Compositions and uses of triglyceride mimetics that selectively target microbial lipases - Patents.com

Abstract

Provided are new products derived from triazelain glycerol, a naturally occurring source of unsaturated fatty acids, compositions, methods of manufacture, and uses in various disease states associated with modulation of the microbiome, and other anti-inflammatory methods.

Description

[Technical field]

[0001] The present invention relates to new products derived from triazelain glycerol. In particular, the present invention relates to products derived from naturally occurring sources of unsaturated fatty acids, compositions, methods of manufacture, and uses in various disease conditions associated with modulation of the microbiome. [Background technology]

[0002] The host commensal and pathogenic microbiome is composed of multiple microbial species and strains of fungi, yeasts and bacteria. Most of this microbiome variety is harmless, many are beneficial and some are even necessary. The bacterial flora that harbors our bodies influences the host's predisposition to metabolic pathologies, inflammation, immune susceptibility and even cancer. Human microbiome species reside both within and on the human body, especially on the skin and mucous membranes.

[0003] Lipases are toxic factors released in opportunistic skin pathologies, such as Cutibacterium acnes and Staphylococcus species, from hydrolyzed sebum triglycerides and wax esters into free fatty acids and glycerol, which inflame the epithelium of the follicle and cause follicle rupture, thus initiating an inflammatory response and excessive proliferation of keratinocytes.

[0004] Azelaic acid is an approved drug and cosmetic ingredient known to be used as an anti-inflammatory, anti-acne, anti-melasma, anti-rosacea, skin lightening active ingredient in topical cosmetic and medical topical preparations. Similar to retinoic acid and lipohydroxy acid, azelaic acid has side effects, such as irritation. Antibiotics are also widely used. However, when applied topically, antibiotics may lose their effectiveness due to resistance expressed by bacteria when used for extended periods. Oral administration of antibiotics exposes the whole body to antibiotic compositions, whereas in acne, only the skin is affected. Moreover, almost all antibiotics have undesirable side effects when taken orally.

[0005] TriAza stands for triglyceride ether of azelaic acid (a known active agent) where azelaic acid is incorporated at the sn-1, sn-2, and sn-3 positions of the triglyceride (triazelide or triazelain). Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there remains a long unmet need for effective and safe treatments for disorders mediated by lipase-producing pathogens. [Means for solving the problem]

[0007] Summary of the Invention It is an object of the present invention to provide effective and safe therapeutic agents and delivery systems for conditions associated with the activity of lipases secreted by microorganisms.

[0008] According to some embodiments, the present invention provides a novel method for the synthesis of TriAza based on the desaturation and oxidation of triolein, the main triglyceride in olive oil, for the production of triglyceride-like compounds.

[0009] According to some embodiments, upon exposure of TriAza and its salts to bacterially associated lipases, azelaic acid disassociates from the molecule, exhibiting specificity and selectivity for lipase-targeted activity.

[0010] According to some embodiments, the present invention provides methods for the preparation of such triazerain derived products and uses of such triazerain derived products.

[0011] According to some embodiments, the present invention provides an effective and safe means of treatment for skin disorders mediated by lipase-producing pathogens.

[0012] According to some embodiments, the present invention provides a composition comprising triazelain for balancing the human microbiome.

[0013] According to some embodiments, the present invention provides compositions for treating a disease or condition associated with an imbalance in the microbiome.

[0014] According to some embodiments, the present invention provides topical compositions that are effective for the treatment of skin disorders, for balancing and maintaining the skin microbiome, for slowing the progression of undesirable skin conditions, such as, without limitation, aging, pigmentation, disorders of the pilosebaceous unit, and other conditions that may benefit from the compositions of the present invention.

[0015] According to some embodiments, the present invention provides a multifunctional carrier for topical compositions that can be used for skin regulating functions, without limitation, as a precursor of azelaic acid, and as a delivery vehicle for biomolecules and microbiome samples.

[0016] According to some embodiments, the present invention provides a topical composition comprising a triazelain and optionally a carrier.

[0017] According to some embodiments, the present invention provides a method of treating an inflammatory skin condition in a subject in need thereof, the method comprising topically administering to the subject an amount of triazelain effective to treat said condition.

[0018] According to some embodiments, the present invention provides a compound of formula:

[0019] [ka] wherein X is azelaic acid, where upon exposure to bacterial lipase, the azelaic acid is cleaved and released from the compound.

[0020] According to some embodiments, the present invention provides a topical composition for the treatment of skin disorders comprising an active therapeutic agent and triazelain as a carrier.

[0021] According to some embodiments, the present invention provides a topical composition for skin care comprising a triazelain.

[0022] According to some embodiments, the present invention provides a composition designed to deliver at least one biomolecule and / or chemical entity and / or biological sample to a subject in need of such delivery, the composition comprising a compound of the formula:

[0023] [ka] wherein each of R1, R2 and R3 is independently selected from the group consisting of dicarboxylic acid, azelaic acid, where n=>1, wherein the amount of carrier is effective to deliver the biomolecule and / or chemical entity and / or biological sample to a given target.

[0024] According to some embodiments, the present invention provides a compound of formula:

[0025] [ka] wherein each of R1, R2 and R3 is independently selected from the group consisting of azelaic acid or a derivative thereof, retinoic acid or a derivative thereof, succinic acid, a lipophilic chain antioxidant, valproic acid, hydroxybutyric acid, nicotinamide, sebaceous acid or a derivative thereof, linoleic acid, gamma-linoleic acid or a derivative thereof, alpha-hydroxy acid or a derivative thereof, cis isomers of fatty acids, lactic acid and zinc, wherein upon exposure to bacterial lipase, each of R1, R2 and R3 becomes cleaved and released from the compound.

[0026] According to some embodiments, the present invention provides a compound of the formula:

[0027] [ka] wherein each of R1, R2, and R3 is independently selected from the group consisting of active pharmaceutical or biological agents released upon exposure to triglyceride lipase, and wherein upon exposure to a microbial lipase, each of R1, R2, and R3 is cleaved and released from the compound.

[0028] According to some embodiments, the present invention provides a method for delivering at least one chemical entity and / or biological molecule into a food for consumption or into raw materials for the preparation of said food, the method comprising adding to said food or to raw materials for the preparation of said food an effective amount of a composition according to an embodiment of the present invention.

[0029] According to some embodiments, the present invention provides a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to an embodiment of the present invention. [Brief description of the drawings]

[0030] [Figure 1] 1 illustrates a schematic route for the synthesis of azelaic acid glyceryl triester. [Diagram 2] 1 illustrates an alternative schematic route for the synthesis of azelaic acid glyceryl triester. [Diagram 3] 1 illustrates a schematic route for the synthesis of retinoic acid glyceryl triester. [Figure 4] 1 illustrates a schematic route for the synthesis of 1,2-retinoin-3-azelaic acid glyceryl triester. [Diagram 5] 1 demonstrates lipase-mediated dose-dependent activity as measured by the release of azelaic acid from a representative in vitro batch (L-PABS). [Figure 6] Figure 1 shows the time-dependent release (1st and 5th day in culture) of a representative batch of azelaic acid form (L-PABS) upon incubation in live cultures of Corynobacterium acnes (P. acnes) in comparison to non-hydrolyzed L-PABS without exposure to bacterial enzymes in the medium. [Figure 7A] Lipase-mediated susceptibility to hydrolysis by triglyceride lipase (Lipase) and release of azelaic acid. (A) Comparison of batches (L-PABS) obtained by oxidative ozonolysis (Oz.) and by chemical synthesis (CS) - Selectivity by hydrolysis by lipase-L and insensitivity to esterase-E treatment. (B) Demonstrating dose-dependent susceptibility and selectivity of azelaic acid release by triglyceride lipase but not phospholipase from the demonstrating batch (L-PABS). [Figure 7B]Lipase-mediated susceptibility to hydrolysis by triglyceride lipase (Lipase) and release of azelaic acid. (A) Comparison of batches (L-PABS) obtained by oxidative ozonolysis (Oz.) and by chemical synthesis (CS) - Selectivity by hydrolysis by lipase-L and insensitivity to esterase-E treatment. (B) Demonstrating dose-dependent susceptibility and selectivity of azelaic acid release by triglyceride lipase but not phospholipase from the demonstrating batch (L-PABS). [Figure 8] A typical chromatogram of olive oil is shown. [Figure 9] A typical chromatogram of trioleate is shown. [Figure 10] FIG. 1 shows a chromatogram of pelargonic acid in methanol by HPLC. [Figure 11] The chromatogram of pelargonic acid standard 0.5 mg / mL obtained by GC method is shown. [Figure 12] The resulting products of the reaction are shown: left - H2O2 in excess of KMnO4, right - KMnO4 in excess of H2O2. [Figure 13] Olive oil is shown before (left) and after (right) reaction with KMnO4. [Figure 14] Samples after 3 hours of reaction are shown. [Figure 15] Samples after addition of large amounts of water are shown. [Figure 16] FIG. 1 illustrates a sample after reaction of KMnO4 with olive oil in the presence of 1 g of the selected surfactant Brij® 35. [Figure 17A] The following are indicated: A - before reaction, B - after reaction, extraction into hexane, C - after reaction, extraction into methanol, D - preparation in acetonitrile:chloroform (90:10). [Figure 17B] The following are indicated: A - before reaction, B - after reaction, extraction into hexane, C - after reaction, extraction into methanol, D - preparation in acetonitrile:chloroform (90:10). [Figure 17C] The following are indicated: A - before reaction, B - after reaction, extraction into hexane, C - after reaction, extraction into methanol, D - preparation in acetonitrile:chloroform (90:10). [Figure 17D] The following are indicated: A - before reaction, B - after reaction, extraction into hexane, C - after reaction, extraction into methanol, D - preparation in acetonitrile:chloroform (90:10). [Figure 18] The oxidation variables of the production process tested in different batches are specified. [Figure 19] The different feed acids and methods used are demonstrated as compared to the liquid synthesis obtained by oxidative ozonolysis. [Figure 20] The identity of the triazeraic reaction end product is demonstrated in NMR and MS spectrography (peak correlated with 602). [Figure 21] The TLC results confirmed by MS are presented, in which the retention times of TriAza final product and other by-products in TLC were detected in various batches to select the optimal parameters for purification (batches: B1, OU3, B6, B13 and B14). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention will now be described more fully hereinafter with reference to the accompanying examples and drawings, in which embodiments of the invention are shown. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0032] According to some embodiments, the present invention provides a composition designed to deliver at least one biomolecule and / or chemical entity and / or biological sample to a subject in need of such delivery, comprising a compound of the formula:

[0033] [ka] wherein each of R1, R2 and R3 is independently selected from the group consisting of dicarboxylic acid, azelaic acid, an amount of carrier effective to deliver said biomolecule and / or chemical entity and / or biological sample to a given target. In the context of the present invention, the term "target" is meant to be understood as any tissue, organ, matrix, medium, cell, organelle, or any other target that may benefit from the carrier. In the context of the present invention, the term "biomolecule" refers to any molecular entity having biological activity as defined above. As used herein, the term "chemical entity" refers to a physical entity of interest in chemistry, including, without limitation, molecular entities, portions thereof, and chemicals. As used herein, the term "biological sample" refers to any substance collected from a subject, including, without limitation, blood, plasma, fluid, and tissue samples, and any accessible substance derived directly or indirectly therefrom. In one embodiment, the carrier fulfills the function of a preservative.

[0034] According to some embodiments of the composition, the composition may be a composition including, without limitation, a disinfectant composition, a chemical composition, a pharmaceutical composition, a cosmeceutical composition, an edible composition, and a microbiome composition. In one embodiment, the composition is a liquid composition. In one embodiment, the composition is a solid composition. In one embodiment, the composition is a semi-solid composition.

[0035] According to some embodiments of the composition, a non-limiting list of compositions of the present invention includes syrups, powders, suspensions, dispersions, emulsions, creams, ointments, transdermal patches, tablets, capsules, pastes, lotions, soaps, surfactant-containing cleansers, oils, powder foundations, emulsion foundations, wax foundations, sprays, and cosmetic bases.

[0036] According to some embodiments, the present invention provides a compound of formula:

[0037] [ka] wherein each R1, R2 and R3 is independently selected from the group consisting of azelaic acid or a derivative thereof, retinoic acid or a derivative thereof, succinic acid, a lipophilic chain antioxidant, a lipocytic acid or a derivative thereof, linoleic acid, gamma-linoleic acid or a derivative thereof, an alpha-hydroxy acid or a derivative thereof, a cis isomer of a fatty acid, lactic acid, vanillin and zinc, wherein upon exposure to a bacterial lipase, each of R1, R2 and R3 becomes cleaved and released from the compound. As used herein, the term "lipophilic chain antioxidant" refers, without limitation, to a non-limiting list of lipophilic chain antioxidants of the present invention, including beta-carotene, vitamin E and lipoic acid, retinoic acid, terpenes, photoprotectants, medium or short chain fatty acids, alpha hydroxy acids, lipoxy acids, hydroxy acids, polyols, sugars, oligosaccharides, glycosides, lipohydroxy acids, salicylic acid, niacinamide, biopeptides, proctone olamines, diols, bactiol, mannitol, zinc gluconate, hormones, nucleosides (oligonucleotides), neurotransmitters, cannabinoids, and the like.

[0038] According to some embodiments, the present invention provides a compound having the formula:

[0039] [ka] wherein each R1, R2 and R3 is independently selected from an active pharmaceutical or biological or metabolic agent, wherein upon exposure to a microbial lipase, each of R1, R2 and R3 is cleaved and released from the compound. In the context of the present invention, a non-limiting list of active pharmaceutical or biological or metabolic agents includes photoprotective agents, protective natural mediators or metabolites, cosmetic agents, anti-aging agents, microbiome modulating agents. As used herein, the term "microbial" refers, without limitation, to bacteria associated with or characteristic of microorganisms, particularly disease- or fermentation-causing bacteria. A non-limiting list of microorganisms of the present invention includes bacteria, fungi, and single-cell parasites.

[0040] According to some embodiments of the above compound, each of R1, R2, and R3 is independently selected from the formula:

[0041] [ka] where X is selected from the group consisting of azelaic acid or other active agents delivered through the controlled release of bacterial flora-associated lipase. In one embodiment, R1, R2 and R3 are similar to each other. In one embodiment, the compound has the structure:

[0042] [ka] wherein X is azelaic acid. In one embodiment, the compound has the structure:

[0043] [ka] wherein X is retinoic acid. In one embodiment, the compound has the structure:

[0044] [ka] where X1 and X2 are both retinoic acid, and X3 is azelaic acid.

[0045] According to some embodiments, the present invention provides compositions comprising a compound according to one or more of the above embodiments and at least one carrier.

[0046] According to some embodiments of the composition, a non-limiting list of compositions of the present invention includes disinfectant compositions, chemical compositions, pharmaceutical compositions, cosmeceutical compositions, edible compositions, and compositions comprising a microbiome. In the context of the present invention, the term "microbiome" refers, without limitation, to microorganisms in a particular environment (including the body or a part of the body). Microbiome also refers to the combined genetic material of microorganisms in a particular environment. Microbiome is considered to be a term describing the genomes of all microorganisms, both symbiotic and pathogenic, living in vertebrates and in all vertebrates. Non-limiting examples of microbiomes include lactobacillus, bacillus, ammonia-oxidizing bacteria, coccus, and bifidum, as well as a balance of host flora that do not overexpress lipase as the main virulence factor inducing biofilm or / and administered probiotic composition implanted, and opportunistic invading contamination-induced pathogens.

[0047] According to some embodiments of the compositions of the present invention, a non-limiting list of compositions of the present invention includes compositions suitable for oral, transdermal, topical, transmucosal, nasal, ocular, mucosal and vaginal administration.

[0048] According to some embodiments of the compositions of the present invention, a non-limiting list of compositions of the present invention includes syrups, powders, suspensions, emulsions, creams, ointments, transdermal patches, suppositories, drops, sprays, foams, soaps, shampoos, oils, mills and colloidal compositions.

[0049] According to some embodiments, the present invention provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to an embodiment of the present invention. In one embodiment, the condition is selected from a skin disorder, overgrowth of lipase-producing microorganisms, inflammation, melasma, melanoma, and hair loss. In one embodiment, the condition is a disorder of the pilosebaceous unit. In one embodiment, the condition is a dysfunction of the immune system. In one embodiment, the condition is a disorder of the skin. In one embodiment, the condition is a disorder of the gastrointestinal tract.

[0050] According to some embodiments, the present invention provides a topical composition comprising a triazelain and optionally a carrier.

[0051] According to some embodiments, the present invention provides a method of treating an inflammatory skin condition in a subject in need of such treatment, the method comprising topically administering to the subject an amount of triazelain effective to treat the condition.

[0052] According to some embodiments, the present invention provides a compound of formula:

[0053] [ka] wherein X is azelaic acid, where upon exposure to bacterial lipase, the azelaic acid is cleaved and released from the compound.

[0054] According to some embodiments, the present invention provides a topical composition for the treatment of skin disorders comprising an active therapeutic agent and triazelain as a carrier.

[0055] According to some embodiments, the present invention provides a topical composition comprising triazelain. Triazelain is glycerol of azelaic acid, which may also be referred to as TriAza in the context of the present invention. In the context of the present invention, the terms triazelain, TriAza, and glycerol of azelaic acid are interchangeable.

[0056] According to some embodiments of the composition, the composition comprises at least one carrier. In the context of the present invention, a non-limiting list of carriers includes non-active ingredients, such as, without limitation, excipients, pH buffers, fillers, disintegrants, lubricants, thickeners, surfactants, adjuvants, or any other cosmetic or pharmaceutical additives conventionally utilized in such compositions. In one embodiment, the composition is a pharmaceutical composition, and the carrier is a pharma- ceutically acceptable carrier. In one embodiment, the composition is a cosmeceutical composition, and the carrier is a cosmeceutical acceptable carrier.

[0057] According to some embodiments of the composition, the triazelain is a carrier. In the context of the present invention, the triazelain is a carrier designed to deliver at least one biomolecule and / or biological sample to its target.

[0058] According to some embodiments of the above composition, the TriAza carrier fulfills the function of a preservative to prevent bacterial and yeast contamination.

[0059] According to some embodiments of the composition, a non-limiting list of biomolecules includes deoxyribonucleic acid (DNA), ribonucleic acid (RNA), organic molecules, inorganic molecules, amino acids, vitamins, polyphenols, steroids, peptides, polypeptides, and protein complexes.

[0060] According to some embodiments of the composition, the microbiome sample is a donor autologous microbiome, an allogeneic microbiome, or an in vitro cultured microbiome.

[0061] According to some embodiments of the composition, a non-limiting list of active agents includes antimicrobial agents, anti-aging agents, antiviral agents, antifungal agents, antibacterial agents, antioxidants, anti-inflammatory agents, antibiotics, antiparasitic agents, anesthetic agents, analgesics, anti-allergic agents, antipruritic agents, immunosuppressants, angiogenesis inhibitors, vasoconstrictors, and probiotics.

[0062] According to some embodiments of the composition, the one or more active agents are samples of non-lipase probiotic microorganisms. According to embodiments of the present invention, the list of non-lipase probiotic microorganisms includes, without limitation, non-lipase probiotic strains of microorganisms known to be bioprotective to the skin, Bifidobacterium (Bif. Adolescentis, Bif. Animalis, Bif. Breve, Bif. Infantis, Bif. Longum, Bif. Thermophilum), Lactobacillus (Lact. Rhamnosus, Lact. Salivarius, Lact. Acidophilus), Lactobacillus subtilis (Lact. Adolescentis, Bif. Animalis, Bif. Breve, Bif. Infantis, Bif. Longum, Bif. Thermophilum), Lactobacillus subtilis (Lact. Adolescentis, Bif. Animalis, Bif. Breve, Bif. Infantis ... Examples of Lactococcus include Lact. Acidophilus, Lact. Brevis, Lact. Casei, Lact. Curvatus, Lact. Fermentum, Lact. Gasseri, Lact. Johnsonii, Lact. Reuteri, Streptococcus (Strep. Thermophilus), Enterococcus (Ent. Faecium), and Lactococcus (L. lactis subsp. cremoris, L. lactis subsp. lactis).

[0063] According to some embodiments of the composition, the composition may be in the form of a powder, suspension, emulsion, cream, paste, gel, ointment, spray, foam, soap, shampoo, and oil.

[0064] According to some embodiments, the pH of the compositions of the present invention is between 5 and 8. According to some embodiments, the pH of the compositions is 5, 5.5, 6, 6.5, 7, 7.5, and 8.

[0065] According to some embodiments, the composition further comprises a surfactant, a preservative, a colorant, or any combination thereof.

[0066] According to some embodiments, the content of triazelain in the composition is 1% to 100%. According to some embodiments, the content of triazelain in the composition is 5% to 95%, 10% to 80%, 15% to 70%, 20% to 60%, and 30% to 50%. According to some embodiments, the triazelain content in the composition is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 109%, 109%, 102%, 103%, 104%, 105%, 106%, 107%, %, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.

[0067] According to some embodiments, the present invention provides a topical composition according to the above embodiments for use in treating skin conditions associated with lipase-producing microorganisms, a non-limiting list of which includes acne, rosacea, atopic dermatitis, seborrhea, abnormal pigmentation including melasma, aging, eczema, or any other disease or condition associated with lipase-producing microorganisms. A non-limiting list of lipase-producing microorganisms includes lipophilic bacterial species such as Pseudomonas spp., Actibacterium acnes, Staphylococcus, including S. Aureus and S. Hominis, and Corynebacterium, including acne pathogens, as well as fungal species such as Candida, including C. Albicans, Acinetobacter, for example A. Radioresistens, yeasts such as Malassezia.

[0068] According to some embodiments, the present invention provides a topical composition according to the above embodiments for use in treating conditions such as eczema, acne, atopic dermatitis, seborrheic dermatitis, tissue necrosis, skin sores, psoriasis, cellulitis, fungal infections, gangrene, disorders of the pilosebaceous unit, shaving and contact induced skin irritation, wounds, and the like.

[0069] According to some embodiments, the present invention provides a composition according to one or more of the above embodiments for use as a medicament. According to some embodiments, the composition is a topical composition.

[0070] According to some embodiments, the present invention provides a compound of formula:

[0071] [ka] wherein X is azelaic acid, wherein upon exposure to bacterial lipase, the azelaic acid is cleaved and released from the compound.

[0072] According to some embodiments, the present invention provides a topical composition for the treatment of skin disorders comprising an active therapeutic agent and triazelain as a carrier.

[0073] According to some embodiments, the present invention provides a topical composition for skin care comprising triazelain. In one embodiment, the composition further comprises at least one biomolecule. In one embodiment, the composition further comprises a microbiome sample.

[0074] According to some embodiments, the present invention provides a composition according to one or more of the above embodiments for use in treating a disease or condition. According to some embodiments, the composition is a topical composition and the disease or condition is skin inflammation.

[0075] According to some embodiments, the present invention provides topical compositions for the treatment of lipase virulence factor overrepresented pathogenic microbiome, such compositions preferably utilize the active ingredient azelate ester, such as glycerol triazelate, alone or in combination with other active ingredients.

[0076] According to some embodiments, the present invention provides a method of treating an inflammatory skin condition in a subject in need of such treatment, the method comprising topically administering to the subject an amount of triazelain effective to treat the condition.

[0077] According to some embodiments, the present invention provides a method of slowing and / or preventing the progression of an inflammatory skin condition in a subject, the method comprising administering to the subject a topical composition according to the above embodiments.

[0078] As used herein, the phrase "slowing and / or preventing progression" refers, without limitation, to the impact of a treatment on the clinical course of a disease or condition. For example, in the case of acne, disease severity ranges from mild to severe, with mild disease classified as a total lesion count <30, moderate disease classified as a total lesion count 30-125, and severe disease having symptoms with a total lesion count >125. In the context of the present invention, the proposed treatment aims to slow and / or prevent the transition from mild disease to severe disease. "Slowing and / or preventing" the progression of a condition according to embodiments of the above method may be measured using any suitable questionnaire, method, scale, diagnostic tool, or any other means known in the art or accepted by relevant functions and professionals. The term "preventing" may mean, but does not necessarily mean, recovery from a disease. As such, the term "prevent" refers to a situation when a patient does not exhibit symptoms and / or signs and / or symptoms of the next "stage" of disease severity, as defined by appropriate and accepted parameters for the particular disease state. The terms "delay" or attenuate, without limitation, can extend the time of transition to the next "stage" of disease severity, thus providing a larger window of opportunity for extensive care and recovery.

[0079] According to some embodiments, the present invention provides a method of treating an inflammatory skin condition in a subject, the method comprising administering to the subject a topical composition according to the above embodiments. In one embodiment, the inflammatory skin condition is associated with a lipase-producing microorganism, including, without limitation, Pseudomonas spp., Actibacterium acnes, Staphylococcus, and Corynebacterium.

[0080] According to some embodiments, the present invention provides a method of treating an inflammatory condition of the skin, such as, but not limited to, eczema, acne, atopic dermatitis, tissue necrosis, sore skin, psoriasis, cellulitis, fungal infection, gangrene, and disorders of the pilosebaceous unit, comprising administering to a subject a topical composition according to the above embodiments.

[0081] According to some embodiments, the present invention provides a method for treating localized skin inflammation, comprising administering a topical composition according to the above embodiment to the site of inflammation. In the context of the present invention, the term "localized skin inflammation" is meant to be understood as a localized inflammatory response that is limited to a certain, well-defined area / part / region of the skin affected by a harmful stimulus. Localized skin inflammation according to embodiments of the present invention may appear simultaneously in several parts of the body. Non-limiting examples of localized skin inflammation include:

[0082] According to some embodiments, the present invention provides a method for balancing the skin microbiome in a subject in need thereof, comprising administering to the subject a topical composition according to the above embodiment.In the context of the present invention, the term "balancing the microbiome" is meant to be understood as maintaining the potential for controlling microbiome homeostasis by selectively targeting desired opportunistic or / and pathogenic species of the microbiome, which leads to the production of triglyceride lipase as a virulence factor that causes disease or disorder, thus reaching the desired effect in reducing the symptoms of disease or disorder while keeping the microbiome in balance.

[0083] According to some embodiments, the present invention provides a method of treating a condition associated with an imbalance of the skin microbiome in a subject in need thereof, comprising administering to the subject a topical composition according to the above embodiments. A non-limiting list of conditions associated with an imbalance of the skin microbiome includes:

[0084] According to some embodiments, the present invention provides a method of maintaining skin microbiome balance in a subject in need thereof, the method comprising administering to the subject a topical composition according to the above embodiments.

[0085] According to some embodiments, the present invention provides a method for preventing skin aging in a subject in need thereof, comprising administering to the subject a topical composition according to the above embodiment.In the context of the present invention, the term "skin aging" refers to phenomena such as, without limitation, wrinkle formation, loss of elasticity, laxity, and the appearance of rough texture of the skin.The aging process is usually accompanied by phenotypic changes in skin cells, and structural and functional changes in extracellular matrix components such as collagen and elastin.

[0086] The present invention further provides a lipase-hydrolyzable (lipase-mediated) site-targeting system that is released upon hydrolysis of an inert or non-inert carrier compound (referred to as a "carrier component") and an active compound (referred to as an "active ingredient"), which is selected from the group consisting of:

[0087] According to some embodiments, the lipase hydrolyzable triglyceride esters include an inert carrier component (the glycerol portion) and an active component (the fatty acid portion). For example, components such as azelaic acid and / or retinoic acid are chemically bound to the glycerol backbone to form triretinol, triazelain and mixed diretinol, monoazelain or diazelain, monoretinol ester derivatives.

[0088] The triglyceride esters of the present invention provide three molecules of active fatty acid per mole of ester.

[0089] According to some embodiments, the lipase hydrolyzable moiety comprises an antibiotic component (eg, an erythromycin, macrolide, or lincosamide moiety) and an anti-acne active carrier (eg, a linoleic acid or azelaic acid moiety).

[0090] According to some embodiments, the esters of the present invention provide one molecule of anti-acne active fatty acid (which also serves as the carrier moiety) and antibiotic per mole of ester.

[0091] According to some embodiments, the present invention provides compounds comprising an inert cholesterol or cholesterol-like carrier moiety and an antibiotic active ingredient moiety (e.g., a macrolide, preferably a 14-membered macrolide, or a lincosamide, preferably clindamycin).

[0092] According to some embodiments, the present invention provides methods for selective loss of malignant pathological microbiome and enhancement of protective microbiome by sparing and controlling the risk of contamination with pathological species.Selective methods and compositions useful for treating / controlling lipase-producing pathogenic / malignant microbiome without damaging the primary host protective microbiome are disclosed.

[0093] According to some embodiments, the present invention provides methods and compositions useful for treating acne-related disorders, lipase-producing malignant / pathogenic microorganisms, which are important targets for the disclosed compositions.

[0094] According to some embodiments, the disclosed compositions are useful for treating S. aureus infections, including, without limitation, those produced by methicillin-MRSA and vancomycin-resistant strains VRSA.

[0095] According to some embodiments, the disclosed compositions may be used alone or in combination with conventional antimicrobials and antibiotics to treat, and may be used in situations such as, without limitation, foreign body, catheter or intravascular infections, hospital-acquired or post-operative infections, recurrent skin infections, or S. aureus infections in immunosuppressed hosts.

[0096] According to some embodiments, the disclosed compositions can act as a preservative to prevent contamination and maintain the sterility of topical formulations, such as, without limitation, prevention of Pseudomonas, Candida, Staphylococcus, and more particularly species regulated by the United States Pharmacopoeia (USP) and the European Pharmacopoeia for release in cosmetic, topical, dermatological, and other formulations and compositions.

[0097] According to some embodiments, the present invention provides for the use of the disclosed compositions in combination with "green" or natural surfactants. In the context of the present invention, the term "green" surfactants is defined as substances that can be obtained from natural and / or sustainable and / or renewable sources, such as, without limitation, glutamate, lauric acid, vitamin E, succinic acid, lactic acid, alkyl polyglycosides, alkyl glucosides, sodium coco sulfate (sodium lauryl sulfate). The green nonionic surfactants of the disclosed compositions include, without limitation, sugar-based surfactants, polyol-based surfactants, alkyl ethers, and alkyl carbonates. Sugar-based surfactants include, without limitation, alkyl polyglycoside (or alkyl polyglucoside) surfactants made from fatty alcohols in coconut oil and polyglucose in corn. In addition to their excellent ecological profile, alkyl polyglycosides are biodegradable and non-irritating to human skin. Additional green nonionic surfactants suitable for use in the disclosed compositions may include, but are not limited to, alkyl glucose amides, triglycerides, N-methyl coconut fatty acid glucamides (C12-14), amino acid-based surfactants, sugar esters, sorbitol esters, sterol esters, glycolipid biosurfactants, and the like. Green anionic surfactants may also be prepared from immediate precursors that may be obtained from natural and renewable sources. Accordingly, green anionic surfactants may include one or more long chain alkyl sulfates. Suitable green anionic surfactants include, without limitation, sodium coco sulfate or sodium lauryl sulfate. Sodium coco sulfate may be prepared from sulfating coconut oil, which contains a wide range of fatty acids (ranging from as few as 8 carbon alkyl chains to as many as 20 carbon alkyl chains, with 45-50% of the fatty acids in coconut oil being fatty acids containing 12 carbons).

[0098] In addition, the PEG-derived "green" Vitamin E-derived surfactants can also be derivatives of Vitamin E TPGS, including Vitamin E TPGS 200, Vitamin E TPGS 300, Vitamin E TPGS 400, Vitamin E TPGS 1000, Vitamin E TPGS 1500, Vitamin E TPGS 2000 and Vitamin E TPGS 4000. The naturally derived green surfactants can belong to the group of polyglyceryl surfactants and can be selected from, without limitation, polyglyceryl monoesters or polyglyceryl multiesters. Non-limiting examples of polyglyceryl monoesters contemplated herein include polyglyceryl-4 caprate, polyglyceryl-4 caprylate, polyglyceryl-4 laurate, polyglyceryl-4 isostearate, polyglyceryl-4 oleate, polyglyceryl-5 laurate, polyglyceryl-5 myristate, polyglyceryl-5 isostearate, polyglyceryl-5 oleate, polyglyceryl-5 stearate, polyglyceryl-6 isostearate, polyglyceryl-6 oleate, polyglyceryl-6 stearate, polyglyceryl-6 oleate ... Polyglyceryl-8 lyceryl, polyglyceryl-8 stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10 isostearate, polyglyceryl-10 linoleate, polyglyceryl-10 oleate, polyglyceryl-10 stearate, polyglyceryl-10 behenate / eicosadiate, polyglyceryl-10 hydroxystearate / stearate / eicosadiate, and / or polyglyceryl-10 fatty esters (POLYALDO.RTM.10-2-P).Non-limiting examples of polyglyceryl multiesters contemplated in the compositions disclosed herein include polyglyceryl-5 triisostearate, polyglyceryl-5 dioleate, polyglyceryl-5-trioleate, polyglyceryl-6 tricaprylate, polyglyceryl-6 dioleate, polyglyceryl-6 distearate, polyglyceryl-6 pentastearate, polyglyceryl-6 octastearate, polyglyceryl-8 decaerucate / decaisostearate / decalcinoleate, polyglyceryl-10 caprylate / caprate, polyglyceryl-10 dipalmitate, polyglyceryl-10 oleate, polyglyceryl-10 di ... C. Polyglyceryl-10 Diisostearate, Polyglyceryl-10 Pentaisostearate, Polyglyceryl-10 Nonaisostearate, Polyglyceryl-10 Decaisostearate, Polyglyceryl-10 Dioleate, Polyglyceryl-10 Pentaoleate, Polyglyceryl-10 Decaoleate, Polyglyceryl-10 Distearate, Polyglyceryl-10 Tristearate, Polyglyceryl-10 Pentastearate, Polyglyceryl-10 Pentahydroxystearate, and Polyglyceryl-10 Heptahydroxystearate. 8~20 Water-soluble salts of alkyl sulfates, C 8~20 Sulfonated monoglycerides of fatty acids, sarcosinates, taurates, etc. Exemplary embodiments of these and other classes include, without limitation, sodium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl sulfate, ammonium lauryl ether sulfate, sodium cocoyl monoglyceride sulfonate, sodium lauryl sarcosinate, sodium lauryl isethionate, sodium laureth carboxylate, and sodium dodecylbenzenesulfonate. In some embodiments, the anionic surfactant is sodium lauryl sulfate (SLS). Co-surfactants include naturally occurring lecithins, such as sunflower lecithin.

[0099] According to some embodiments, the present invention provides the use of the disclosed compositions as a delivery vehicle to control the release (by the skin microbiome) of azelaic acid components as active compounds to improve permeability and reduce the irritation and poor permeability of pure azelaic acid.

[0100] According to some embodiments, the present invention provides specific compositions and additives of a TriAza-based microbiome bioregulated delivery system of prebiotics, postbiotics and probiotics.

[0101] According to some embodiments, the present invention provides for the use of TriAza as a delivery and microbiome stabilizing agent for topical application of probiotic, prebiotic, postbiotic and microbiome compositions.

[0102] According to some embodiments, the present invention provides selective compositions for the enhancement of probiotic strains of microorganisms to the skin, such as, without limitation, Bifidobacterium (Bif. adolescentis, Bif. animalis, Bif. brewe, Bif. infantis, Bif. longum, Bif. thermophilum), Lactobacillus (Lact. rhamnosus, Lact. salivarius, Lact. acidophilus, Lact. brevis, Lact. casei, Lact. carbatus, Lact. fermentum, Lact. gasseri, Lact. johnsonii, Lact. reuteri), Streptococcus (Strep. thermophilus), Enterococcus (Ent. faecium), Lactococcus (L. lactis subsp. cremoris, L. lactis subsp. lactis).

[0103] According to some embodiments, the present invention provides for the use of TriAza as a selective antimicrobial delivery vehicle or preservative to deliver non-lipase probiotic strains of microorganisms known to be bioprotective to the skin, such as, without limitation, Bifidobacterium (Bif. adolescentis, Bif. animalis, Bif. brewe, Bif. infantis, Bif. longum, Bif. thermophilum), Lactobacillus (Lact. rhamnosus, Lact. salivarius, Lact. acidophilus, Lact. brevis, Lact. casei, Lact. carbatus, Lact. fermentum, Lact. gasseri, Lact. johnsonii, Lact. reuteri), Streptococcus (Strep. thermophilus), Enterococcus (Ent. faecium), Lactococcus (L. lactis subsp. cremoris, L. lactis subsp. lactis).

[0104] According to some embodiments, the present invention provides TriAza formulated with a postbiotic composition. Examples of such postbiotics are, without limitation, secondary bile salt and / or acid metabolites, while Bacteroides and Lactobacillus species metabolize such metabolites. Accordingly, the postbiotics may be represented by Bifidobacterium processed sphingolipids. Such postbiotics may be delivered directly or indirectly as a combo of Bifidobacterium and / or Lactobacillus delivered by TriAza-based formulations, and related substrate enrichments (i.e. bile acids, sphingolipids, etc.). Accordingly, it may result in metabolites, such as dihydroceramides, and oxidized, hydroxylated, and other derivatives / metabolites of choline acid.

[0105] According to some embodiments, the present invention provides active agents and methods for treating rosacea.

[0106] According to some embodiments, TriAza may be used in combination with anti-rosacea agents, including, but not limited to, topical alpha-adrenergic receptor agonists, such as brimonidine and oxymetazoline; non-selective beta-blockers, botulinum toxins, topical sodium sulfacetamide, topical metronidazole, topical ivermectin, topical retinoids, topical calcineurin inhibitors, etc. According to some embodiments, the above combinations demonstrate synergistic effects in anti-rosacea treatment.

[0107] According to some embodiments, the TriAza-based compositions are used as anti-infective, anti-seborrheic, anti-acne, anti-candidal agents, as preservatives, and as deodorants.

[0108] According to some embodiments, the present invention provides natural-based preservatives in combination with other preservatives to reduce toxicity levels and provide complementary additive benefits in product stability.

[0109] According to some embodiments, the present invention provides TriAza-based cosmetic preparations.

[0110] According to some embodiments, the present invention provides TriAza-based compositions that include active ingredients that enhance the function of azelaic acid.

[0111] According to some embodiments, the present invention provides TriAza-based compositions that may be used as an active ingredient and / or as a diluent.

[0112] According to some embodiments, the present invention provides TriAza that may be used as a cosmetically acceptable diluent "base" that has preservative activity.

[0113] According to some embodiments, the TriAza-based compositions can act as a cosmetically acceptable base and / or as active bacteriostatic antiseptic and antibiotic compositions, as preservatives, skin lightening agents, azelaic acid prodrugs for approved medical and cosmetic indications, and can be mixed with other functional actives or added to acceptable formulations.

[0114] According to some embodiments, the cosmetically acceptable base can act as a carrier for diluents, dispersants and / or other materials present in the composition and optionally facilitate their distribution when the composition is applied to the skin.

[0115] According to some embodiments, a non-limiting list of cosmetic actives that may be used with azelaic acid include vitamin B6, vitamin C, vitamin A, resorcinol derivatives, 12-hydroxystearic acid, glutathione precursors, galardin, adapalene, aloe extract, ammonium lactate, arbutin, butylated hydroxyanisole, butylated hydroxytoluene, citrate esters, deoxyarbutin, 1,3-diphenylpropane derivatives, 2,5-dihydroxybenzoic acid and its derivatives, 2-(4-acetoxyphenyl)-1,3-dithiane, 2-(4-hydroxyphenyl)-1,3-dithiane, ellagic acid, glucopyranosyl-1 ascorbate, gluconic acid, glycolic acid, green tea extract, 4-hydroxyphenyl benzoate, glyceryl stearate ... 5-methyl-3[2H]-furanone, 4-hydroxyanisole and its derivatives, 4-hydroxybenzoic acid derivatives, hydroxycaprylic acid, inositol ascorbate, lactic acid, lemon extract, linoleic acid, magnesium ascorbyl phosphate, 5-octanoylsalicylic acid, salicylic acid, 3,4,5-trihydroxybenzyl derivatives, octadecenedioic acid, acetylglucosamine, Pitera™ extract, SymWhite™, calcium pantothenate (melanoblock), SEPPIWHITE™, soybean extract (Bowman-Birk inhibitor), and mixtures thereof, vitamin B6, resorcinol derivatives, such as 2,4-substituted resorcinol derivatives and 3,5-substituted resorcinol derivatives, hexylresorcinol and phenylethylresorcinol, 12-hydroxystearic acid, glutathione precursors, galardin, beta-alanine derivatives, including 1-piperidinepropionic (1PP) acid as an anti-wrinkle agent, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, local anesthetics, angiogenesis inhibitors, derivatives of retinoic acid, natural compounds and compounds acting as sunscreens, skin moisturizers, antioxidants such as natural phenols, flavonoids, lycopene, terpenes, cannabinoids, essential oils, phytosterols and telomerase activators, plant-based extracts (such as TA65), adaptogens, anti-aging compounds, plant and medicinal mushroom extracts, sterols, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA, succinic acid and citric acid.

[0116] According to some embodiments, the present invention provides topical, cosmetic, and dermatological pharmaceutical preparations, as well as non-active ingredients, excipients, and enhancers.

[0117] According to some embodiments, a non-limiting list of pharma- ceutically acceptable excipients includes protectants, adsorbents, and pharma- ceutically acceptable carriers are selected from the group including sprays, mists, aerosols, solutions, lotions, gels, creams, ointments, pastes, unguents, emulsions, and suspensions. Optional excipients are analgesics, emollients, preservatives, antioxidants, moisturizers, buffers, solubilizers, skin penetrating agents, and surfactants.

[0118] According to some embodiments, the selected additional functionalizing agent may be present in an amount ranging from about 0.01-5% by weight, wherein the TriAza-based topical composition has a physiologically acceptable pH ranging from about 5-8.

[0119] According to some embodiments, excipients added to maintain osmolality are in the range of 250-650 mOsmol / kg.

[0120] According to some embodiments, the cosmetically acceptable base may be made from ingredients including, without limitation, fatty acids having 10 to 30 carbon atoms and their salts, water, liquid or solid emollients, solvents, humectants, thickeners, powders. These ingredients may be used alone and / or in combination with each other to form the cosmetically acceptable base.

[0121] According to some embodiments, the cosmetically acceptable base may contain a skin penetration enhancer, such as, without limitation, dimethylsulfoxide.

[0122] According to some embodiments, emollients that may be used in the cosmetically acceptable base include, without limitation, stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, Polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petrolatum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, ethyl alcohol, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, and mixtures thereof.

[0123] According to some embodiments, the topical TrAza formulation has a pH buffer in the range of 6.5 to 7.0, such as, without limitation, phosphate buffers, citrate buffers, and acetate buffers.

[0124] According to some embodiments, the compositions of the present invention are stable and comparable to controls during six months of storage at 25°C.

[0125] According to some embodiments, TriAza-based soaps produced by catalytic ozonolysis and subsequent purification steps are stable (without change in odor, color, and waxy consistency) for up to two years at 25° C. in light.

[0126] According to some embodiments, TriAza was prepared based on hydrogen peroxide / permanganate oxidation of crude olive oil. A non-limiting list of natural additives added to the various fractions includes probiotic mixtures, extracts, essential oils, postbiotics and prebiotics.

[0127] According to some embodiments, the present invention provides compositions and uses of TriAza as functional formulations.

[0128] According to some embodiments, the compositions may include, without limitation, amphiphilic biomaterials and antimicrobial systems that can incorporate active compounds into the skin.

[0129] In some embodiments, TriAza may be useful in reducing the concentration of antimicrobial agents required to achieve effective reductions in opportunistic pathogenic microorganisms that typically infect wounds, and in biofilm formation and hospital-acquired infections, thus reducing the risk of resistance.

[0130] According to some embodiments, TriAza in combination with conventional antibiotic and antifungal active agents, and / or nicotinamide natural antiplanktonic and / or anticandida active agents, results in a significant reduction in the MIC of the active ingredients.

[0131] According to some embodiments, TriAza in combination with conventional antibiotic and antifungal active agents, and / or nicotinamide natural antiplanktonic and / or anticandida active agents, leads to a reduction in the required dose, simplifies the formulation, improves compliance with administration, and reduces the risk of resistance and side effects.

[0132] According to some embodiments, TriAza-based soaps are an effective treatment option for conditions involving infections induced by P. acnes, S. aureus, and C. albicans, which are also associated with the dermatological after-shave disorder Pseudofolliculities Barbae (PFB).

[0133] According to some embodiments, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of TriAza, and other combinations in S. aureus and P. aeruginosa, are determined using any standard method, such as, without limitation, a protocol in which overnight cultures of S. aureus and P. aeruginosa are grown in TSB and adjusted to an optimal density (OD) of 0.1, and then each culture is incubated with a 2-fold serial dilution of the TriAza or combination being tested.

[0134] According to some embodiments, TriAza-based compositions may be tested for additive and synergistic antimicrobial properties with other microbiome control agents that have been shown to prevent biofilm formation by resistant strains.

[0135] According to some embodiments, a combination of Tri-Aza with L-Glu acetate amino acid in both bacteria is disclosed that can be applied in multiple indications at risk of antibiotic resistance.

[0136] According to some embodiments, additional natural antibiotics may be used in at-risk patients as an additional, supplemental, or preventative method, such as, without limitation, plant extracts, tea tree oil, other essential oils, copper, Zn, EDTA. Specific and selective targeting of pathogen-produced triglyceride lipase provides a "suicide" "biofeedback"-based pathogen activation mechanism by taking advantage of essential host-pathogen interactions, thus making resistance and the development of resistance less likely.

[0137] According to some embodiments, the present invention provides TriAza-based microbiome-enriched topical formulations.

[0138] According to some embodiments, in psoriasis, TriAza balances a protective microbiome through eradication of malignant Staph. aureus (SA) and reduces SA-induced inflammation.

[0139] According to some embodiments, the anti-aging TriAza-based treatment is synergistic with Nitrosomonas eutropha, as demonstrated by improvements in skin appearance, skin barrier, and wrinkles.

[0140] According to some embodiments, in photoaging, TriAza in combination with Lactobacillus buchneri fermented with plant extracts reduces UV-B induced cytokine and ROS release, thus stabilizing melanin.

[0141] According to some embodiments, the TriAza-based formulations further comprise one or more active agents including, without limitation, microbiome active agents (probiotics, postbiotics, prebiotics), anti-infective agents, topically / dermatologically active agents, antifungals, antivirals, antibiotics, adaptogens, growth factors, cytokines, chemokines, nucleic acids, vitamins, minerals, anesthetics, anti-inflammatory agents, moisturizers, extracellular matrix proteins, enzymes, stem cells from plants, extracts from eggs and eggshells, honey (preferably date honey), hyaluronic acid, botanical and medicinal mushroom extracts (i.e. polysaccharides, sterols, phenols, organic acids, polyphenols, stilbenes, flavonoids, sterols, waxes, squalene and other lipids and oils, triterpenes and glycosides / saponins, alkaloids, glucans, long chain, allicin, medium and short chain fatty acids, purines and their derivatives, polyamines (e.g. spermine and spermidine) and antiproliferative agents, allicin, dicarboxylic acids, and skin penetration enhancers.

[0142] According to some embodiments, the active agent is in the range of about 0.1% to about 40% by weight of the total composition. According to some embodiments, the active agent is in the range of about 0.5% to about 40% by weight, 2% to about 40% by weight, 5% to about 40% by weight, 10% to about 40% by weight, 15% to about 40% by weight, 20% to about 40% by weight, 30% to about 40% by weight, 0.5% to about 35% by weight, 0.5% to about 30% by weight, 0.5% to about 25% by weight, 0.5% to about 20% by weight, 0.5% to about 15% by weight, and 0.5% to about 10% by weight.

[0143] According to some embodiments, disclosed herein are retinoids (e.g., vitamin A, acitretin, isotretinoin, tretinion, and tazarotene); peroxides (e.g., benzoyl peroxide); antibiotics (e.g., tetracycline, clindamycin, erythromycin, metronidazole, sulfacetamide, doxycycline, oxytetracycline, minocycline, and trimethoprim); hormones (e.g., co-cyprindiol); adapalene; nicotinamide; salicylic acid; phenylephrine hydrochloride, pramoxine HCL, corticosteroids, vitamin TriAza based formulations further comprising: amine D and its derivatives; anthralin, and calcineurin inhibitors, elastin, hyaluronic acid, collagen or chitosan, steroids or hormones or pheromones (e.g., co-cyprindiol, estradiol, testosterone or derivatives thereof); anesthetics, hemostatic agents, anti-inflammatory agents, hemp based extracts (cannabinoids), tryptophan / indole / melanin derivatives, serotonin, dopamine derivatives, deodorants, pain relievers, UV protection agents, and combinations thereof, aloe vera, and combinations thereof.

[0144] According to some embodiments, the topically active agent may be selected from, without limitation, antibiotics, antibacterials, antivirals, anthelmintics, antifungals, anesthetics, analgesics, analgesics, antiallergy agents, antiacne agents, antimitotics, antipruritics, antihistamines, immunosuppressants, corticosteroids, keratolytics, antiangiogenic agents, anti-inflammatory agents, phosphodiesterase 4 inhibitors, anticancer agents, antineoplastic agents, anthracene derivatives, psoralens, antiproliferative agents, vitamin D analogs, anti-alopecia (prostaglandin analogs), antiheretic agents, photosensitizers, depigmenting agents, hormones, vasoconstrictors, and mixtures of two or more thereof.

[0145] According to some embodiments, disclosed are acetaminophen, acetylsalicylic acid, acitretin, acyclovir, adapalene, alclomefazone, alpha-tocopherol, amcinonide, amorolfine, amphotericin B, tetracycline, benzoyl peroxide, betamethasone, brimonidine, calcipotriol, calcitriol, ciclopirox, clindamycin, crisaborole, clobetasol, crotamiton, cyproheptadine, dapsone, desonide, diclofenac, diflucorotron, difluprednafe, dioxyanthranol, econazole, efinaconazole, erythromycin, estradiol, etretinate, fluocinolone acetonide, fluticasone, fusidic acid, momefazol. and mixtures of two or more thereof.

[0146] According to some embodiments, the anti-infective agent may be, without limitation, an antibiotic (e.g., tetracycline, clindamycin, erythromycin, metronidazole, sulfacetamide, doxycycline, oxytetracycline, minocycline, and trimethoprim); or an antibacterial agent: alcohol, chlorine, peroxide, aldehydes, triclosan, triclocarban, benzalkonium chloride, linezolid, quinupristin-dalfopristin, daptomycin, oritavancin and dalbavancin, quinolones, and moxifloxacin, essential oils, or terpenes; or an antifungal agent: antifungal compositions include clotrimazole, econazole, miconazole, tert-butyl ether ... binafine, fluconazole, ketoconazole, mofotericin, nystatin, sporanox, diflucan, telazol, intraconazole, mycostatin, boric acid, triconazole, undecylenilic acid, tolnaftate, imidazole, luliconazole, tavaborole, allylamine, amorolfine, oxiconazole, gluconazole, cyclotilox, naftifine, amphotericin B, sulconazole, butenafine, sertaconazole, efinacanazole, derivatives or prodrugs thereof, and combinations thereof; chitosan, sulfadiazine, silver sulfadiazine, silver nitrate, silver nanoparticles, and combinations thereof.

[0147] According to some embodiments, the composition may contain anti-aging cosmetic ingredients, such as, without limitation, alginate oligosaccharides, hydrogenated algins, gluta peptides, indoles, melanin mimetics, Artemisia extracts, Pinolumin™, vanilloid-1 receptor agonists, neurotransmitter agonists, bioactive ingredients (e.g., D-tyrosine, hyaluronic acid derivatives; perlecan and algin derivatives); natural plant extracts (e.g., polyphenol stilbenes); grifoline derivatives; thioredoxin and other bioactive proteins, naturally derived or synthetic approved peptides and their analogs (e.g., collagen tripeptides, Lipotec SNAP-8™ Peptide; leucylproline, Lipotec ARGIRELINE® Peptide; Lipotec Inyline Peptide; Bachem Cosmetic Peptides, SPACE-peptide carriers, Prospector BONT-L Peptide, Solution (PF), argireline®, acetyl hexapeptide-3, BODYFENSINE® Peptide, BASF skin asensyl® LS 9749, dipeptides (e.g. derivatives and analogues of kyotorphin; lipid dipeptides, tetrapeptides); proven active ingredients for branded cosmetics, namely BASF LS Skinasensyl; SensAmone P5; Neurobiox™ The Skin Biosurfacer, CRODA Calmosensine™; RAHN DEFENSIL®-SOFT, Sederma Prospector Calmosensine™ SP, Infinitec X50® Myocept Evercool® Skin; Codif STOECHIO.

[0148] According to some embodiments, disclosed is TriAza as an emollient and / or skin barrier protector.

[0149] According to some embodiments, TriAza is an amphiphilic, sebum-mimetic functional emollient characterized by a pleasant fragrance and a pleasant, smooth texture when applied to the skin.

[0150] According to some embodiments, TriAza protects the skin by forming a thin hydrophobic film on the surface of the skin, slowing transepidermal water loss.

[0151] According to some embodiments, as an emollient, TriAza provides an occlusive barrier for AD skin, retaining moisture and protecting against irritation.

[0152] According to some embodiments, as an emollient, the functionality of TriAza emollient is additive and optionally synergistic with its antimicrobial, anti-itch and anti-inflammatory actions.

[0153] According to some embodiments, additional emollient ingredients may be added to the TriAza formulation when designed as functional sebum mimetics and / or skin barrier protectors. Non-limiting examples include lanolin, mineral oil, olive oil, petroleum ceramides, paraffin and silicones, collagen, elastin, glyceryl stearate and shea butter.

[0154] According to some embodiments, humectants may be added to attract water vapor to moisturize the skin, such as glycerin, alpha hydroxyl acids, and sorbitol.

[0155] According to some embodiments, osmoprotectants may be added, including, without limitation, glycosides, photoprotectants, trehalose and ectoine, and organic osmomodulators.

[0156] According to some embodiments, due to its environmentally safe methods of sourcing and production, TriAza is a safe and suitable emollient for patients with atopic dermatitis and eczema, as well as KP, improving acceptability and adherence for emollient treatments.

[0157] According to some embodiments, TriAza enhances the olive oil process of oxidation.

[0158] According to some embodiments, the TriAza-based formulations further comprise a histone deacetylase inhibitor (HDACi), such as phenylbutyrate, valproic acid (VPA) or vorinostat (SAHA), which exert several immunostimulatory properties and contribute, at least in part, to their anti-cancer effects.

[0159] According to some embodiments, TriAza-based formulations further include alpha hydroxy acids (AHA), poly-AHA, complex poly-AHA, retinoids, fish polysaccharides, anti-enzymes, antioxidants (including ascorbic acid, pycnogenol, ursolic acid, plant isoflavones, vitamin E, coenzyme Q10, lipoic acid, resveratrol, l-carnosine and taurine) and agaricic acid, as well as various botanical extracts.

[0160] According to some embodiments, the present invention provides a composition designed to deliver at least one biomolecule and / or chemical entity and / or biological sample to a subject in need of such delivery, the composition comprising a compound of the formula:

[0161] [ka] wherein each of R1, R2, and R3 is independently selected from the group consisting of dicarboxylic acid, azelaic acid, where n=1 (one or more), and wherein the amount of carrier is effective to deliver the biomolecule and / or biological sample to a given target.

[0162] According to some embodiments of the composition, the composition may be a composition including, without limitation, a disinfectant composition, a chemical composition, a pharmaceutical composition, a cosmeceutical composition, an edible composition, and a microbiome. In the context of the present invention, the term "microbiome" refers to the microorganisms in a particular environment (including a body or a part of a body) without limitation. Microbiome also refers to the combined genetic material of the microorganisms in a particular environment. Microbiome is considered to be a term describing the genomes of all the microorganisms living in or on all vertebrae, both symbiotic and pathogenic. Non-limiting examples of microbiomes include Lactobacillus, Bacillus and Bifidus, and implanted and administered probiotic compositions that induce a balance of host flora or / and biofilms and opportunistic and invasive pollution-induced pathogens that do not overexpress lipase as a major virulence factor.

[0163] According to some embodiments, the present invention further provides a lipase hydrolyzable (lipase-mediated) site-targeted inert or non-inert carrier compound (referred to as a "carrier component") that is released upon hydrolysis, and an active compound (referred to as an "active ingredient"), which are selected from the group consisting of:

[0164] According to some embodiments, the lipase hydrolyzable triglyceride esters include an inert carrier component (the glycerol portion) and an active component (the fatty acid portion). For example, components such as azelaic acid and / or retinoic acid are chemically linked to the glycerol backbone to form tri-retinol, triazelaic and mixed di-retinol, mono-azelaic, or di-azelaic, mono-retinol ester derivatives.

[0165] According to some embodiments, the triglyceride esters of the present invention provide three molecules of active fatty acid per mole of ester.

[0166] According to some embodiments, the lipase hydrolyzable moiety comprises an antibiotic moiety (eg, an erythromycin, macrolide or lincosamide moiety) and an anti-acne active carrier (eg, a linoleic acid or azelaic acid moiety).

[0167] According to some embodiments, the esters of the present invention provide one molecule of anti-acne active fatty acid (which also serves as the carrier moiety) and antibiotic per mole of ester.

[0168] According to some embodiments, the compound comprises an inert cholesterol or cholesterol-like carrier moiety and an antibiotic active ingredient moiety (eg, a macrolide, preferably a 14-membered macrolide, or a lincosamide, preferably clindamycin).

[0169] The dosage depends on the severity of symptoms and on the subject's responsiveness to the active drug. The dosage is determined by the attending physician, taking into account age, sex, weight and disease state. According to some embodiments, the present invention provides a method for the production of acylglycerols, a mixture enriched with azelaic acid ("glycerol triazelate, triazeline") ("TriAza", or 3Az, or TriAza, or 3Az), from unsaturated fatty acid containing triglyceride starting materials such as oleic oil.

[0170] According to some embodiments, TriAza is produced using an ozonolysis or oxidation process under alkyne conditions, in which ozonolysis of one mole of triolein produces an unsaturated ozonide of triolein, which is further oxidized to give one mole of triazelain and three moles of pelargonic acid following cleavage of the unsaturated bonds. In one embodiment, pure TriAza can be produced by chemical liquid synthesis production.

[0171] According to some embodiments, TriAza is produced according to the methods described in Examples 1-5, 10 and 11.

[0172] According to some embodiments, the resulting product, TriAza, is further modified by saponification, polymerization, emulsification, suspension, gelation and then used as soaps, polymers, emulsions, suspension gels in a wide variety of cosmetic, natural-based pharmaceutical, nutraceutical and other practical compositions.

[0173] According to some embodiments, the present invention provides new chemical conjugates that can be hydrolyzed by bacterial lipases, which upon hydrolysis by said lipases release active ingredients that are effective in treating diseases associated with the pilosebaceous unit, preferably acne pathogens. Upon hydrolysis, the compounds of the present invention also release inactive or non-inactive carrier components.

[0174] According to some embodiments, the present invention provides bacterial lipase hydrolyzable esters that provide upon hydrolysis of an active ingredient in the treatment of diseases of the pilosebaceous unit from the group consisting of (1) an inert or non-inert carrier component selected from the group consisting of glycerol, mono- or dicarboxylic acids and cholesterol or cholesterol-like compounds, and (2) an antibiotic or fatty acid compound exhibiting anti-acne activity. The same anti-acne fatty acid may be an aliphatic, cyclic, aromatic, saturated, unsaturated, mono-, di- and polycarboxylic acid, and mixtures thereof.

[0175] According to some embodiments, the present invention provides prodrug conjugates that are hydrolyzable by P. acnes lipase or any other lipase produced by lipase-producing microorganisms specific to the pilosebaceous unit. A non-limiting list of lipase-hydrolyzable conjugates includes the following: triglyceride esters that release three molecules of anti-acne active fatty acid; esters that release one molecule of anti-acne active fatty acid and an antibiotic; and cholesterol esters that release antibiotics. Each of the conjugates releases an ingredient that is active in the treatment of pilosebaceous unit disorders, including, without limitation, acne, alopecia, seborrhea, and hirsutism, upon exposure to lipases specific to the pilosebaceous unit. In one embodiment, the triglyceride conjugates that release azelaic acid are useful in the treatment of hormone-dependent acne. In one embodiment, the non-glycerol conjugates are useful in the treatment of infectious acne.

[0176] According to some embodiments, the present invention provides cosmetic preparations based on special acylglycerols, preferably triazelains, with improved bioprotective properties, which are based, without limitation, on a dual mechanism of action: the release of sterile azelaic acid and the substrate competition of triazelains with natural triglyceride substrates.

[0177] According to some embodiments, the obtained triazelain can be further incorporated into an emulsion to provide the preparation according to the invention with improved bactericidal and bacterial stabilizing properties against triglyceride lipase producing microorganisms.

[0178] According to some embodiments, the present invention provides novel compositions and their compositions for the topical treatment of disorders of the pilosebaceous unit.

[0179] According to some embodiments, the present invention provides a nutritional or topical emulsion comprising the structured triglycerides of the present invention. The emulsion composition according to the present invention can comprise a natural, biologically compatible emulsifier, such as, without limitation, lecithin, phosphatidylcholine, phosphatidylethanolamine, or mixtures thereof. In one embodiment, the emulsion further comprises vitamin E, preferably alpha tocopherol. In one embodiment, the emulsion further comprises a pharma-ceutically acceptable non-natural surfactant. A non-limiting list of suitable surfactants includes TYLOXAPOL; POLOXAMER; POLYOXYL 40 Stearate; POLYSORBATE, TWEEN, PLURONIC F-68, polyoxyethylated oils, and polyoxamines. In one embodiment, the oil mixture comprises the structured triglycerides, and also an antioxidant. Typically, the emulsion of the present invention is sterilized by filtering through a membrane filter or by heating under an inert gas atmosphere, such as nitrogen.

[0180] According to some embodiments, the compositions of the present invention are cosmetically or dermatologically acceptable, i.e., non-toxic, and may be applied to human skin, including, without limitation, the inside of the eyelids or lips.

[0181] According to some embodiments, the composition further comprises at least one emulsifier. The addition of the emulsifier improves the incorporation of the triazelain into the final composition. In one embodiment, the emulsifier improves the lipase-mediated release of azelaic acid from the triazelain.

[0182] According to some embodiments, the active agent may be used in a formulation / delivery system that may be applied to human skin or coated onto fabric or disposable sheet surfaces for eradication of skin microflora, including corynebacterial, staphylococcal, proioniumbacteria, and candida, for reduction or elimination of body irritation, inflammation, infection, odor, itching, chafing, or moisture. By application of the antimicrobial topical formulations disclosed herein consisting of acylglycerols of azelaic acid and / or other antimicrobial "triglyceride mimetics" named TriAza herein, deodorant and anti-irritant activity may be achieved, which may be used to relieve odor, or topical or skin irritation in a subject.

[0183] According to some embodiments, TriAza-containing formulations may be used as coatings for disposable absorbents, such as, without limitation, diapers, fabrics, medical devices and other relevant surfaces.

[0184] According to some embodiments, the active agent of the present invention may be used in an amount effective to deactivate the microflora. Only these microflora are capable of catabolizing triglycerides, especially triolein, by means of specific triglyceride lipases. According to some embodiments, the active agent may be present in an amount ranging from 0.01 to 20% by weight of the composition. According to some embodiments, the active agent may be present in an amount ranging from 0.1 to 90%.

[0185] According to some embodiments, the present invention provides a method for preparing a composition comprising triazelain, the method comprising oxidizing triolein in a vegetable oil without hydrolyzing the acylglycerol bonds.

[0186] According to some embodiments of the above method, a non-limiting list of vegetable oils includes corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, peanut oil, and castor oil. EXAMPLES

[0187] Example 1: Synthesis of azelaic acid glyceryl triester Ethyl chloroformate (ca. 10 mmol) was added to a solution of azelaic acid (ca. 10 mmol) and triethylamine (TEA, ca. 10 mmol) in dry tetrahydrofuran (THF, ca. 40 ml) at -5 to 0°C. The mixture was separated by centrifugation and the supernatant was added to a solution of dry glycerol (ca. 2.5 mM). The resulting mixture was stirred at 25°C for 1 h and at 50°C for 1 h. Water (ca. 30 ml) was then added to the cooled reaction mixture followed by evaporation under reduced pressure. The product was extracted with chloroform (2 x ca. 30 ml). The resulting organic solution was dried over sodium sulfate followed by distillation, which resulted in a fine white crystalline material. The yield was 10%. Figure 1 shows a schematic route for the synthesis of azelaic acid glyceryl triester.

[0188] Example 2: Synthesis of azelaic acid glyceryl triester An alternative method for the synthesis of azelaic acid glyceryl triester A solution of 2.06 g (10 mmol) of dicyclohexylcarbodiimide (DCC) in 15 ml of dry MeCl2 was added very slowly (dropwise) to a solution of 0.23 g (2.5 mmol) of dry glycerol, 0.03 g (0.25 mmol) of N,N-dimethylaminopyridine and 1.65 g (8.8 mmol) of azelaic acid in 30 ml of dry CHCl2 and 5 ml of dry tetrahydrofuran (THF). The resulting suspension was stirred overnight at 25°C. Dicyclohexylurea (DCU) was filtered in vacuum and the solvent was evaporated under reduced pressure without heating. The residue was redissolved in THF and the undissolved material (DCU) was separated. The THF was evaporated to dryness until an oily residue remained in the flask. This oily residue solidified after lyophilization. The obtained material was purified by preparative thin layer chromatography using chloroform / methanol / water (65:25:4, v / v / v) as the developing solvent. Yield: approximately 25-30%. NMR analysis of the obtained compound clearly showed relevant peaks. Figure 2 shows a schematic route for this synthesis of azelaic acid glyceryl triester.

[0189] Example 3: Synthesis of retinoic acid glyceryl triester A solution of dicyclohexylcarbodiimide (DCC, ca. 20 mmol) in dry dichloromethane (ca. 30 ml) was added dropwise to a mixture of dry glycerol (ca. 5 mmol), N,N-dimethylaminopyridine (DMAP, ca. 0.5 mmol) and retinoic acid (ca. 17.5 mmol). The resulting suspension was stirred overnight at 25° C. The resulting solution was filtered and the methylene chloride was evaporated under reduced pressure without heating. The product was allowed to recrystallize. Figure 3 shows a schematic route for this synthesis of retinoic acid glyceryl triester.

[0190] Example 4: Synthesis of 1-azelaic acid 2,3-retinoic acid glyceryl triester A solution of dicyclohexylcarbodiimide (DCC, ca. 7 mmol) in dry dichloromethane (ca. 20 ml) was added dropwise to a mixture of 2,3-isopropylidene-sn-glycerol (ca. 5 mmol), N,N-dimethylaminopyridine (DMAP, ca. 1 mmol) and azelaic acid (ca. 6 mmol) in dichloromethane (ca. 30 ml). The suspension was stirred at 25° C. for ca. 12 h. The resulting precipitate was filtered, washed with water and lyophilized. The dried product was dissolved in dry dichloromethane (ca. 30 ml) and slowly added to the mixture. The suspension was stirred overnight at 25° C. After filtration of the precipitate, the dichloromethane was evaporated under reduced pressure and the crude product was lyophilized and subsequently recrystallized. Figure 4 shows a schematic route for this synthesis of 1-azelaic acid, 2-3-retinoic acid glyceryl triester.

[0191] Example 5: Synthesis of 2'-O-erythromycin ester of 2'-O-linoleoylerythromycin linoleic acid To an ice-cold solution of 1.0 mmol of methyl ester of erythromycin in 50 ml of CHCl3, 1.1 mmol of Et3N was added dropwise under argon atmosphere. After 3 min, a solution of 1.1 mmol of linoleic acid in 35 ml of CHCl3 was added at 0°C, followed by 1.1 mmol of dicyclohexylcabodiimide and 1.1 mmol of hydroxybenztriazole as solids. Finally, 35 ml of N,N-dimethylformamide (DMF) was added and the mixture was stirred at 0°C for 2 h and at room temperature for another 40 h. Ethyl acetate (50 ml) was added, the mixture was filtered, concentrated in vacuum and filtered again. Ether (30 ml) was added and the mixture was extracted with water, 1% KOH solution and water. The organic phase was dried over MgSO4, distilled and the residue was chromatographed on a silica column (h=30 cm, d=3.2 cm). FIG. 5 shows a schematic pathway for 2'-O-erythromycin ester of linoleic acid.

[0192] Example 6: Lipase-Mediated Activity To determine the affinity of bacterial lipases to active ingredients according to embodiments of the present invention, the ability of the lipases to utilize TriAza as a substrate was tested. For this purpose, a commercial lipase from P. cepacian was used. Increasing amounts of the enzyme were mixed with a fixed concentration of the substrate and incubated at 37° C. for several hours. The enzyme activity was monitored by TLC by registering the production of azelaic acid. Increasing concentrations of the enzyme are coupled to the progressive accumulation of azelaic acid at the expense of TriAza (FIG. 5). The results suggest that TriAza was available as a substrate for bacterial lipase activity.

[0193] Example 7: Lipase-Mediated Specificity The pure prodrug activity of the designed molecules suggests their high specificity towards the target enzymes. TriAza represents a glycerol ester of a specific fatty acid that can be recognized by mammalian esterases or other triglyceride-utilizing lipases. To establish the specificity of bacterial lipases towards TriAza, the lipase activity from P. cepacia was compared with that of mammalian esterases and phospholipase A2. The enzymes were exposed to a fixed concentration of TriAza in equal activity amounts. The degree of enzyme activity was registered according to the level of azelaic acid production. In contrast to lipases, we found that neither esterases nor phospholipase A2 were able to generate azelaic acid (Figures 6-7). These results indicate that the consumption of TriAza by bacterial lipases is highly specific.

[0194] Example 8: Antibacterial Activity TriAza was designed as a prodrug of azelaic acid, a known antibacterial agent, for the treatment of skin disorders associated with pathogenic proliferation of bacteria. For example, the development of acne vulgaris is strongly associated with the widespread deposition of P. acnes in the sebaceous glands, the environment of the disease. To determine the antibacterial activity of TriAza against P. acnes, the minimum bactericidal concentration (MBC) of TriAza was determined. The effect of TriAza was compared to the MBC of two major competitors used in the treatment of acne, azelaic acid and benzoyl peroxide (BPO). It was found that TriAza and the reference molecules exhibited antibacterial activity against P. acnes in the range of 0.5 mg / ml to 5 mg / ml (Table 1). Although all molecules behaved similarly, the activity of TriAza was found to be two times more potent than that of azelaic acid, supporting the use of TriAza in the treatment of acne vulgaris.

[0195] [Table 1]

[0196] To compare the antimicrobial activity of various batches of TriAza, the MICs of a number of batches prepared with non-principal modifications were determined. Selected batches were labeled TriAza-3, TriAza-6, TriAza-7, and TriAza-19 and fed to the growth medium of P. acnes. The minimum inhibitory concentrations of the batches were monitored and compared with each other. It was found that all samples possessed similar antibacterial activity with small deviations (Table 2). Batch TriAza-19 was chosen for further analysis as the batch containing the least amount of pelargonic acid.

[0197] Since TriAza is designed to be marketed as a soap, it was decided to define the antibacterial activity of the soap. For this purpose, the sodium salt (soap) of the most active batch of TriAza (TriAza-19-Na) was prepared and the MBC of the material was determined. TriAza-19-Na was found to exhibit both antibacterial and bactericidal activity, but less significant than that of TriAza-19 itself (Table 1). This finding indicates that TriAza soap can be used in anti-P. acnes treatment, despite its low antibacterial activity. It should be emphasized that despite the reduced activity of TriAza soap, it is still higher than the activity of azelaic acid (Tables 1 and 2).

[0198] [Table 2]

[0199] Example 8: Antibacterial specificity: spectrum of activity Since TriAza possesses antibacterial activity, the degree of its specificity for P. acnes was determined. For this purpose, several major skin pathogens were selected to be tested for susceptibility to TriAza. Staphylococcus aureus and Candida albicans were chosen, representing bacterial and fungal genera, respectively. Both organisms express lipase. Bacteria and fungi were exposed to various concentrations of TriAza and its sodium salt, and both the MIC and MBC of the agent were statistically determined. Both organisms were found to be susceptible to the agent, with S. aureus exhibiting a higher susceptibility. The level of TriAza activity was similar to that demonstrated against P. acnes. The slight differences in the MIC of TriAza against the tested organisms may be due to differences in their lipase activity. Our findings revealed that TriAza could be used in the treatment of various infectious diseases associated with S. aureus and C. albicans infections.

[0200] [Table 3]

[0201] Example 9: Determination of optimal conditions for carrying out the conversion of trioleate to triazelate Trioleates in olive oil were analyzed using the HPLC-CAD method under the following chromatographic conditions: Detector:CAD Column: C18, 150 x 4.6 mm, 5 microns Oven temperature: 40℃ Flow rate: 1.5mL / min Run Time: 26 minutes Eluent A: Acetonitrile Eluent B: Chloroform The gradient profile is shown in Table 4:

[0202] [Table 4] Diluent: Acetonitrile:Chloroform (90:10)

[0203] A typical chromatogram of olive oil is shown in Figure 1. The largest peak is trioleate.

[0204] FIG. 8 shows a typical chromatogram of olive oil, while FIG. 9 demonstrates a typical chromatogram of trioleate.

[0205] Analysis revealed the production of 28% trioleate in the olive oil.

[0206] Analysis of Pelargonic Acid Pelargonic acid was analyzed by two different methods, RP-HPLC and GC-FID. The HPLC method has important limitations: the oily phase cannot be directly analyzed, while pelargonic acid is poorly soluble in water. HPLC conditions: Detector: UV, 210nm Column: XBridge C18, 150 x 4.6 mm, 5 microns Mobile phase: Acetonitrile:Water:H3PO4 (50:50:0.1) Flow rate: 1.0mL / min Run Time: 15 minutes Column temperature: 35℃

[0207] FIG. 10 demonstrates the chromatogram of pelargonic acid in methanol by HPLC.

[0208] Pelargonic acid is much more soluble in oils and organic solvents than in water, and therefore it is very difficult to extract it for analysis in HPLC. GC conditions: Detector: FID Column: Supelco, Nukol, 15m x 0.5mm, 0.53mm Inlet temperature: 210℃ Detector temperature: 220℃ Oven program: 110℃ (1 min) → 20℃ / min → 220℃ (10 min) Run Time: 22.5 minutes Constant flow: 3mL / sec Split ratio: 1:20 Injection volume: 1mL

[0209] The chromatogram of 0.5 mg / mL pelargonic acid standard obtained by GC method is shown in FIG.

[0210] Determining the optimal parameters for the reaction For the determination of the optimal conditions for trioleate conversion, 20 g of olive oil was mixed with 2.8 g of KMnO4.

[0211] Olive oil is placed in a flask and KMnO4 is added as a solid along with a small amount of water. The mixture is heated to 60-80°C. After approximately 15 minutes, 35% H2O2 is added and the flask is placed in the refrigerator. After the addition of H2O2, the volume of the reaction mixture increases at least two-fold and intensive bubbling is observed. After a short time, the reaction mixture lightens and two liquid layers are observed. The products of the reaction are water-soluble. If KMnO4 is still in excess relative to H2O2, the KMnO4 will be pink in the aqueous phase and unreacted KMnO4 will be observed at the bottom of the flask, as clearly shown in Figure 12.

[0212] When H2O2 was added together with KMnO4, HPLC analysis showed that the amount of trioleate remained the same and no pelargonic acid was observed.

[0213] When no H2O2 was added, the HPLC results for trioleate and pelargonic acid remained approximately the same. However, in this case, separation between the two phases was difficult to achieve due to the high content of unreacted potassium permanganate and the MnO2 formed. A clear separation was achieved by filtering off the solid phase. The analysis of trioleate showed only a non-significant reduction after the reaction. The assay of trioleate in olive oil fell from 28% to 20%. The assay of pelargonic acid was even lower, which did not correspond to 8% of trioleate conversion.

[0214] The ratios were found to be sufficient with equal ratios between moles of trioleate and moles of KMnO4 multiplied by 3, with ratio values ​​of 1:1, 1:2, and 1:4. There was no significant difference between reaction temperatures in the range of 20-80°C and exposure times (15-45 min). The content of triolein in olive oil was reduced, but only about 0.15% of pelargonic acid was formed. This indicates that the reaction of trioleate with potassium permanganate mainly led to hydroxylation of the double bond rather than cleavage, e.g. only a small amount of triolein reacted to form triazelate and pelargonic acid.

[0215] Thus, despite the low conversion of trioleate, the reaction is easy to carry out and the products are liquid and separate well. It should be noted that there is a noticeable change in the color of the olive oil after the addition of hydrogen peroxide from a deep yellow-green to a yellowish color, and there is only a slight difference in the brightness of the chromatograms of the olive oil before and after the reaction, as shown in Figure 13.

[0216] To increase the conversion of triolein to triazelate, olive oil was allowed to continue in excess of KMnO4 for 3 h at RT.

[0217] The reactions were carried out as follows: 40 g of saturated KMnO4 solution was mixed with 20 g of olive oil and mixed for 3 hours. After 3 hours, 1 mL of H2SO4 concentrate was added and mixed for an additional hour.

[0218] The result of this process was a marsh-like black-brown viscous liquid, as shown in FIG.

[0219] Upon addition of a large amount of water, MnO2 was evident in the dark oil phase, as shown in FIG.

[0220] Filtration was difficult due to the high amount of viscous MnO2. In addition, the oil and water phases could be separated via centrifugation. The oil phase remained in a very small amount, about 1 g.

[0221] Addition of H2O2 resulted in bubbling for a few seconds, indicating that a portion of the permanganate was still not consumed.

[0222] To increase the exposure of the olive oil to the permanganate, reactions were carried out in the presence of Brij® 35 to combine the oil and water phases, thus exposing the olive oil to KMnO4.

[0223] Visually, the results were similar; however, the sample with Brij® 35 appeared to be more liquid and filtered more easily. In the sample with Brij® 35, the MnO2 was distributed throughout the entire volume of the flask.

[0224] After filtration, a single phase was observed, as shown in Figure 16. Complete clearance of the liquid was achieved by centrifugation.

[0225] The liquid that formed in the reaction was not miscible with hexane or in methanol, but it was miscible with water.

[0226] As shown in FIG. 17, the trioleate disappeared due to the reaction.

[0227] In the chromatogram in the methanol extraction, it can be seen that more hydrophilic products were formed and new peaks appeared.

[0228] Pelargonic acid was detected in all samples, but the amount of pelargonic acid did not correlate with the fall in trioleate.

[0229] conclusion · H2O2 is not involved in the conversion of trioleate to triazelate. Only KMnO4 is required for the reaction. The trioleate conversion rate depends on the reaction time. The trioleate was completely converted with extended exposure. · The presence of surfactants in the reaction medium accelerates the reaction until the oil phase disappears completely. Testing for triazelates The triazelate preparation was repeated using a larger amount of olive oil.

[0230] Olive oil was prepared using three methods: Addition of H2O2 followed by a short period of KMnO4 Long-term KMnO4 KMnO4 in the presence of surfactant Brij® 35 Five samples were prepared:

[0231] [Table 5]

[0232] Since a standard standard for triazelate is not available, the only way to conclude about the presence of triazelate is by MS.

[0233] All samples were run under the same conditions on the GC-MS.

[0234] After extended treatment, azelaic acid was observed only in the aqueous phase (sample 4). Pelargonic acid was not observed in this sample. However, pelargonic acid is present to a significant extent in the oil phase.

[0235] The sample with Brij® 35 had a high concentration of pelargonic acid and the chromatogram shows many peaks attributable to polyethylene glycol.

[0236] None of the samples showed a peak with molecular weight 602. Therefore, it is unclear whether the triazelate is formed or simply cannot be detected. Table 6 summarizes the prominent peaks in the GC-MS chromatograms.

[0237] [Table 6]

[0238] Finally, no triolein or triolein peaks were found by this method. Additionally, the same samples were run on HPLC-MS without the HPLC column, simply scanning the molecular weights in the samples.

[0239] In the diluent acetonitrile / chloroform, no triolein or triazelate peaks were observed.

[0240] After addition of ammonium formate in diluent, a strong trioleate signal appeared with mass +903, indicating the ammonium ion at +18. The triazelate appeared as a peak with mass +603, indicating that the ammonium ion was not required.

[0241] Triazelate was observed in all samples in both the water and oil phases.

[0242] No peaks attributable to the monoazelate and diazelate were observed. The trioleate was completely converted to a more hydrophilic product under extended reaction with KMnO4. The presence of triazelate and pelargonic acid in the reaction product was verified by HPLC-MS.

[0243] Example 10: Ozonolysis and synthesis examples The synthesis consists of only three steps, which makes it simple and optimized as being ecologically safe and cost-effective: (1) Olive oil → (2) Oxidation / ozonolysis → (3) Soap-like preparations (10%-20% of 3A) The synthesis was carried out by ozonolysis, an eco-friendly method that utilizes the natural material triolein as a substrate. Ozonolysis relies on the ozone-mediated cleavage of triolein-containing double bonds followed by the generation of COOH groups (Scheme 1). The method involves two steps: 1. exposure of triolein to a mixture of ozone and oxygen (in a solvent), and 2. oxidation of the first reaction product by oxygen in an acidic environment.

[0244] [ka] Scheme 1: Synthesis of Triaza by ozonolysis

[0245] Transesterification is an additional method of the present invention, which is a structural lipid modification method of preparation of TriAza to prepare TriAza-tributyrin, triolein, or other natural-based selected triglycerides, comprising at least one unsaturated or medium chain fatty acid as a constituent fatty acid can be subjected to transesterification, and lipase-catalyzed methods can be used in such reactions, or the catalytic methods based on chemical catalysts to be used in transesterification can be chemically catalyzed. In transesterification using chemical catalysts, the constituent fatty acids are bonded at random positions. Applicable chemical catalysts can be exemplified by alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, or alkali metal alkoxides, such as lithium methoxide and sodium methoxide. When chemical catalyst is used, about 0.1-2 wt% of the catalyst may be first added to the mixed oil of triglyceride (natural triglyceride and azelaic acid, or any R selected from the R descriptions), and the resulting mixture is reacted at 50-270°C for 3-120 minutes under stirring at ambient or reduced pressure. The final product can be obtained by carrying out the usual purification steps such as washing with water, drying, bleaching and deodorizing.

[0246] A substrate (Triaza) for lipase-mediated activity was synthesized. The synthesis was carried out by ozonolysis, an eco-friendly method that utilizes the natural material triolein as a substrate. Ozonolysis relies on the ozone-mediated cleavage of triolein, which contains a double bond, followed by the generation of a COOH group (Scheme 1). The method involves two steps: 1. exposure of triolein to a mixture of ozone and oxygen (in a solvent), and 2. oxidation of the first reaction product by oxygen in an acidic environment.

[0247] The parameters that were varied were the solvent (dichloromethane, pelargonic acid, formic acid, water, n-propyl acetate), the feed acids (pelargonic acid, formic acid, acetic acid, citric acid) and the reaction time. As a result, 17 batches were generated, which were analyzed by thin layer chromatography (TLC), nuclear magnetic resonance (NMR) and mass spectrometry (MS). To confirm the results produced by ozonolysis of triolein, Triaza was synthesized either by oxidation of triolein using OsO4 or by reacting glycerol with azelaic acid (four batches), as shown in Figures 18-21. The materials synthesized by these methods were analyzed by TLC along with the products of ozonolysis. Triaza synthesized by ozonolysis was subjected to MS, TLC and NMR analysis. Molecular mass analysis revealed that all synthesized batches contained mono-, di- and triglycerides of the Triaza family. In addition, triolein, Triaza-containing aldehydes, diglycerides were determined with both OH and COOH termini, triglycerides with dimers of azelaic acid, and pelargonic acid. To further confirm the presence of ozonides in the batches, 3H-NMR was performed. Analysis revealed that none of the batches contained ozonides and all batches contained few molecules possessing double bonds. Since triolein was the only double bond containing molecule, it was concluded that the substrate was not fully utilized in the reaction. Moreover, the absence of ozonides in the samples was evident for their destruction, resulting in modified forms of medium chain triglycerides. For detailed analysis of Triaza, the batches produced by ozonolysis were analyzed by TLC and compared to the batches synthesized by liquid synthesis. All samples were separated by normal phase chromatography and visualized by either a general dye (primulin) or a COOH-specific stain (BromCresol Green). Most batches of ozonolysis were found to contain 4-7 clear spots (the Rf of the resulting products was determined and compared with known standards), among which three major spots were visualized with BromCresol Green, suggesting the presence of carboxyl termini.Among them, one spot represented pelargonic acid, and therefore the two additional spots should have corresponded to Triaza molecules. Comparison of the Rf of the materials obtained by ozonolysis and liquid synthesis revealed that among the COOH-containing spots, two of them were normal, i.e., they could represent Triaza. Overall, we concluded that we were successful in producing Triaza by using ozonolysis of triolein.

[0248] [ka] Scheme 2. Synthetic route to triazelaylglycerol

[0249] [ka] Scheme 3. Synthetic route to triazelaylglycerol

[0250] [ka] Scheme 4. Synthetic route to triazelaylglycerol

[0251] Example 11: Selection of process conditions for producing TriAza with green surfactants Raw olive oil contains up to 50% oleic acid. Oleic acid exists as free oleic acid, monooleate, di-oleate and trioleate. KMnO4 added to olive oil cleaves the double bond of oleic acid leading to the formation of the following products: pelargonic and azelaic acids (following cleavage of oleic acid), monoazelates (following cleavage of monooleate), diazelates (following cleavage of dioleate) and triazelates (following cleavage of trioleate). Additional products of this reaction are MnO2 and the precipitate of a black powder. The reaction between olive oil and potassium permanganate was carried out under various conditions. The results are summarized in Table 7:

[0252] [Table 7]

[0253] Consider In the present invention utilizes topical compositions for the treatment of lipase virulence factor overexpressing pathogenic microbiome, such compositions preferably utilize active ingredient azelate ester, such as triazelate glycerol, alone or in combination with other active ingredients. TG mimics are composed of azelaic acid, not oleic fatty acid. It has been found that oxidation of triolein-containing substrates can obtain triazelate as a prodrug precursor of AzA, which can be released extracellularly into the host by triglyceride lipase in the GI system or by microbiome-released TG lipase, thus inducing the release of azelaic acid from TriAzA. The antimicrobial activity of TriAzA is unexpectedly high compared to equimolar AzA, and surprisingly has no effect on non-malignant microbiome. The disclosed method of oxidative cleavage of the double bond of triolein or of olive oil containing triolein results in an industrially familiar method of the production of glycerol of azelaic acid, named TriAza or triazelain, which can serve as a metabolic substrate for microbial lipases. In this way, control over lipases, which are the main virulence factors overexpressed in pathogenic microorganisms, can be achieved. The observed selectivity and specificity towards malignant lipase-producing microbiomes allows maintaining control of pathogenic and opportunistic infections and pathologies without causing damage to the host microbiome. The disclosed invention thus has excellent properties in terms of biocontrol (pathogens vs. host microbiome). In addition, the disclosed compositions can deliver and confer excellent preservation of donor or cultured microbiomes. In addition, superior MIC and MBC performance compared to azelaic acid was observed in several lipase-producing species, including resistant planktonic pathogens. The microbiome modulating effects of Triaza provide multi-functional benefits in enhancing health span for various conditions in the human body.

[0254] According to some embodiments, the present invention provides a method for delivering at least one chemical entity and / or biomolecule into a food for consumption or into raw materials for the preparation of said food, comprising adding to said food or to raw materials for the preparation of said food an effective amount of a composition according to an embodiment of the present invention. In one embodiment, the food is a product for human consumption. In one embodiment, the food is an animal feed.

[0255] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of embodiments of this invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the content clearly dictates otherwise.

[0256] It is further understood that the terms "comprise" or "comprising," as used herein, specify the presence of stated features, integers, steps, operations, elements, components and / or groups, or combinations thereof, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or groups, or combinations thereof. As used herein, the terms "comprise," "comprising," "include," "including," "having," and conjugations thereof mean "including but not limited to." The term "consisting of" means "including and limited to."

[0257] As used herein, the term "and / or" includes any and all possible combinations, or one or more, of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0258] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. It is further understood that terms such as those defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of the present specification and claims, and should not be interpreted in an idealized or overly formal sense unless so expressly defined in the present specification. Well-known functions or structures may not be described in detail for the sake of brevity and / or clarity.

[0259] It is understood that although the terms first, second, etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections are not to be limited by these terms, but rather, these terms are used only to distinguish one element, component, region, layer and / or section from another element, component, region, layer and / or section.

[0260] As will be appreciated by those skilled in the art, compounds of various formulas disclosed herein may contain chiral centers, e.g., asymmetric carbon atoms. Thus, the present disclosure relates to the synthesis of both (i) racemic mixtures of active compounds and (ii) enantiomeric forms of active compounds. Resolution of racemic compounds into enantiomeric forms and racemization of optionally active enantiomeric forms may be performed according to procedures known in the art. Geometric isomers, such as double bonds, may also be present in the compounds disclosed herein, and all such stable isomers are included within the present disclosure unless otherwise specified. Also included in the compounds of the present disclosure are tautomers (e.g., tautomers of triazoles and / or imidazoles), as well as rotational isomers. All chains containing three or more carbons as defined by the formulas herein may be saturated or unsaturated unless otherwise specified.

[0261] It is understood that the substituents and substitution patterns in the compounds used in the methods of the present invention are selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art from readily available starting materials. It is understood that when a substituent is itself substituted with more than one group, these multiple groups can be on the same carbon or on different carbons, so long as a stable structure is produced.

[0262] An "optionally substituted" group refers to a functional group in which one or more bonds to a hydrogen atom contained therein are replaced with a bond to a non-hydrogen or non-carbon atom, provided that the normal valence is maintained and the replacement results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen are replaced with one or more bonds, including double or triple bonds to heteroatoms. Where multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted singly or multiply by one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents may be the same or different. In selecting the compounds of the present invention, one skilled in the art will recognize that the various substituents will be selected in accordance with well-known principles of chemical structure connectivity.

[0263] As used herein, "H" refers to a hydrogen atom. "C" refers to a carbon atom. "N" refers to a nitrogen atom. "O" refers to an oxygen atom. "Halo" refers to F, Cl, Br or I. The term "hydroxy" as used herein refers to an -OH moiety. "Br" refers to a bromine atom. "Cl" refers to a chlorine atom. "I" refers to a sulfur atom. "F" refers to a fluorine atom. "Acyl group" is intended to mean a -C(O)-R group, where R is a suitable substituent, such as an acetyl group, a propionyl group, a butyroyl group, a benzoyl group or an alkylbenzoyl group. "Alkyl" as used herein refers to a straight or branched chain hydrocarbon containing 1 or 2 to 10 or 20 or more carbon atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, etc.). In some embodiments, the alkyl can be a lower alkyl. "Lower alkyl" refers to a straight or branched chain alkyl having 1 to 3, or 1 to 5, or 1 to 8 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. As used herein, definitions of carbon number ranges, such as C1-C12 alkyl, are intended to include each of the carbon number portions of the components within such ranges, and thus each intervening carbon number, and any other stated or intervening carbon number within that stated range, may be independently specified, such that subranges of carbon numbers within a particular carbon number range.For example, C1-C12 alkyl is intended to include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, including the linear and branched groups described above, and the carbon number range C1-C12 alkyl can also be more precisely specified as a subrange, such as C1-C4 alkyl, C2-C8 alkyl, C2-C4 alkyl, C3-C5 alkyl, or any other subrange within the broader carbon number range. In addition, carbon number ranges that specifically exclude carbon numbers are contemplated, which are subranges that exclude either or both of the carbon number limits of a particular range. As generally understood by those skilled in the art, "saturated" refers to a state in which all available valence bonds of an atom (e.g., carbon) are bonded to other atoms. Similarly, "unsaturated" refers to a state in which not all available valence bonds are bonded to other atoms, and in such compounds, the extra bonds usually take the form of double or triple bonds (usually to carbon). For example, a carbon chain is "saturated" when there are no double or triple bonds along the chain or directly connected to the chain (e.g., carbonyl), and is "unsaturated" when there is at least one double or triple bond along the chain or directly connected to the chain (e.g., carbonyl). Furthermore, it is understood by those skilled in the art that the presence or absence of a substituent that depends on the saturation of the chain depends on the valency requirements of the atom (e.g., carbon) to which the substituent is attached. "Alkenyl" as used herein refers to a straight or branched chain hydrocarbon containing 1 or 2 to 10 or 20 or more carbons and containing at least one carbon-carbon double bond, e.g., structurally formed by the replacement of two hydrogens. Representative examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and the like. "Alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing from 1 or 2 to 10 or 20 or more carbon atoms and containing at least one carbon-carbon triple bond.Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, etc. The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group containing 3 to 8 or more carbons.

[0264] It is understood that the compounds, compositions and methods provided herein may be further specified in some embodiments by conditions or limitations that exclude, as applicable, particular substituents, groups, moieties, structures, components, steps or conditions in the context of the various broader specifications and exemplifications described herein.

[0265] Certain features of the invention which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention.

[0266] Certain features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0267] Throughout this application, various embodiments of the invention may be presented in the format of ranges. It should be understood that the description in the format of ranges is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have all possible subranges specifically disclosed, as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This is true regardless of the breadth of the range.

[0268] Whenever a numerical range is given herein, it is meant to include any recited number (fractional or integer) within the given range. The phrases "range between" a first recited number and a second recited number, and "range to" a first recited number "from" a second recited number, are used interchangeably herein and are meant to include the first recited number and the second recited number, and all fractions and integers therebetween.

[0269] Whenever the term "about" is used, it is meant to refer to a measurable value, such as an amount, a period of time, and the like, and is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the particular value, such variations being appropriate for performing the disclosed methods.

[0270] As used herein, the term "method" refers to methods, means, techniques and procedures for accomplishing a given task, including, but not limited to, those methods, means, techniques and procedures that are either known or readily developed from known methods, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0271] As used herein, the term "patient" or "subject" is meant to include any mammal. "Mammal," as used herein, refers to any animal classified as a mammal, including, but not limited to, humans; laboratory animals, including monkeys, rats, mice, and guinea pigs; domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.

[0272] As used herein, a "pharmacologically acceptable" carrier or excipient is one that is suitable for use in humans and / or animals without undue adverse side effects (e.g., toxicity, irritation, and allergic reactions), commensurate with a reasonable benefit / risk ratio.

[0273] As used herein, "treating" a disease or "treatment" of a disease includes the following: preventing the disease, i.e., causing the clinical symptoms of the disease to not develop in a mammal that may be exposed to or susceptible to the disease but has not yet experienced or exhibited symptoms of the disease; inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing the regression of the disease or its clinical symptoms.

[0274] "Therapeutically effective amount" or "effective amount" means an amount or dosage form of a compound that, when administered to a subject for treating a disease, is sufficient to be effective in such treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.

[0275] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of a compound that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts refer to pharma- ceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counterions well known in the art.

[0276] Pharmaceutical dosage forms can be prepared as medicaments to be administered orally. Suitable dosage forms for oral administration include, without limitation, solutions, syrups and suspensions, such as ready-to-use syrups and suspensions, or those reconstituted from solid dosage forms, such as, without limitation, from dry powders. Dosage forms can contain suitable binders, lubricants, colorants, flavorings, flow inducers, stabilizers, solubilizers, antioxidants, buffers, chelating agents and fillers, all of which, collectively or individually, fall under the definition of the term "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient". For oral administration in dosage forms, active drug ingredients can be combined with oral, non-toxic, pharmaceutical acceptable, inert fillers, such as gelatin, agar, starch, methylcellulose, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone; cellulose-based soluble polymers such as, but not limited to, hydroxypropylmethylcellulose, polyethylene glycol, etc. Glidants used in these dosage forms include sodium benzoate, sodium acetate, polyethylene glycol, etc. Stabilizers (antimicrobial agents) include benzoic acid and its salts, parahydroxybenzoate and its salts, sorbic acid and its salts, etc. (Physical) stabilizers include viscosity-enhancing polymers such as hydroxyethylcellulose, xanthan gum, etc.

[0277] It will be appreciated by those skilled in the art that the present invention is not limited to what has been particularly shown and described herein above. Instead, the scope of the present invention is defined by the appended claims and includes both the combinations and subcombinations of the various features described herein above, as well as variations and modifications thereof that may occur to those skilled in the art upon reading the foregoing detailed description. While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents may occur to those skilled in the art. It will therefore be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention. Various embodiments have been presented. Each of these embodiments may, of course, include features from other embodiments presented, and embodiments not specifically described may include various features described herein.

Claims

1. A topical composition comprising triazeline and optionally a carrier.

2. The composition according to claim 1, wherein the composition is a pharmaceutical composition or a cosmetic composition.

3. The composition further comprises one or more active agents, wherein the active agent is selected from the group consisting of biomolecules, samples of the microbiome, antibacterial agents, anti-aging agents, antiviral agents, antifungal agents, antibacterial agents, antioxidants, anti-inflammatory agents, antibiotics, anthelmintics, anesthetics, analgesics, anti-allergy agents, anti-itch agents, immunosuppressive agents, anti-angiogenic agents, vasoconstrictors, probiotic agents, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), organic molecules, inorganic molecules, amino acids, vitamins, polyphenols, steroids, peptides, polypeptides, protein complexes, non-lipase-producing probiotic microorganisms, or any mixture thereof. The composition according to claim 1.

4. It is a solid composition, semi-solid composition or liquid composition, The composition according to claim 1, selected from the group consisting of powders, suspensions, emulsions, creams, pastes, gels, suppositories, ointments, sprays, foams, soaps, shampoos, mils, colloids and oils.

5. The composition according to claim 1, further comprising at least one of a surfactant, a preservative or a coloring agent.

6. The composition according to claim 1, for use in the treatment of conditions associated with lipase-producing microorganisms selected from the genus Pseudomonas, Cutibacterium acnes, Staphylococcus and Corynebacterium.

7. The composition according to claim 6, wherein the condition associated with the lipase-producing microorganism is a skin condition.

8. The composition according to claim 6 or 7, wherein the skin condition is selected from the group consisting of eczema, acne, atopic dermatitis, tissue necrosis, skin folds, psoriasis, cellulitis, fungal infections, gangrene, and disorders of the hair follicle sebaceous gland unit.

9. The composition according to claim 1, for use as a medicament.

10. The composition according to claim 1, for use in the treatment of diseases or conditions associated with microbiome imbalance.

11. A method of preventing skin aging in a subject, comprising administering to the subject the composition according to claim 1.

12. A composition designed to deliver at least one biomolecule and / or chemical element and / or biological sample to a subject in need thereof, the composition comprising an amount of a carrier having the formula 1: 【Chemical 1】 (wherein R １ , R ２ and R ３ are each independently selected from dicarboxylic acid or azelaic acid, and in the formula, n ≤ 1) wherein the amount of the carrier is effective to deliver the biomolecule and / or chemical element and / or biological sample to a given target. **Claim 13** A method for the preparation of a composition comprising triazerine, the method comprising oxidizing triolein in a vegetable oil without hydrolyzing the acylglycerol bond. **Claim 14** The method according to claim 13, wherein the vegetable oil is selected from corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, peanut oil and castor oil. **Claim 15** The method according to claim 13, wherein the vegetable oil is olive oil.

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