclovir, penciclovir, famciclovir, docosanol, avacavir, cidofovir, efavirenz, entecavir, imiquimod , lopinavir, emtricitabine, lamivudine, tenofovir, zidovudine, doravirine, etravine, nevirapine, rilpivirine, atazanavir, darunavir, fosamprenavir, sasquinavir, tipranivir, efuviritide, Maraviroc, ralteravir, ibalzumab, or any combination of the same.
[0279] In some embodiments, a composition comprising a bioactive extract obtained from Melissa officinalis further comprises one or more vitamin B complexes (eg, one or more members of a vitamin B complex). In some embodiments, the one or more members of the vitamin B complex are cobalamins (eg, vitamin B12). In some embodiments, the cobalamins are methylated (eg, methylcobalamines) or cyanatized (eg, cyanocobalamin). In some embodiments, the composition comprises a combination of methylcobalamin and cyanocobalamin. Without wishing to be bound by any particular theory, cobalamins are useful, in some embodiments, to promote peripheral nerve repair and reduce neuropathic pain.
[0280] The amount of cobalamin (eg, methylcobalamin and / or cyanocobalamin) in a composition can vary. In some embodiments, the amount of methylcobalamin in a composition ranges from about 0.1% (w / w) to about 0.5% (w / w), for example, about 0.1%, about 0 , 2%, about 0.3%, about 0.4%, or about 0.5% w / w. In some embodiments, the amount of cyanocobalamin in a composition ranges from about 0.1% (w / w) to about 2% (w / w), for example, about 0.1%, about 0.2 %, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% , about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0% w / w.
[0282] The ratio of methylcobalamin to cyanocobalamin in a composition can vary. For example, in some embodiments, a composition comprises methylcobalamin to cyanocobalamin in a ratio ranging from about 10: 1 to about 1:10 (eg, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 102: 1,2: 3, 2: 4, 2: 5, 2: 6, 2: 7, 2: 8, 2: 9, 3: 1, 3: 2, 3: 4, 3: 5, 3: 6, 3: 7, 3: 8, 3: 9, 4: 1, 4: 2, 4: 3, 4: 5, 4: 6, 4: 7, 4: 8, 4: 9, 5: 1, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9, 6: 1, 6: 2, 6: 3, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 7: 1, 7: 2, 7: 3, 7: 4, 7: 5, 7: 6, 7: 8, 7: 9, 8: 1, 8: 2, 8: 3, 8: 4, 8: 5, 8: 6, 8: 7, 8: 9, 9: 8, 9: 7, 9: 6, 9: 5, 9: 4, 9: 3, 9: 2, 9: 1, 10: 1, etc.).
[0284] Therapeutic methods
[0286] The disclosure relates, in some respects, to methods of administering compositions (eg, therapeutic compositions) to a cell or an individual. In some embodiments, the methods of administration of compositions described by the disclosure are useful for the treatment of certain diseases and disorders associated with damaged tissue or damaged skin (eg, damaged skin or cells), eg, mucositis, ulcers, wounds ( e.g. surgical incisions, etc.), burns and tissue damage due to viral infection (e.g. damage to peripheral nerves resulting from herpes virus 1 infection), or blisters resulting from herpes virus infection 2 (HSV-2), chickenpox infection, etc.).
[0287] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progress of a "disease state" (eg, a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, the treatment can be administered after one or more signs or symptoms have developed or been observed. In other embodiments, the treatment can be administered in the absence of signs or symptoms of the disease or condition. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (eg, in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to delay or prevent recurrent herpes virus infections.
[0289] As described herein, the compositions can be administered by any suitable route. For example, an effective amount of the composition and / or other therapeutic agents can be administered to an individual by any mode that delivers the agent to the desired tissue, eg, skin, mucosal tissue, nervous system tissue, muscle tissue, etc. . In some embodiments, the compositions are administered topically. Other suitable routes of administration include, but are not limited to, oral, parenteral, intravenous, intraperitoneal, intranasal, intramuscular, sublingual, intratracheal, inhalational, subcutaneous, ocular, vaginal, and rectal. Systemic routes include oral and parenteral.
[0291] For oral administration, the compositions can be administered in the form of tablets, pills, lozenges, capsules, liquids, mouthwashes, gels, syrups, pastes, suspensions, and the like. In some embodiments, the disclosure provides compositions in the form of a medicated mouthwash, spray, gel, cream, ointment, or toothpaste, which in some embodiments, removes the bacterial biofilm responsible for infections and periodontal diseases, and promotes the wound-healing action of the oral mucosa that provides a faster recovery of the injured tissue. In some embodiments, the compositions for oral administration comprise a combination of bioactive propolis extract and one or more surfactants (eg, one or more biotensive agents).
[0293] In some embodiments, a composition formulated for oral administration is compatible with the use of autologous grafting techniques, for example, biomaterials such as platelet rich fibrin (PRF). In some embodiments, the compositions of the disclosure do not chemically interact with the grafted tissue and associated clots, making the compositions suitable for use by individuals who have undergone dental procedures (e.g., dental tissue grafting, etc.).
[0295] Accordingly, in some embodiments, the compositions described in the present invention are useful for treating mucositis (eg, oral lesions caused by radiation therapy, etc.). Mucositis is an inflammation and ulceration of the mucous tissue in the oral cavity, which is usually caused by chemotherapy and / or radiation therapy for cancer.
[0297] In some embodiments, the disclosure provides a method of treating oral cavity lesions in an individual (eg, an individual who has mucositis), the method comprising administering a composition (eg, an oral composition) as described by disclosure to an individual who has one or more lesions of the oral cavity. In some embodiments, the oral composition comprises a bioactive extract derived from propolis. In some embodiments, the oral composition is administered in the form of an aqueous oral solution or mouthwash.
[0299] In some embodiments, an individual who has or is suspected of having mucositis has undergone chemotherapy (eg, administration of one or more doses of a chemotherapeutic agent) and / or radiation therapy (eg, administration of one or more doses of radiation. therapeutic, for example, head and neck radiation therapy). In some embodiments, an individual has previously been administered chemotherapy, radiation therapy, or a combination of chemotherapy and radiation therapy. In some embodiments, an individual who has or is suspected of having mucositis has undergone whole body irradiation prior to receiving a hematopoietic stem cell transfer.
[0301] In some embodiments, the compositions (eg, oral compositions) described by the disclosure are useful for treating tissue that has been mechanically damaged. In some embodiments, an individual having mechanically impaired oral tissue has undergone an oro-maxillofacial surgery, eg, a dental implant procedure. In some embodiments, an oral composition comprising a bioactive extract obtained from propolis is compatible with biomaterials commonly used in oral surgery (eg, platelet-rich fibrin, etc.) and reduces the possibilities, relative to the use of compositions based on alcohol such as antiseptic mouthwashes, that a dental implant will be rejected by an individual's immune system.
[0303] In some embodiments, administration of an oral composition as described herein inhibits the formation and / or growth of bacterial biofilms in an individual (eg, biofilm formation in mucosal tissue and / or in the oral cavity. of an individual). Removal of bacterial biofilm from ulcerated mucosa results, in some embodiments, in decreased polymorphonuclear cell infiltrate and subsequently in reduced release of pro-inflammatory mediators such as TNF-a, IL-ip, IL-6. and major prostaglandins that mediate hyperalgesic pain.
[0305] In some aspects, the disclosure relates to methods of topically administering the compositions described in the present invention. Pharmaceutical formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, drops, sprays, suppositories, liquids, and powders. In addition, conventional pharmaceutical carriers, aqueous, powdered or oily bases, or thickeners can be used in pharmaceutical preparations for topical administration. Compositions of the disclosure that are formulated for topical administration are useful, in some embodiments, for treating damaged tissues such as skin. In some embodiments, the formulation is a hydrogel. Generally, a "hydrogel" refers to a network of polymer chains that are hydrophilic and form a colloidal gel in which water is the dispersion medium. In some embodiments, a hydrogel comprises at least 10% w / w water (eg, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% water).
[0307] "Damaged tissue" (eg, damaged skin) refers to tissue that has been chemically or mechanically damaged. Examples of damaged tissue include wounds (eg, cuts, scrapes, puncture wounds, surgical incisions, neuropathic (diabetic) wounds, etc.), burns (eg, chemical burns, sunburns, heat burns, etc.) , blisters, ulcers, muscle and tendon tears, and degenerated nerve tissue.
[0309] In some aspects, the disclosure provides a method of treating damaged tissue in an individual, the method comprising topically administering a composition as described herein to an individual in need thereof. In some embodiments, the individual has an ulcer (eg, a diabetic ulcer). In some embodiments, the individual has a burn, eg, a chemical burn (eg, as a result of a dermatological or cosmetic procedure, such as a chemical peel of the skin).
[0311] In some embodiments, a composition is administered topically to the individual in the form of a spray, foam, gel, or aqueous solution. In some embodiments, a composition is administered to the individual as part of a device or apparatus (eg, a medical device), eg, a solid substrate impregnated with the composition or coated with the composition. Examples of solid substrates that can be impregnated or coated with the composition include, but are not limited to, fibers (eg, natural cotton fibers, synthetic fibers such as nylon, etc.), bandages, pads, coatings (eg, masks facials), plastics, metals (eg stainless steel, titanium, etc.) and the like.
[0313] In other embodiments, a composition as described by the disclosure is administered multiple times. In some cases, the composition can be administered daily, biweekly, weekly, every two weeks, every three weeks, monthly, every two months, every three months, every four months, every five months, every six months or less often than every six months. In some cases, the composition is administered several times a day, week, month and / or year. For example, the composition can be administered approximately every hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, or more than twelve hours. In some embodiments, the composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day.
[0315] Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, the oligonucleotide can be administered repeatedly, eg, several doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation. One skilled in the art will readily be able to determine the appropriate dosages and schedules of administration of the subject compositions, whether the compositions are administered to cells or individuals.
[0317] Aspects of the disclosure relate to methods for use with an individual (eg, a mammal). In some embodiments, a mammalian individual is a primate. human or non-human. Non-limiting examples of nonhuman primates include macaques (eg, Indian or crab-eating macaques), marmosets, tamarins, spider monkeys, owl monkeys, Vervet monkeys, squirrel monkeys, baboons, gorillas, chimpanzees, and orangutans. In some embodiments, the individual is a human individual. Other examples of individuals include domestic animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters
[0319] Examples
[0321] Example 1: Drug Delivery Compositions
[0323] This example describes various embodiments of drug delivery compositions of the disclosure. Generally, the drug delivery compositions described herein comprise the following components: a carbonate buffer solution, at least two different bio-surfactants, at least one hygroscopic agent, at least one antioxidant, and at least one bioactive agent.
[0325] The carbonate buffer system has a pH between 7.5 and about 9.5, preferably between 8.0 and 9.0. When administered to impaired tissue of an individual, the drug delivery compositions described by the disclosure provide a microenvironment that promotes tissue healing and regeneration. Certain ions present in buffers increase the concentration of large Na + or NH4 + ions in a composition or in a microenvironment created when the composition comes into contact with damaged tissue. Large ions bind to certain molecules on the surface of mammalian cells, such as heparin sulfate (HS), and prevent pathogens from entering cells by disrupting the attachment of microbes, such as bacteria and viruses, by HS on the surface of target cells. The ability of the compositions disclosed by the disclosure to provide such an environment at this pH is surprising in view of currently available wound healing compositions, which typically have pH values in the neutral to acid range.
[0327] The combination of two bio-surfactants in the compositions described herein serves several purposes. In some embodiments, bio-surfactants disrupt the surface tension of cells, such as bacterial cells and cells. cells of damaged tissue, thus promoting molecular debridement. In addition, surfactants help the bioactive molecules in the composition to penetrate deeply into damaged tissue.
[0329] The hygroscopic agent provides moisture to the wound bed and promotes proper hydration of the tissue as it heals. Hygroscopic agents further provide, in some embodiments, a matrix that can serve as a scaffold for cell adhesion and differentiation in tissue regeneration.
[0331] The antioxidants present in the compositions scavenge free radicals and reduce reactive oxygen species (ROS), which is important to reduce inflammation in damaged tissue as the healing process occurs. Antioxidants can also function as preservatives in the compositions.
[0333] The compositions further include one or more bioactive agents, which are delivered by the composition. As described in the following examples, the bioactive agent can be substituted or modified to include bioactive molecules that achieve the desired therapeutic result. An embodiment of a drug delivery composition formulation described by the disclosure is provided in Table 1 below.
[0334] Table 1
[0339] In summary, the drug delivery compositions described in the specification provide a microenvironment that promotes tissue healing and regeneration by simultaneously providing 1) molecular debridement, 2) adequate hydration, and 3) anti-inflammatory and antimicrobial activity, such as removal of bacterial biofilms as a result of disruption of the support structure of the mucopolysaccharide or inhibition of the binding of the pathogen to the target cells of an individual)
[0341] Example 2: Tissue repair composition
[0343] Reducing the symptoms and complications of IOMR, for example, through nutritional support, pain control, prophylaxis, and / or treatment of secondary infections, is currently considered the main cornerstone in the treatment of IOMR.
[0344] Regenerative therapy in dentistry involves the replacement and / or regeneration of oral tissues altered as a consequence of disease or injury. One of the reported aspects that complicate this effort has been the complex nature of the tissues found in the oral cavity. These include both mineralized tissues such as cementum, alveolar bone, and dentin, as well as soft tissues connected by ligaments (periodontal ligament), each of which comprises different populations of cells from various tissue origins (ectodermal and mesodermal).
[0346] Platelet-rich fibrin (PRF) is obtained simply by centrifugation of the patient's peripheral blood without anticoagulants and is therefore strictly autologous. This fibrin matrix contains platelets and leukocytes, as well as a variety of growth factors and cytokines including beta-transforming growth factor (TGF-P1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF). ), interleukin (IL) -ip, IL-4 and IL-6. Furthermore, the fibrin that forms during the final stages of the coagulation cascade, combined with the cytokines secreted by platelets, makes PRF a highly biocompatible matrix, especially at damaged sites where the fibrin network also acts as a deposit of tissue growth factors. Several randomized comparative trials (RCT) have shown that an autologous PRF is more effective for the regeneration of oral tissues than any biomaterial available on the market. However, traditional mouthwashes are designed to disinfect the oral cavity, help remove bacterial plaques and prevent cavities, and are characterized by high concentrations of denaturing and antimicrobial active compounds. The use of mouthwashes containing ethanol, triclosan and chlorhexidine is not recommended for the rinse of postoperative grafts using PRF because they can dissolve the clot and disintegrate the fibrin membrane, affecting the healing process.
[0348] This example describes a tissue repair solution useful for the prevention and healing of the ulcerative phase of RIOM and as an adjunct in dental implant surgery. Mouthwash is usually applied as a spray solution directly to lesions in the oral cavity before and after meals, 3 times a day. An example of a tissue repair solution is described in Table 2 below.
[0349] Table 2
[0354] The composition comprises a drug delivery composition as described in Example 1 and includes bioactives from a balanced blend of high quality propolis extract. In some embodiments, the composition promotes simultaneous biological actions important for mucosal tissue repair, such as anti-inflammatory, antioxidant, immune-inducing, antimicrobial, and antifungal actions. The composition is fully compatible with the use of autologous grafting techniques, such as PRF, since it does not chemically attack the clot or the grafted tissue.
[0356] The bioactive propolis complex comprises several groups of flavonoids, isoflavonoids, caicones and pterocarpans, which possess antibacterial, antifungal and antioxidant actions important for wound healing and for the elimination of bacterial biofilm from the lesion bed in the mucosa and mucosa layers. submucosa. The high antioxidant action of the isoflavonoid bioactive also promotes a sequestration of reactive oxygen species (ROS) generated by the DNA damage of the cellular elements subjected to radiation, causing in turn the reduction of the degradation of the extracellular matrix of the oral mucosa.
[0358] Removal of bacterial biofilm from ulcerated mucosa, in some embodiments, results in decreased polymorphonuclear cell infiltrate and, subsequently, decreased release of pro-inflammatory mediators such as TNF-a, IL-1p, IL-6 and major prostaglandins that mediate hyperalgesic pain.
[0360] The presence of biomolecules with high tensile strength, such as rhamnolipids and sopho-lipid biotensive agents in the drug delivery system, promotes biochemical microdebridement that effectively disrupts the polysaccharide matrix of the bacterial biofilm and removes devitalized tissues. and necrotic caused by damage to cellular tissue.
[0362] All these synergistic actions together promote rapid and effective tissue repair of the injured mucosa.
[0364] Example 3: Wound healing composition
[0366] Chronic wounds do not progress through the normal pattern of wound repair, but remain in a state of chronic inflammation characterized predominantly by abundant cellular infiltration of peripheral mononuclear cells (PMN) and macrophages (MF). Persistent inflammatory cells play an important role in the generation of pro-inflammatory cytokines (eg, IL-1, TNF-α, IL-6) and a hostile pro-oxidant and protease-rich microenvironment. Increased proteolytic activity (eg, neutrophil elastase, MMP-8, and gelatinase) leads to the degradation of growth factors and structural proteins of the extracellular matrix that are crucial for repair. Increased ROS (H2O2, O2-) can lead to direct damage to cells or molecules of the extracellular matrix, or contribute to a higher expression of matrix metalloproteases (MMP), such as (MMP-1, -2, -3, -9 and 13). Bacterial biofilms affect chronic non-healing wounds in the following ways: 1) wounds containing biofilms may not be identified; 2) ineffective biofilm treatment can delay healing; 3) debridement is one of the most important biofilm treatment strategies, but it does not remove all biofilms and therefore cannot be used alone; 4) biofilms can reform quickly; repeated debridement on its own is unlikely just avoid regrowth of biofilm; however, application of an effective topical antiseptic within this time-dependent window can suppress biofilm reformation; and 5) biofilms occur in most chronic wounds and are likely to be located both on the surface and in the deeper layers of the wound. The components of the biofilm (e.g., extracellular adhesion protein (Eap), formyl methionyl peptides, N-acetylmuramyl-L-alanyl-D-isoglutamine) may contribute to altering host repair mechanisms by interfering with cell-matrix interactions or promoting the inflammatory response.
[0368] The following examples describe pharmaceutical administration compositions in the form of a cell activating fluid foam, which includes a bioactive extract comprising sulfated polysaccharides from seaweed, with emollient and healing action, to promote the growth of granulation tissue, and a hydrogel that includes inhibitors of bacterial biofilms such as propolis, baicalin, and adrographolide to promote debridement and removal of dead tissue and debris, and to maintain a moist environment conducive to wound healing. One embodiment of the cell-activating fluid foam is described in Table 3A, and one embodiment of the bacterial biofilm mitigation hydrogel is described in Table 3B below.
[0369] Table 3A
[0370]
[0371] Table 3B
[0376] The bioactive components present in the composition act synergistically at various points in the chronic wound healing process. For example, the saponoside compounds present in the Aloe vera phytocomplex, combined with bacterial lipid surfactants, facilitate the elimination of bacterial biofilms by altering their mucopolysaccharide matrix, thus reducing infection and the inflammatory response in the wound bed.
[0378] The sulfated polysaccharides from seaweed present in the cell activating fluid foam are important antioxidants and scavengers of free radicals, such as hydroxyl and superoxide (H2O2, O2), which reduce the pro-oxidant and proteolytic activity avoiding the destruction of immune cells, growth factors and the extracellular matrix. In addition, they can stimulate the immune system by controlling the activity of macrophages. Sulfated polysaccharides such as carrageenan, ulvan, and fucoidan can modify macrophage activity by increasing bacterial binding and killing activities in the colonized wound. The anticoagulant and antithrombotic activity of sulfated polysaccharides also contributes to this synergistic action of the product, preventing the formation of microthrombosis and consequently promoting angiogenesis in the new growing tissue.
[0379] Example 4: Skin repair cosmetic composition
[0381] This example describes a therapeutic skin repair mask impregnated with a composition useful as a cosmeceutical in post-skin peel procedures, eg, fractionated laser, chemical and pulsed light peel. The composition can also be used as a regenerative treatment after minor dermatological procedures to remove signs, spots, cysts and freckles.
[0382] The composition comprises a biodegradable natural fiber face mask that is impregnated or coated with a drug delivery composition comprising bioactives such as beta-carotene (for example, derived from carrot oil), alpha-tocopherol and other important components in the dermal regeneration process. The bioactives are incorporated into a fluid matrix of hyaluronic acid and panthenol, which plays a key role in preserving the remaining vegetative tissues after a laser burn, for example.
[0384] Hyaluronic acid (HA) also works in the epidermis to maintain the extracellular space and provide an open structure, in addition to being hydrated, for the passage of nutrients. Bioactives and nutrients such as retinoic acid (vitamin A), alphatocopherol (vitamin E), and vitamin B5 (dexpanthenol) can be transported extensively through the HA matrix to the tissue under repair. Furthermore, HA is likely to play a multifaceted role in mediating matrix and cellular events followed by trauma, inflammation, granulation tissue formation, re-epithelialization, and remodeling. An example of the drug delivery composition described in this example is provided in Table 4 below.
[0385] Table 4.
[0390] Example 5: Therapeutic composition for herpes infection
[0392] The VSH-1 virus resides on the skin of the lips and causes cold sores (HSL). Cold sores (HSL), also known as fever or fever blisters, affects millions of Americans. There are an estimated 98 million cases of HSL each year in the United States alone.
[0394] Initial infection with the virus is by direct contact between the mucous membranes or scraped skin of the lips or mouth and the saliva or other secretions of a person with active or recurrent primary infection. Primary HSV infection usually occurs in early childhood, often without symptoms, but can also present as herpetic gingivostomatitis, characterized by oral and perioral vesicles (small blisters) and ulcers. HSL is preceded by warning signs, which are known as "prodromal symptoms"; These are pain, burning, itching, or tingling sensations at the site of later gallbladder development. The Headache can also occur in the prodromal phase. Within 24 hours after the prodromal phase, multiple clustered vesicles appear and then ooze until they finally crust over. These scabs can often bleed quite easily, forming unsightly blackish scabs due to dried blood, which can bleed again when the skin is stretched, for example when eating and smiling. These usually heal without scarring within 5 to 15 days. Cold sores can cause pain, discomfort, discomfort, and a certain amount of psychological and social distress as a result of cosmetic disfigurement.
[0396] After primary infection, the virus resides in the sensory ganglia (nerve endings) in a latent form. After reactivation, HSV migrates from these sensory nodes to the outer layer of the skin of the lips or mouth to cause recurrent HSL. The virus replicates in neurons, causing recurrent outbreaks. Outbreaks are usually induced by exposure to ultraviolet light (sunlight and / or tanning beds), stress, immunosuppression, the common cold, fatigue, fever (hence the term “fever” or “fever blisters”), overexposure to wind, extreme temperatures, menstrual periods, pregnancy, dental work or trauma to the lips. Perioral laser dermabrasion or injection of perioral botulinum toxin or fillers can stimulate a flare. Currently, there is no cure for HSL, so theoretically, once contracted, the infection remains for life.
[0398] This example describes a medicated solution containing natural antiviral bioactive extracts combined with peripheral nerve repair factors to treat cold sore (HSL) and genital herpes. The composition comprises a topical formulation for the treatment of fever and genital herpes. No topical product currently available on the market addresses both the reduction of viral infection and the recovery of injured nerve tissue. One embodiment of the topical composition is described in Table 5 below.
[0399] Table 5
[0401]
[0404] Melissa officinalis bioactive comprises monoterpenoid compounds, such as geranial, a-bisabolol, p-caryophyllene, linalol, neral, citronellal, a-cadinol, p-cadinene and others, which have synergistic antiviral effects against HSV-1 and HSV-2 . In addition to monoterpenoid bioactives, Melissa officinalis bioactive extracts comprise polyphenolic compounds, such as rosmarinic acid, which exhibit antiviral activity for both cold sores (VSH-1) and genital herpes (VSH-2). In some embodiments, the composition further comprises (or is co-administered with) one or more antiviral agents (eg, acyclovir, etc.) that are currently used to treat VSH infection.
[0406] Methylated vitamin B12 and methylcobalamin have been shown to be involved in the repair mechanism of degenerated and injured peripheral nerves, in addition to reducing neuropathic pain and promoting neural growth.
[0408] In some embodiments, the biosurfactants and ions present in the composition (via the buffering system) can block virus entry into target cells by interfering with HS binding on the cell surface.
[0409] Example 6: Evaluation of Tissue Repair Hydrogel Formulations in an Ex vivo Porcine Dermal Model with Biofilm Formation
[0411] This example describes experiments to investigate the efficacy of four different wound treatments (formulations A, B, C and D) in a porcine dermal explant model. Briefly, 3 day old mature explants were treated with the gel formulations for 24 or 72 hours, followed by recovery of microbial survivors. Three representative microbial species were used in this study: Staphylococcus aureus (Gram positive) resistant to methicillin, Pseudomonas aeruginosa (Gram negative) and Candida albicans (yeast).
[0413] Overall, the tested tissue healing formulations performed well at the 72-hour treatment time, showing a markedly higher level of efficacy of the treatments relative to the 24-hour time, with <1.5 log load. microbial in all species evaluated. It is important to note in this case that the treatments were not reapplied, but the original treatment was left on the explants during the treatment time of 72 h.
[0415] Materials and methods
[0417] Test formulations: Five different tissue healing formulations containing propolis (formulations A, B, C and D) were tested. Each formulation was a hydrogel containing a different concentration of active agent (eg, propolis) . A hydrogel without active agent was tested as a negative control (excipient). For each hydrogel formulation, approximately 2 ml was applied to each explant that was used in the study.
[0419] Test organisms: Efficacy against Gram positive and Gram negative bacteria, as well as fungal species, was evaluated. The species and associated ATCC numbers are listed in Table 6.
[0420] Table 6
[0425] Establishment of the biofilm
[0427] Porcine tissue for explants was obtained from a USDA licensed facility that uses precision leveling technology to prepare porcine dermis to a specific thickness of approximately 2mm. Using a needle biopsy, the tissue was cut into circular explants approximately 12 mm in diameter and artificially injured using a Dremel tool to create a wound approximately 2 mm in diameter with a cavity 1.5 mm deep. The explants were then thoroughly washed and sterilized with chlorine gas. Before inoculation and application of the test formulations, the explants were placed on 0.5% agar in an incubator at 37 ° C for approximately 2 h to equilibrate. The explants were then inoculated with 15-20 μl of log phase cultures of the specified bacteria, or 48 h culture of C. albicans, at approximately 105 CFU per explant, and allowed to incubate for 3 days on 0 agar. , 5% with daily transfer to fresh agar plates.
[0429] Treatment
[0431] The 3 day old explants were washed for 2 min in 2 ml of sterile PBS followed by treatment with the test compositions. Formulations A, B, C and D were loaded into 10 ml syringes to allow controlled dosing of the explants with approximately 2 ml of the formulations. After washing, the explants were transferred to individual wells of a 24-well plate, followed by the addition of the test formulations. Then the plates were placed in the incubator for 24 h. In the second round of testing, the treatment time was extended to 72 h to assess whether there was any benefit from extending the treatment time. All four formulations and the vehicle control were treated in the same way. After the designated treatment time, the surviving bioburden recovered from all explants and numbered by serial dilution and plating.
[0433] Recovery of surviving bacteria
[0435] After incubation for 24 or 72 hours, surviving bacteria and yeast were recovered from the tissue and enumerated. First, the remaining formulations were gently removed from the explants by tilting the explants followed by two washes in 2 ml of sterile PBS (2 min each) to remove any remaining material. The washed explants were then placed in a 15 ml centrifuge tube containing 2 ml of Dey / Engley broth, a general neutralizer. The explants were vortexed for 10 seconds and subjected to a series of 5 debridement steps with sonication: 90 sec sonication / 60 sec rest intervals. Samples were vortexed again to ensure homogeneity, serially diluted and spotted (10 µl sample / spot, in triplicate) to the -6 dilution and plated as necessary (200 | jl of undiluted recovery solution).
[0437] Efficacy data
[0439] The data are summarized in Table 7 and Figures 1-3.
[0441] Table 7
[0446] The efficacy of tissue repair formulations against methicillin- resistant S. aureus three-day-old biofilms is summarized in Figure 1. In general, the AD formulations showed comparable efficacy with approximately 5 logs of survival after 24 h of treatment, compared to approximately 7.5 logs for untreated controls. The extended treatment time reduced survival significantly to levels below 1 log for formulations AC and approximately 1.5 logs for formulation D. Interestingly, the excipient also showed a reduction in microbial load at the 24 treatment mark. h, almost a log reduction of 2, but the extended treatment time decreased S. aureus survival by only about 1 log, while the formulations tested showed significantly greater efficacy.
[0448] The efficacy of the tissue repair formulations against three-day P. aeruginosa biofilms is summarized in Figure 2. Similar to what was reported for S. aureus, the extended treatment time increased the efficacy of all formulations. All AD formulations showed a reduction of more than 5 log in 24 h and less than 1 log of survival after 72 h. These formulations appear to have better efficacy against P. aeruginosa than S. aureus at the 24 h treatment time point; however, the excipient alone also showed a time-dependent increase in efficacy against P. aeruginosa biofilms, during the 72 hr treatment resulting in 2 log survival.
[0450] The efficacy of the tissue repair formulations against three-day C. albicans biofilms is summarized in Figure 3. The overall efficacy profile against C. albicans is similar to that observed for Gram-positive S. aureus where all formulations show an increase in efficacy with an extended treatment time (72 h treatment versus 24 h), and the efficacy at the 72 h treatment time point is significantly greater than that of the excipient alone.
[0452] In general, all the formulations evaluated in the study showed very high efficacy against the biofilms of the three representative microbial species evaluated: Gram positive S. aureus , Gram negative P. aeruginosa and yeast C. albicans. The extended treatment time of 72 h resulted in an overall increase in efficacy for all formulations, resulting in <1.5 logs of viable bacteria in all species. The excipient alone also showed a decrease in the microbial load with a logarithmic reduction of approximately 2-3 after treatment times of 24 h and 72 h for S. aureus and C. albicans, and a logarithmic reduction of 3 to 24h and logarithmic reduction of almost 7 at 72h for P. aeruginosa.
[0454] There are some important things to keep in mind in this case that may be relevant to explain the observed efficacy of the excipient:
[0455] • In this study, the total microbial load, planktonic bacteria biofilm, was listed. This could explain the partial efficacy of the excipient, especially for the 24-hour treatment. As a reference, if the 3-day explants with biofilm are treated for 24 h in a solution of antibiotic or an antifungal agent at concentrations> 200x the MIC value, a reduction in microbial load of <2 logarithms is generally observed.
[0456] • P. aeruginosa produces biofilms with much more biomass than other species. If the excipient components are disrupting the P. aeruginosa biofilm, this may result in an increase in observed efficacy, although it may not come from microbial kill, but rather from physical removal of the biofilms from tissue.
[0458] Example 7: Evaluation of Full-Thickness Porcine Model Excision Wound Healing Using Hydrogel Formulations Containing Antibiofilm Inhibitors
[0460] This example describes the evaluation of four tissue healing hydrogel formulations containing different concentrations of propolis, baicalin and andrographolide in a porcine full thickness excisional wound healing dermal model.
[0462] The healing properties of tissue repair hydrogels (eg hydrogels comprising propolis) and three predicates were studied on full thickness skin wounds in a porcine model. Before surgery, a male pig ("Large white") weighing approximately 39.5 kg was acclimated for 3 days and fasted for 12 h. The animal was sedated with intramuscular ketamine (5 mg / kg), midazolam (0.5 mg / kg), and acepromazine (0.05 mg / kg). After sedation, the animal was anesthetized by an atrial intravenous injection of Propofol (5 mg / kg) after isoflurane inhalation to maintain sedation. Anesthetic blockade was performed at the incision site with 2% lidocaine. Before surgery, the dorsal surface was shaved and sterilized with 2% chlorhexidine. Sixteen full thickness incision wounds with a diameter of 2 cm were made symmetrically in four rows with N.11 scalp and pig loin scissors using a steel template. stainless.
[0464] Eight duplicate tissue healing treatments were tested at wound sites: InnovaCorium Dressing Hydrogel (IWD) -formulation A, B, C and D, Plurogel® (PG-Medline, Northfield, IL), Medihoney ® (MH-Derma Sciences, Toronto, Canada), Amerigel® (AMG -Amerx, Clearwater, FL) and saline control (SAL). The sites were randomly selected for each treatment according to Figure 4. The amounts of selected components in formulations A, B, C and D are shown in Table 8 below.
[0466] Table 8
[0468]
[0471] An amount of 0.5 g of each product was administered to the wound bed every 24 hours for the 22 days of the study. Wounds were initially rinsed with sterile saline to remove product residue from the previous application. The area around the wound was then cleaned with sterile gauze for better fixation of the new dressing cover. To reduce stress and pain to the animal during dressing changes, sedation of intramuscular ketamine (10 mg / kg) and midazolam (0.5 mg / kg) was administered during the first week. Wound sites were covered with Curatec clear film (Urgo Medical, France) and 3M ™ Micropore ™ surgical tape (3M, Maplewood, MN). After covering the injuries, the animal was dressed in a clean cotton garment for comfort and protection from occasional trauma.
[0473] To assess the wound healing efficacy of the treatment, the wounds were photographed every week to estimate the area using Image J software (NIH, USA) with a known circular area template as a reference. Wound bed biopsies were collected on day 15 (duplicate 1) and day 22 (duplicate 2) to assess the histological healing stage of the wounds. Histological slides they were made with 3 micron sections and then left for 30 minutes in an oven at 75 ° C to drain the paraffin. Masson's hematoxylin eosin and trichrome stains were used. Briefly, the samples were dewaxed in 3 xylene vats for 5 min. each one, then they were hydrated with 10 passes in decreasing alcohol, 100%, 90%, 80%, 70% and water. Nuclear staining was performed with Harrys hematoxylin for 3 min. followed by washing in tap water for 1 min. Overlap with hematoxylin performed by 10 passes in Scoth solution and rinse under running water for an additional 2 min. The cytoplasm was stained with eosin for 3 min. Finally, the dehydration carried out by increasing the alcohols and clarification by means of 3 xylol vats, 10 passes in each one for assembly in a synthetic medium. Masson's trichrome staining was performed by deparaffinization in 3 xylene vats for 5 min each and hematoxylin staining for 3 min. The samples were overlapped in the Scoth solution for 10 passes. The samples were then subjected to Briebrich Scarlat's solution-15 min, phosphotungstic acid / phosphololybdic acid-10 min, aniline blue-5 min and 1% acetic acid -2 min. Dehydration in increasing alcohols, clarification and assembly in a synthetic medium.
[0475] Figures 5A-5H are photographs depicting the healing process of deep excision wounds in pigskin with various treatments and controls. After twenty-four hours of causing the excision wounds, they were clean, with no signs of bleeding, infection, edema or erythema. At 7 days of treatment, all wounds treated with tissue repair formulation, regardless of formulation A, B, C or D, showed a slight impregnation of the product in the wound bed. In the region of tissue around the wound, a slight impregnation of the product was observed with difficulty in rinsing with saline solution. These impregnations were more pronounced in the formulations with the highest concentration of propolis (Figures 5A and 5D). Wounds treated with different predicates and control saline also had impregnations, but not as dark and deep as in the propolis-containing formulations. After 14 days of treatment, none of the lesions had more product accumulation in the wound bed. Among the formulations, Formulation C exhibited the largest granulation tissue area associated with the lowest percentage reduction rate in the wound (Figure 5C). One of the wounds treated with MH showed hypergranulation and edema, but no infections, exudates, or erythema were observed in any of the wounds throughout the study period (Figure 5G). The data show that in the first week of treatment there was no significant reduction in the area of the lesion in any of the treatments in comparison with saline control. However, in the second week of treatment, all formulations performed better than with the control saline solution. Table 9 shows the wound area of each treatment and control during the observation period. At the end of the study, Formulation A shows the highest percentage wound reduction (98.6%), compared to saline control (93.3%), as shown in Figure 6. Treatment with MH did not result in wound healing during this study.
[0477] Table 9
[0479]
[0482] The histological characteristics of intact porcine skin and of all wounds treated with the different products were evaluated. Biopsies of intact tissue without damage showed a very characteristic dermal structure of porcine integuments, with unaltered connective tissue, with bundles of collagen fiber, absence of atypical and / or inflammatory cell infiltrate, as well as few dermal papillae. In general, the observed fragments were completely epithelialized with a thin layer of uncompressed keratin. The histological sections of the biopsies obtained from the wounds showed epidermal structures not as organized as in the case of intact skin, in addition to being characterized mainly by the presence of inflammatory infiltrates and loose connective tissue deposition, with more dispersed and less dense fibers. The biopsies collected from the wounds showed that, in general, formulations A and D had greater tissue replacement in 15 days with epidermis formation, in addition to invagination and keratin deposition by the stratified keratinocytes. Formulation C was the one that required the most time to reach this stage. Among the predicates, AMG was the product that rebuilt the epidermal and dermal structures more quickly. On the other hand, MH was the one that took the longest to repair the layers of skin. After 21 days, the histological sections of the biopsies of the wounds treated with the tissue repair composition showed organization and complete stratification of the epidermal structures, with distinction between the different layers of epidermis strata, even in lesions treated with the Formulation C. On the other hand, the wounds treated with MH and SAL presented incomplete epidermal formation after finishing 21 days of treatment.
[0484] The data described above indicates that all wound healing formulations (eg, A, B, C and D) demonstrated high healing ability in full thickness excision wounds in porcine skin compared to saline treated lesions. PG and AMG products also showed high healing effectiveness in the study. Those that performed best during the test were formulation A and AMG, with a reduction of more than 98% of the wound after 21 days of treatment. Differences in swine skin excision wound healing stages between different treatments and controls were followed histologically to confirm tissue reorganization in the skin repair process. Again, Formulation A, Formulation D and AMG showed advanced restructuring of the epidermis layers after 15 days of treatment.
[0486] EQUIVALENCES
[0488] Having thus described various aspects of at least one embodiment of this invention, it is appreciated that various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure and to be within the spirit and scope of the invention. Accordingly, the above description and drawings are by way of example only.
[0490] While various embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily see a variety of other means and / or structures for performing the functions and / or obtaining results and / or a or more of the advantages described herein, and each such variation and / or modification is considered within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein they are intended to serve as an example and that the actual parameters, dimensions, materials and / or configurations depend on the specific application or specific applications for which the knowledge of the present invention is used. Those skilled in the art will recognize, or be able to verify without more than routine experimentation, many equivalents of the specific embodiments of the invention as described in the present invention. Therefore, having understood that the above embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereof, the invention may be practiced in a manner other than that specifically described and claimed. The present invention relates to every feature, system, article, material, and / or method herein. Furthermore, any combination of two or more of said features, systems, articles, materials and / or methods, if such features, systems, articles, materials and / or methods are not mutually inconsistent, are included within the scope of the present invention.
[0492] The indefinite articles "one / one" and "one", used herein in the specification and claims, unless otherwise indicated, are to be construed as "at least one".
[0494] The phrase "and / or", as used herein in the specification and in the claims, should be construed as "one or both" of the interrelated elements, that is, elements present together in some cases and disjunctively present. in other cases. Optionally, elements other than the elements specifically identified by the “and / or” clause may be present, whether or not they are related to the specifically identified elements, unless otherwise clearly indicated. Accordingly, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open language such as in the case of "comprising" may refer, in one embodiment, to A without B (of optional form including elements other than B); in another embodiment, it may refer to B without A (optionally including elements other than A); in yet another embodiment, it may refer to A and B (optionally including other elements); etc.
[0496] As used herein in the specification and claims, "or" is to be construed as having the same meaning as "and / or" as defined above. For example, when items are separated in a list, "or" or "and / or" should be interpreted as inclusive, that is, the inclusion of at least one, but also including more than one, of a number or list of items, and, optionally, additional items not listed. Only terms that clearly indicate otherwise, such as "only one of" or "exactly one of", or, when used in the claims, "consisting of", will refer to the inclusion of exactly one element of a number or list Of elements. In general, the term "or" as used herein should only be construed as an indication of exclusive alternatives (ie, "one or the other, but not both") when preceded by exclusivity terms, such as " either "," one of "," only one of ", or" exactly one of ". About "consisting essentially of", when used in claims, should be considered in its ordinary meaning, as used in the field of patent law.
[0498] As used herein in the specification and claims, the phrase "at least one", in reference to a list of one or more items, is to be construed as indicative of at least one of the items selected from one. or more of the items in the item list, but not necessarily including at least one of each and every item specifically listed within the item list and without excluding any combination of items in the item list. This definition further allows items to be optionally present in addition to specifically identified items within the list of items to which the phrase "at least one" refers, whether related or unrelated to the specifically identified items. Therefore, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B”, or, equivalently, “at least one of A and / or B ") may refer, in one embodiment, to at least one; optionally including more than one A, with no B present (and optionally including elements other than B); in another embodiment, at least one, optionally including more than one B, without A being present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); etc.
[0500] In the claims, as well as in the above specification, all transition phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "which sustains ”, and the like should be interpreted as open, that is, in the sense of including, but not limited to. Only the phrases “consisting of” and “consisting essentially of” will be closed or semi-closed transition phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examination Procedures, Section 2111.03 .
[0502] The use of ordinal terms such as "first", "second", "third", etc., in claims to modify a claim element does not in itself connote any priority, precedence or order of one claim element over another, nor the temporal order in which the actions of a method are carried out, but act only as labels to distinguish a claim element that has a certain name from another element that has the same name (but to use the ordinal term ), to distinguish the elements of the claims.
[0504] It should be further understood that, unless clearly stated otherwise, in any of the methods claimed herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which that the steps or actions of the method are listed.

权利要求:
Claims (76)
[1]
1. Composition comprising:
(i) a drug delivery system comprising a carbonate buffer solution, at least two different bio-surfactants, at least one hygroscopic agent, and at least one antioxidant; and
(ii) at least one bioactive agent,
wherein the composition has a pH ranging from about 7.5 to about 9.5.
[2]
Composition according to claim 1, in which the carbonate buffer solution comprises one of the following ions: sodium, potassium, calcium and magnesium; optionally, wherein the carbonate buffer solution is a bicarbonate buffer solution.
[3]
Composition according to claim 1 or 2, in which each of the at least two bio-surfactants is selected from a polymeric glycolipid, lipopeptide and biotensurfactant.
[4]
Composition according to claim 3, in which the glycolipid is selected from a rhamnolipid, sophoolipid, trehalolipid, cellobiolipid, mannosyl erythritol lipid and any combination thereof.
[5]
Composition according to claim 3, in which the lipopeptide is selected from a surfactin, plipastatin, bacilomycin, fengicin, subtilisin, gramicidin, polymyxin and any combination thereof.
[6]
Composition according to claim 3, in which the polymeric biotensurfactant is selected from emulsan, biodispersan, liposan, mannan-lipidoprotein complex, carbohydrate-lipid-protein complex, and any combination thereof.
[7]
Composition according to any one of Claims 1 to 4, in which at least two biosurfactants comprise a rhamnolipid and a sophorolipid.
[8]
Composition according to any one of Claims 1 to 7, in which the total amount of the biotensive agents in the composition ranges from about 1.5% (w / w) to about 10% (w / w).
[9]
Composition according to claim 7, wherein the ratio of rhamnolipid to sophoolipid ranges from about 1: 9 to about 9: 1; optionally, wherein the ratio is about 1: 1 or about 7: 3.
[10]
Composition according to any one of Claims 1 to 9, in which the hygroscopic agent comprises an agent selected from a glycol polymer, glycosaminoglycan and a cellulosic polymer.
[11]
Composition according to claim 10, in which the glycol polymer comprises a polyethylene glycol polymer.
[12]
Composition according to claim 10, in which the glycosaminoglycan is hyaluronic acid.
[13]
Composition according to claim 10, in which the cellulosic polymer comprises carboxymethylcellulose or hydroxyethylcellulose.
[14]
Composition according to any one of claims 1 to 12, wherein the amount of hygroscopic agent in the composition ranges from about 1% (w / w) to about 10% (w / w).
[15]
Composition according to any one of Claims 1 to 14, in which at least one antioxidant comprises a lipophilic antioxidant.
[16]
16. Composition according to claim 15, in which the lipophilic antioxidant is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and / or a tocopherol; optionally, wherein the tocopherol is alpha-tocopherol.
[17]
Composition according to any one of Claims 1 to 16, in which the at least one bioactive agent is a small molecule, protein, nucleic acid or a bioactive extract.
[18]
Composition according to claim 17, in which the bioactive extract is obtained from one or more types of propolis.
[19]
Composition according to claim 18, wherein the propolis comprises green propolis, brown propolis, red propolis, or a combination of any of the foregoing.
[20]
20. Composition according to claim 18 or 19, in which the natural bioactive extract comprises one or more of the following: flavonoid, artepilin C, triterpenoid, isoflavone and aromatic acid.
[21]
21. Composition according to claim 19 or 20, wherein the ratio of green propolis to brown propolis ranges from about 1: 9 to about 9: 1.
[22]
Composition according to any one of claims 18 to 21, in which the total amount of bioactive propolis extract ranges from about 5% (w / w) to about 20% (w / w).
[23]
23. Composition according to claim 17, in which the bioactive natural extract is obtained from one or more types of seaweed.
[24]
24. Composition according to claim 23, wherein the one or more types of algae marinas are selected from the genus Enteromorpha, Ulva, Monostroma, Codium, Caulerpa, Bryopsis, Porphyra and Laminaria.
[25]
25. Composition according to claim 23 or 24, wherein the bioactive natural extract comprises one or more sulfated polysaccharides; optionally wherein each of the one or more sulfated polysaccharides is selected from carrageenan, ulvan, galactan, and fucoidan.
[26]
Composition according to any one of Claims 23 to 25, in which the total amount of bioactive extract ranges from about 5% (w / w) to about 20% (w / w).
[27]
Composition according to any one of claims 18 to 26, in which the bioactive extract further comprises Aloe vera, baicalin or andrographolide.
[28]
28. Composition according to claim 17, in which the bioactive natural extract comprises one more carotenoids and / or vitamin A; optionally in which the carotenoids and / or vitamin A are obtained from carrot oil.
[29]
29. Composition according to claim 28, wherein the natural bioactive extract comprises one or more vitamin B complexes.
[30]
30. Composition according to claim 28 or 29, wherein the one or more vitamin B complexes is a derivative of pantothenic acid or a derivative or analog thereof; optionally wherein the vitamin B complex comprises dexpanthenol.
[31]
31. Composition according to any one of claims 28 to 30, wherein the composition further comprises one or more proteins; optionally wherein the protein comprises collagen and / or albumin.
[32]
32. Composition according to any one of claims 28 to 31, in which the total amount of the bioactive natural extract ranges from approximately 1% (w / w) to approximately 5% (w / w).
[33]
33. Composition according to claim 17, in which the bioactive natural extract is obtained from Melissa officinalis.
[34]
34. Composition according to claim 33, wherein the bioactive natural extract comprises one or more vitamin B complexes.
[35]
35. Composition according to claim 33 or 34, wherein the one or more vitamin B complexes comprise methylcobalamin and / or cyanocobalamin.
[36]
36. Composition according to claim 33 or 34, wherein one or more vitamin B complexes is a derivative of pantothenic acid or a derivative or analog thereof; optionally wherein the vitamin B complex comprises dexpanthenol.
[37]
37. Composition according to any one of claims 34 to 36, in which the total amount of the bioactive natural extract ranges from approximately 1% (w / w) to approximately 5% (w / w).
[38]
38. Composition according to any one of claims 1 to 37, wherein the composition is formulated as a solid (eg powder, such as lyophilized powder), liquid, gel or foam.
[39]
39. A composition according to claim 38, wherein the liquid is a mouthwash.
[40]
40. A composition according to claim 38, wherein the gel or foam is formulated as an aerosolized spray or a hydrogel.
[41]
41. Composition according to claim 38, wherein the composition is presented on or on a solid substrate.
[42]
42. Composition according to claim 41, in which the solid substrate comprises cotton fibers.
[43]
43. Composition according to claim 41 or 42, wherein the solid substrate is a cotton bandage or mask.
[44]
44. Solid substrate comprising the composition according to any one of claims 1 to 38.
[45]
45. A solid substrate according to claim 44, wherein the substrate comprises cotton fibers.
[46]
46. A solid substrate according to claim 44 or 45, wherein the substrate is a bandage or a mask.
[47]
47. Kit comprising:
(i) the composition according to any one of claims 1 to 38; and, (ii) a non-adherent wound dressing.
[48]
48. The kit of claim 47, wherein the non-adherent wound dressing comprises cotton fibers.
[49]
49. Kit according to claim 47 or 48, further comprising one or more elastic bandages.
[50]
50. Kit according to any one of claims 47 to 49, wherein the composition is formulated as a foam, gel or liquid.
[51]
51. Kit comprising:
(i) the composition according to any one of claims 1 to 38; and, (ii) one or more antiviral agents effective to treat a herpes simplex virus.
[52]
52. A kit according to claim 51, wherein the one or more antiviral agents is selected from acyclovir, valacyclovir and famciclovir.
[53]
53. Kit according to claim 51 or 52, wherein the herpes simplex virus is herpes simplex labialis (HSL).
[54]
54. A method of treating oral cavity lesions in an individual, the method comprising administering a composition according to any one of claims 1 to 38 to an individual having one or more oral cavity lesions.
[55]
55. The method of claim 54, wherein the individual has or is suspected of having mucositis.
[56]
56. A method according to claim 54 or 55, wherein the individual has previously received chemotherapy, radiotherapy or a combination of chemotherapy and radiotherapy.
[57]
57. Method according to any one of claims 54 to 56, wherein the individual has undergone oral maxillofacial surgery.
[58]
58. A method according to any one of claims 54 to 57, wherein the composition is administered directly into the oral cavity of the individual; optionally wherein administration is via oral spray or mouthwash.
[59]
59. The method of any one of claims 54 to 58, wherein the individual is administered the composition more than once a day (eg 2, 3, 4 or more times a day).
[60]
60. Method according to any one of claims 54 to 59, wherein the individual is administered the composition before a meal, after a meal, or both before and after a meal.
[61]
61. Method according to any one of claims 54 to 60, wherein the administration of the composition inhibits the formation and / or growth of bacterial biofilm.
[62]
62. Method comprising administering the composition according to any one of claims 1 to 38, to the skin of an individual in need thereof.
[63]
63. The method of claim 62, wherein the skin has been subjected to a cosmetic procedure; optionally wherein the cosmetic procedure is a laser skin peel.
[64]
64. A method according to claim 62 or 63, wherein the individual's skin is damaged; optionally wherein the damaged skin is a wound, ulcer or blister.
[65]
65. The method of any one of claims 62 to 64, wherein the administration comprises contacting the skin of the individual with a solid substrate comprising the composition.
[66]
66. The method of claim 65, wherein the solid substrate is a non-adhesive bandage or a cotton face mask.
[67]
67. A method according to any one of claims 62 to 64, wherein the administration is topical administration.
[68]
68. Method according to any one of claims 62 to 67, wherein the administration occurs at least 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 times a day.
[69]
69. Method according to any one of claims 62 to 68, wherein the administration occurs at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times per week.
[70]
70. Method according to any one of claims 62 to 69, wherein the individual has or suspects that he or she has a chronic wound as a result of diabetes, or damaged skin associated with insufficient blood flow (for example, varicose veins, bedsores, decubitus, etc.).
[71]
71. Method according to any one of claims 62 to 69, wherein the individual is infected or suspected of being infected with the herpes simplex virus; optionally wherein the herpes simplex virus is cold sore.
[72]
72. Method for regenerating a peripheral nerve ending in an individual in need, the method comprising administering to the individual:
(i) a first composition comprising a bioactive extract of Melissa officinalis; and
(ii) a second composition comprising methylcobalamin and / or cyanocobalamin.
[73]
73. The method of claim 72, wherein the first composition and the second composition are administered as the composition of any one of claims 33 to 37.
[74]
74. The method of claim 72 or 73, wherein the first and / or second composition is administered topically.
[75]
75. A method according to any one of claims 72 to 74, wherein the individual's skin is damaged; optionally wherein the damaged skin is a wound, ulcer or blister.
[76]
76. Method according to any one of claims 72 to 75, wherein the individual is infected or suspected of being infected with the herpes simplex virus; optionally wherein the herpes simplex virus is cold sore.

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SG11202107572TA|2021-08-30|

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DE112020000406T5|2021-10-28|

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CO2021010366A2|2021-10-29|

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KR20210114438A|2021-09-23|

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JP2022517225A|2022-03-07|

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AU2020207071A1|2021-08-12|

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IL284733D0|2021-08-31|

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WO2020146752A1|2020-07-16|

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CN113412125A|2021-09-17|

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法律状态:
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US201962791005P| true| 2019-01-10|2019-01-10|

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PCT/US2020/013118|WO2020146752A1|2019-01-10|2020-01-10|Pharmaceutical delivery compositions and uses thereof|

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