Compositions and methods for treating inflammation

Abstract

Provided herein are methods and compositions related to a pharmaceutical composition comprising bark resin extract from a plant of genus Calycophyllum and / or oleoresin extract from a plant of genus Copaifera. Disclosed herein are methods of treating or preventing a skin disease, pain, inflammation, scar formation, and / or cancer comprising administering the pharmaceutical composition.

Description

[0001] COMPOSITIONS AND METHODS FOR TREATING INFLAMMATION

[0002] RELATED APPLICATIONS

[0003] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 530,380, filed August 2, 2023, which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] Wound healing consists of 4 interconnected stages, hemostasis, acute inflammation, proliferation and remodeling. Virtually all skin wounds are remodeled with varying amounts of scar tissue that fill in the void left by the injury. Scars are formed from the deposition of collagen by fibroblasts in an attempt to remodel and ultimately heal injured tissue. Early in the process, scars appear red or dark and raised, but become paler and flatten over time. While visible scarring may be inevitable in the healing process of most cutaneous wounds, results vary depending upon the individual, the type of injury, and time after injury. For example, scars that are between two months and two years old may fade in color but continue to remain obvious components of the healed tissue. These scars are difficult if not impossible to remodel into functional skin. Beyond this time period, surgery is often necessary to remove the scars, resulting in new scar formation.

[0006] Excessive scarring results from an imbalance in anabolic and catabolic wound healing processes. In the formation of an abnormal scar, more collagen is produced than is degraded. Therefore, the scar grows larger than is required for wound healing, with an over-production of cells, collagen, and extracellular matrix proteins. Excessive scarring or abnormalities in wound healing include fibrosis, fibromatosis, keloidosis, adhesions (e.g., surgical adhesions), hypertrophic scarring, fibrocystic conditions, and joint stiffness. For example, keloids grow multidirectionally, become elevated above the skin, and remain hyperemic. The exact mechanisms of excessive scarring are poorly understood. Abnormal scars or abnormalities in wound healing can also be categorized based on the type of tissue in which a wound occurs. Abnormal scar formation in skin may lead to the formation of, for example, a keloid, hypertrophic scar, contracture, or scleroderma.

[0007] Wound healing is a complex and highly regulated process in which skin and underlying tissues repair themselves after injury. Rapid wound closure is imperative to prevent tissue destruction, potential infection and eventual loss of tissue function. TNF-a plays a key role in the course of healthy wound healing, and dysregulation in the level of this cytokine can inhibit the normal process of wound healing, resulting in non-healing chronic wounds. There is a critical need, worldwide, for topical treatments that can correct the imbalance of TNF-a at the wound sites of patients experiencing chronic inflammation, ulcerations and lack of wound closure. Further, there is a need for pharmaceutical formulations to treat skin conditions that improve wound and scar healing processes.

[0008] SUMMARY

[0009] In some aspects, disclosed herein is a composition comprising bark resin extract from a plant of genus Calycophyllum and oleoresin extract from a plant of genus Copaifera. In some embodiments, the pharmaceutical composition comprises about 0.001%-50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 0.001%-50% (w / v) oleoresin extract from the plant of genus Copaifera. In some embodiments, the pharmaceutical composition comprises about 0.01%-l%, 1%- 10%, 10%-20%, 20%-30%, 30%-40%, or 40%-50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 0.01%-1%, l%-10%, 10%-20%, 20%-30%, 30%-40%, or 40%-50% (w / v) oleoresin extract from the plant of genus Copaifera. In some embodiments, the pharmaceutical composition comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v) oleoresin extract from the plant of genus Copaifera. In some embodiments, ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is 1:1. In some embodiments, ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is more than 1:1 (e.g., 2: 1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11 :1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36: 1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44: 1, 45: 1, 46: 1, 47: 1, 48: 1, 49:1, or 50:1) or less than 1:1 (e.g., 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50). In some embodiments, ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is 5:1, 10:1, 1:5, or 1:10. In some embodiments, the pharmaceutical composition further comprises colloidal oatmeal, arrow root powder, amiticide coconut, aspen bark, Carapa guianensis oil, or lemon ferment. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) colloidal oatmeal. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) arrow root powder. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%- 3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) amiticide coconut. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) aspen bark. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%- 3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) lemon ferment. In some embodiments, the pharmaceutical composition comprises about 0.1 %- 1 %, l%-2%, 2%- 3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) Carapa guianensis oil. In some embodiments, the pharmaceutical composition further comprises colloidal shea butter or emulsification wax. In some embodiments, the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%-14%, or 14%-15% (w / v) shea butter. In some embodiments, the pharmaceutical composition comprises about 0.1%- 1%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%- 11%, 11%-12%, 12%-13%, 13%-14%, or 14%-15% (w / v) emulsification wax. In some embodiments, the bark resin extract from the plant of genus Calycophyllum and the bark oleoresin extract from the plant of genus Copaifera are aqueous extracts. In some embodiments, the pharmaceutical composition comprises at least 50% (v / v) water. In some embodiments, the plant of genus Calycophyllum is Calycophyllum spruceanum. In some embodiments, the plant of genus Copaifera is Copaifera officinalis. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical composition further comprises one or more antibiotic agents. In some embodiments, the pharmaceutical composition further comprises one or more antiseptic agents. In some embodiments, the pharmaceutical composition further comprises one or more antifungal agents. In some embodiments, the pharmaceutical composition further comprises one or more antiviral agents. In some embodiments, the pharmaceutical composition further comprises one or more analgesic agents. In some embodiments, the pharmaceutical composition further comprises an emulsifier, a moisturizing agent, an essential oil, a sunscreen, a pharmaceutically active agent, a cosmetic ingredient, a triglyceride, a structuring agent, an antioxidant, a preservative, a gum, a polysaccharide, a polymer, a thickening agent, a gelling agent, or a vitamin. In some embodiments, the emulsifier is cetearyl olivate or sorbitan olivate. In some embodiments, the moisturizing agent is allantoin. In some embodiments, the pharmaceutical composition further comprises an adjuvant. In some embodiments, the adjuvant is shea butter, meadowfoam seed, tea tree oil, lemon grass oil, eucalyptus oil, lemon eucalyptus oil, sweet almond, arnica, argan, avocado, borage, calendula, calophyllum, carrot, wheat germ, jojoba, macadamia, St. John's wort, apricot, hazel, olive, rosehip, sunflower, cocoa butter, cottonseed oil, evening primrose, grapeseed oil, wheatgerm, hemp, tamanu, macadamia, olive or sesame. In some embodiments, the pharmaceutical composition is formulated as a topical formulation. In some embodiments, the pharmaceutical composition further comprises one or more UV-absorbing agents. In some embodiments, the pharmaceutical composition further comprises one or more moisturizing agents. In some embodiments, the pharmaceutical composition is formulated as an emulsion, a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, lip balm, a serum, or a solution.

[0010] In some aspects, disclosed herein is a method of treating a skin condition in a subject in need thereof. The method may comprise administering to the subject the pharmaceutical composition disclosed herein. In some embodiments, the skin condition is skin wound, dry skin, itchy skin, inflamed skin, erythema, sensitive skin, pruritus, blotches, fine lines or wrinkles, sun damaged skin, dermatitis, psoriasis, folliculitis, blemish, rosacea, acne, eczema, sunburns, burned skin, or skin inflammation. In some embodiments, the skin wound is a chronic wound. In some embodiments, the chronic wound is a venous ulcer, a diabetic ulcer, a pressure ulcer, or rash associated with shingles, psoriasis, allergy, or dermatitis. In some embodiments, the wound is an acute wound. In some embodiments, the acute wound is a trauma wound, a bum wound, or a surgical wound.

[0011] In some aspects, disclosed herein is a method of treating pain or inflammation in a subject in need thereof. The method may comprise administering to the subject the pharmaceutical composition disclosed herein. In some aspects, disclosed herein is a method of inhibiting scar formation in a subject in need thereof. The method may comprise administering to the subject the pharmaceutical composition disclosed herein. In some aspects, disclosed herein is a method of improving wound healing in a subject in need thereof. The method may comprise administering to the subject the pharmaceutical composition disclosed herein. In some aspects, disclosed herein is a method of treating cancer in a subject in need thereof. The method may comprise administering to the subject the pharmaceutical composition disclosed herein.

[0012] In some embodiments, the cancer is skin cancer or premalignant skin lesions. In some embodiments, the pharmaceutical composition is administered to the subject topically. In some embodiments, the pharmaceutical composition is administered to the subject as a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, or lip balm. In some embodiments, the pharmaceutical composition is administered to the subject for 15 days or less. In some embodiments the pharmaceutical composition is administered to the subject for 10 days or less. In some embodiments, the pharmaceutical composition is administered to the subject for 7 days or less. In some embodiments, the pharmaceutical composition is administered to the subject for 15 days or more. In some embodiments, the pharmaceutical composition is administered to the subject for the lifetime of the subject. In some embodiments, the pharmaceutical composition reduces inflammation. In some embodiments, the pharmaceutical composition induces wound contraction. In some embodiments, the pharmaceutical composition induces wound closure. In some embodiments, the pharmaceutical composition reduces release of TNF-a from peripheral blood mononuclear cells. In some embodiments, the pharmaceutical composition increases release of TNF-a from keratinocytes. In some embodiments, the pharmaceutical composition stimulates release of TGF-P from keratinocytes. In some embodiments, the pharmaceutical composition induces cytostasis in keratinocytes. In some embodiments, the pharmaceutical composition induces migration of epidermal keratinocytes. In some embodiments, the keratinocytes are adult human keratinocytes. In some embodiments, the keratinocytes are LPS-distressed keratinocytes. In some embodiments, the pharmaceutical composition is administered after skin cancer removal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the nonhuman mammal is a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

[0013] In some aspects, disclosed herein is a method of treating a skin condition in a subject in need thereof. The method may comprise administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition disclosed herein. In some embodiments, the skin condition is skin wound, dry skin, itchy skin, inflamed skin, erythema, sensitive skin, pruritus, blotches, fine lines or wrinkles, sun damaged skin, dermatitis, psoriasis, folliculitis, blemish, rosacea, acne, eczema, sunburns, burned skin, or skin inflammation. In some embodiments, the skin wound is a chronic wound. In some embodiments, the chronic wound is a venous ulcer, a diabetic ulcer, a pressure ulcer, or rash associated with shingles, psoriasis, allergy, or dermatitis. In some embodiments, the wound is an acute wound. In some embodiments, the acute wound is a trauma wound, a bum wound, or a surgical wound.

[0014] In some aspects, disclosed herein is a method of treating pain or inflammation in a subject in need thereof. The method may comprise administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition disclosed herein.

[0015] In some aspects, disclosed herein is a method of inhibiting scar formation in a subject in need thereof. The method may comprise administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition disclosed herein.

[0016] In some aspects, disclosed herein is a method of improving wound healing in a subject in need thereof. The method may comprise administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition disclosed herein.

[0017] In some aspects, disclosed herein is a method of treating cancer in a subject in need thereof. The method may comprise administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition disclosed herein.

[0018] In some embodiments, the cancer is skin cancer or premalignant skin lesions. In some embodiments, the pharmaceutical composition is administered to the subject topically. In some embodiments, the pharmaceutical composition is administered to the subject as a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, or lip balm. In some embodiments, the pharmaceutical composition is administered 1 to 7 days after the bark resin extract from a plant of genus Calycophyllum is administered. In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, or 7 days after the bark resin extract from a plant of genus Calycophyllum is administered. In some embodiments, the pharmaceutical composition is administered 1 to 24 hours after the bark resin extract from a plant of genus Calycophyllum is administered. In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after the bark resin extract from a plant of genus Calycophyllum is administered. In some embodiments, the pharmaceutical composition is administered to the subject for 15 days or less. In some embodiments, the pharmaceutical composition is administered to the subject for 10 days or less. In some embodiments, the pharmaceutical composition is administered to the subject for 7 days or less. In some embodiments, the pharmaceutical composition is administered to the subject for 15 days or more. In some embodiments, the pharmaceutical composition is administered to the subject for the lifetime of the subject. In some embodiments, the pharmaceutical composition reduces inflammation. In some embodiments, the pharmaceutical composition induces wound contraction. In some embodiments, the pharmaceutical composition induces wound closure. In some embodiments, the pharmaceutical composition reduces release of TNF-a from peripheral blood mononuclear cells. In some embodiments, the pharmaceutical composition increases release of TNF-a from keratinocytes. In some embodiments, the pharmaceutical composition stimulates release of TGF-P from keratinocytes. In some embodiments, the pharmaceutical composition induces cytostasis in keratinocytes. In some embodiments, the pharmaceutical composition induces migration of epidermal keratinocytes. In some embodiments, the keratinocytes are adult human keratinocytes. In some embodiments, the keratinocytes are LPS-distressed keratinocytes. In some embodiments, the pharmaceutical composition is administered after skin cancer removal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the non-human mammal is a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

[0019] DESCRIPTION OF THE FIGURES

[0020] Figure 1 shows TNF-a: control primary human PBMCs and those stimulated with LPS and treated with Calycophyllum spruceanum Aqueous Bark Extract (CSABE).

[0021] Figure 2 shows TNF-a: control primary human PBMCs and those stimulated with LPS and treated with Calycophyllum spruceanum Aqueous Bark Extract (CSABE).

[0022] Figure 3 shows TNF-a: control primary adult human keratinocytes and those stimulated with LPS followed by treatment with Calycophyllum spruceanum Aqueous Bark Extract (CSABE).

[0023] Figure 4 shows TNF-a: control primary adult human keratinocytes and those stimulated with LPS followed by treatment with Calycophyllum spruceanum Aqueous Bark Extract (CSABE) and Copaifera officinalis resin (CO). Figure 5 shows TGF-P: control primary adult human keratinocytes and those stimulated with LPS followed by treatment with Calycophyllum spruceanum Aqueous Bark Extract (CSABE).

[0024] Figure 6 shows scratch assay: primary human adult keratinocytes treated with a range of concentrations of CSABE.

[0025] Figure 7 shows scratch assay: primary human adult keratinocytes treated with 10% (%w / v) CSABE.

[0026] Figures 8a-8d show scratch assays: primary human adult keratinocytes treated with CSABE. Controls include non-LPS-stimulated keratinocytes (Figure 8a) and LPS-stimulated keratinocytes treated with 0.2% DMSO (Figure 8b). Following 24 hours, a standard scratch assay was performed, and keratinocyte cultures were supplemented with either 0.1% (Figure 8c) or 10.0% (Figure 8d) CSABE (%w / v).

[0027] Figure 9a shows LPS stimulation of primary human adult keratinocytes treated with 10% (%w / v) Calycophyllum spruceanum aqueous bark extract (CSABE) alone, 7.0% (%w / v) Copaifera officinalis (CO) resin alone and a combination of the two resins.

[0028] Figure 9b shows scratch assay: following LPS stimulation as seen in Figure 9a, all cultures were subjected to wounding by scratch assay. Primary adult human keratinocytes were cultured as described in Figure 9a.

[0029] Figure 10 shows the process of wound healing, Following cutaneous injury, wound healing proceeds through four overlapping stages: hemostasis, acute inflammation, proliferation and remodeling.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] Inflammation and wound healing are (highly orchestrated biochemical, cellular, and physical processes. Unresolved inflammation can result in chronic inflammation, tissue ulceration and tissue death. Described herein, for the first time, is a novel combination of extracts from two different plant species that support immediate keratinocyte pro- inflammatory responses with concomitant suppression of systemic pro-inflammatory signals resulting in rapid resolution of inflammation following cell and tissue injury. Additionally, human application following cutaneous damage results in rapid wound repair with lack of scarring.

[0032] When exposed to Calycophyllum spruceanum aqueous bark extract (CSABE), TNF-a release from adult human PBMCs is modulated in a dose dependent manner at which concentrations above 7.0% (w / v) are associated with release inhibition. Conversely, concentrations above 7.0% (w / v), specifically 10.0% (w / v) of CSABE, stimulate release of TNF-a from both healthy control and LPS-distressed adult human keratinocytes. This response diminishes by day 3 of a 7-day culture. The in vitro responses appear to be specific to exposure to CSABE as untreated non-LPS and untreated LPS-distressed keratinocytes do not release TNF-a within the same culture duration. Rapid onset and then decline of TNF-a release from adult human keratinocytes treated with CSABE suggest induction of a pro- inflammatory state followed by rapid resolution. This cytokine, profile along with inhibition of TNF-a release from PBMCs treated with CSABE, may suggest sequestration of inflammation to the keratinocyte layer of skin with prevention of systemic involvement potentially leading to chronic inflammation.

[0033] TGF-P release from adult human keratinocytes is also modulated by CSABE. 10.0% (w / v) of CSABE stimulates the release of TGF-P from non-LPS and LPS-distressed keratinocytes with decreased cytokine levels by day 7 in culture. A similar TGF-P release profile can be seen from untreated control cells. Release of TGF-P from untreated LPS- distressed cells and DMSO treated cells, however, increases over 7 days in culture. The similar release profiles between CSABE-treated, LPS- stimulated adult human keratinocytes and control adult human keratinocytes in opposition to the release profile observed in untreated LPS-distressed keratinocytes suggest that CSABE modulates adult human keratinocytes by driving them towards cellular homeostasis. CSABE, therefore, appears to modulate the release of both TNF-a and TGF-P from adult human keratinocytes and these responses occur in tandem however diminishing at different time points.

[0034] Copaifera officinalis oleoresin (CO) stimulates keratinocyte release of TNF-a from 1- 7 days in culture. When CSABE is combined with CO at concentrations of 10.0% (w / v) and 7.0% (w / v), respectively, LPS-distressed adult human keratinocytes are inhibited from releasing TNF-a from days 1-7 in culture. Unexpectedly, the modulatory effect of the combined plant extracts is converse to the effects of each aqueous plant extraction individually and suggests significant anti-inflammatory properties of the aqueous combination. Unlike effects observed when testing the individual species, the combination may biochemically modulate keratinocytes towards a more anti-inflammatory state which is critical for chronic conditions such as psoriasis.

[0035] As compared to well-known inflammatory pathways following cutaneous injury, the current in vitro studies support the theory that circulating PBMCs, including monocytes, neutrophils and T cells, are not stimulated and thus not chemo-attracted when exposed to CS ABE and a formulation containing both CSABE and CO further promotes an antiinflammatory state in adult human keratinocytes. Modulation of inflammatory states pertaining to both acute and chronic wounds is critical for wound healing and application of this unique formulation to chronic conditions such as psoriasis may lead to overall reduction in local TNF-a levels, disruption of the chronic inflammatory cycle and ultimately healing. In vitro modulation of PBMC and keratinocyte-mediated release of cytokines appears to align with reduction in the overall acute inflammatory time frame and immediate tissue remodeling and healing observed in human applications. The novel formulation itself is highly antimicrobial and local immune cells such as resident macrophages, mast cells and dendritic cells may provide enough phagocytic support for rapid debridement and wound closure.

[0036] Supportive human applications are consistent with rapid wound healing for epidermal and dermal injuries with markedly shortened healing times and lack of scar formation.

[0037] Finally, inhibition of adult human keratinocyte migration when tested in traditional scratch assays may provide insight into keratinocyte-mediated wound closure and reduced fibroblast proliferation resulting in less collagen production and therefore less scarring. Keratinocyte cytostasis induced by exposure to the novel resin formulation is repeatedly observed in vitro and also supports the use of this formulation as an anti-cancer treatment. Previous studies have shown significant mechanistic relationships between inflammation and cancer and both extracts contain phytochemicals capable of arresting the cell cycle and reducing inflammation (Hanahan, D., et al. Cell. 2011 Mar 4;144(5):646-74.; Greten, F. R., et al. Immunity. 2019 Jul 16;51( 1):27-41 ; Zhao, H., et al. Signal Transduct Target Ther. 2021 Jul 12;6( 1) :263. These pivotal modulatory mechanisms support the idea of controlled inflammation and cutaneous healing without risk of progression to chronic inflammation. Components of each extract such as sesquiterpenes, iridoid glycosides and cell cycle regulators such as taxifolin may modulate inflammation and proliferation in keratinocytes as well as provide anti-microbial protection. Cyanidin and 5 -hydroxy morin are secondary metabolites of Calycophyllum spruceanum that can provide protection against ROS by acting as free radical scavengers. Together with the biological data presented here and chemical analysis, this novel combination of two different plant species is effective at biochemically modulating the cutaneous inflammatory response and can be formulated to treat both acute and chronic wounds with enhanced efficacy.

[0038] To summarize the process of wound healing, following cutaneous injury, wound healing proceeds through four overlapping stages: hemostasis, acute inflammation,

[0039] - IO proliferation and remodeling. As shown in Figure 10, hemostasis begins immediately following injury and ceases within hours and the durations of acute inflammation, proliferation and remodeling can span hours to days, days to weeks and weeks to months respectively (Plast Aesthet Res 2015;2:250).

[0040] Acute inflammation is a necessary process during the initial stages of wound healing as pathogens must be destroyed and removed in preparation for tissue restoration. Both keratinocytes, resident tissue macrophages (Ml) and blood PBMCs provide proinflammatory signals such as TNF-a and modulatory signals such as TGF-p. Aqueous extracts of Calycophyllum spp. alone stimulate the immediate release of proinflammatory and modulatory molecules TNF-a and TGF-P from keratinocytes thus quickly initiating the wound healing process. In parallel, aqueous extracts of Calycophyllum spp. suppress release of TNF-a from PBMCs. This modulation sequesters inflammation to injured tissue and prevents further involvement from systemic immune cells ultimately preventing the risk of chronic inflammation induced by PBMC involvement. In addition, aqueous extracts of Calycophyllum spp. provide antibacterial properties that protect the wound and prepare the site for tissue restoration. In support of this claim, studies have shown that depletion of one subset of PBMC cells, neutrophils, promotes faster wound healing and excessive recruitment of neutrophils results in hyperinflammation and delayed wound healing (Int. J. Mol. Sci, 2017, 18, 1545).

[0041] The duration of acute inflammation is critical in that prolonged proinflammatory stimulation leads to chronic inflammation and results in lack of healing and tissue death. Chronic inflammation is characterized by ineffective phenotypic changes of Ml proinflammatory macrophages to M2 anti-inflammatory macrophages, T cell infiltration and a highly inflammatory microenvironment containing excessive amounts of TNF-a. The injured tissue cycles through a positive feedback loop of hyperinflammation and bacterial growth leading to bacterial biofilm formation and tissue necrosis. The combination of aqueous extracts from Calycophyllum spp. and Copaifera spp. suppresses release of TNF-a from keratinocytes and stops the hyperinflammatory state of chronic inflammation thereby sparing injured tissue from necrosis and promoting wound healing. Several advanced therapies including cell-based, molecular-based and biomaterial-based therapies have been developed to treat chronic wounds (Biomolecule 2021,11,700). Each of these therapies provides varying levels of success in modulating the hyperinflammatory state of chronic wounds. A combination of aqueous extracts from Calycophyllum spp. and Copaifera spp. is successful at suppressing pro-inflammatory signaling in chronic wounds, providing anti- pathogenic protection and supporting the healing of chronic wounds and skin conditions.

[0042] In summary, the application of Calycophyllum spp. alone is an effective treatment for acute wounds; the application of combined extracts from Calycophyllum spp. and Copaifera spp. is effective at treating chronic wounds and chronic skin conditions. Similarly, Calycophyllum spp. alone can be used as a treatment during the initial stages of wound healing, e.g., acute inflammation, and the combination of aqueous extracts from Calycophyllum spp. and Copaifera spp. can be used at later stages of wound healing, e.g., proliferation and remodeling, thus completing the wound healing process successfully.

[0043] Definitions

[0044] For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0045] As used herein, the singular forms “a”, “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Further, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.” The transitional terms “consist” and any grammatical variations thereof, are intended to be limited to the elements stated in the claims and exclude any elements not stated in the claims. The phrases “consisting essentially of’ and any grammatical variant thereof indicate that the claim encompasses embodiments containing the specified elements and includes additional elements that do not materially affect the basic and novel characteristic(s) of the claim.

[0046] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system, and the conventional variability accepted in the art for the concerned parameter.

[0047] As used herein, the term “administering” means providing a therapeutic agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. The means of providing a therapeutic agent are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, topical administration, intravaginal administration, intraaural administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.

[0048] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully “treated,” for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated.

[0049] The term “preventing” is art-recognized, and when used in relation to a condition is well understood in the art and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of scar formation includes, for example, reducing the incidence, number, and / or size of scarring in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of scars in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0050] In certain embodiments, a therapeutic agent may be used alone or conjointly administered with another therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the subject, which may include synergistic effects of the two agents). For example, the different therapeutic agents can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. In certain embodiments, the different therapeutic agents can be administered within about one hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0051] In certain embodiments, conjoint administration of the combinations of compositions of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the combinations of compounds of the invention or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the combinations of compositions of the invention and the one or more additional therapeutic agent(s).

[0052] The term “effective amount” or “therapeutically effective amount,” as used herein, means an amount of a composition of the present invention, that, when administered to a subject (e.g., a human subject or an animal model) in need of such treatment, is sufficient to effect treatment, as defined herein. For example, an effective amount or therapeutically effective amount of the composition described herein, when administered to a subject (e.g., a human subject or an animal model), is sufficient to treat wounds, induce wound healing, induce wound contracture, induce wound closure, and reduce inflammation (e.g., reduce release of inflammatory cytokines (e.g., TNF-a, IFNg, IL-1 , IL-6, IL-1 b, IL- 12, IL- 18, etc.)).

[0053] “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both humans and non-human animals. In some embodiments, the subject is a mammal (such as an animal model of disease), and in some embodiments, the subject is human. In some embodiments, the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee).

[0054] As used herein, the term “keratinous tissue” includes keratin-containing layers disposed as the outermost protective covering of mammals and includes, but is not limited to, skin, hair, and nails.

[0055] As used herein, the terms “healthy skin” or “normal skin” refers to non-lesioned skin, i.e., with no visually obvious erythema, edema, hyper-, hypo-, or uneven pigmentations, scale formation, xerosis, or blister formation. Histologically, healthy or normal skin refers to skin tissue with a morphological appearance comprising well-organized basal, spinous, and granular layers, and a coherent multi-layered stratum comeum. In addition, the normal or healthy epidermis comprises a terminally differentiated, stratified squamous epithelium with an undulating junction with the underlying dermal tissue. Normal or healthy skin typically includes no signs of fluid retention, cellular infiltration, hyper- or hypoproliferation of any cell types, mast cell degranulation, parakeratoses, etc., and implies normal dendritic processes for Langerhans cells and dermal dendrocytes. This appearance is documented in dermatological textbooks, for example, HISTOPATHOLOGY OF THE SKIN, Lever and Schaumburg-Lever (eds.), J.B. Lippincott Company (1991) and TEXTBOOK OE DERMATOLOGY, Champion et al. (eds.), 5th Ed. Blackwell Scientific Publications (1992), especially Chapter 3 “Anatomy and Organization of Human Skin”; PHYSIOLOGY, BIOCHEMISTRY AND MOLECULAR BIOLOGY OF THE SKIN, VOLS. I AND II, Goldsmith (ed.), Oxford Press (1991), relevant portions incorporated herein by reference.

[0056] Pharmaceutical Compositions

[0057] The compositions and methods of the present invention may be utilized to treat an individual in need thereof.

[0058] Copaifera is a genus of tropical plants in the legume family Fabaceae. Oil extracts from the genus are of particular interest as a source of antimycobacterial agents. Species of the genus Copaifera include Copaifera epunctata, Copaifera guyanensis, Copaifera langsdorffii, Copaifera martii, Copaifera multijuga, Copaifera officinalis, Copaifera panamensis, Copaifera reticulate, Copaifera salikounda, Copaifera trapezifolia, Copaifera cearensis, Copaifera jacquinii, and Copaifera coriacea. Copaifera officinalis, the copaiba balsam, is a species of flowering plant in the family Fabaceae, native to Bolivia, Brazil, and Venezuela. Like other members of its genus, its trunks are tapped for its oleoresin, sometimes termed balsam of copaiba or, when refined, copaiba oil.

[0059] Calycophyllum is a genus of flowering plants in the family Rubiaceae. Members of the genus Calycophyllum are found in Mexico, Central America, South America and the West Indies. Species of the genus Calycophyllum include Calycophyllum candidissimum (Vahl) DC. (common names: Lemonwood, Digame Lancewood), Calycophyllum intonsum Steyerm., Calycophyllum megistocaulum (K. Krause) C.M.Taylor., Calycophyllum merumense Steyerm. , Calycophyllum multiHorum Griseb. , Calycophyllum obovatum (Ducke) Ducke., Calycophyllum papillosum J.H.Kirkbr., Calycophyllum spectabile Steyerm., Calycophyllum spruceanum (Benth.) Hook.f. ex K.Schum., Calycophyllum tefense J.H.Kirkbr., and Calycophyllum venezuelense Steyerm.

[0060] Bark resin extract is a substance that can be obtained from the bark of trees, herbs, or shrubs. Plants produce resins in special cells, or when they are injured.

[0061] Bark resin extract (e.g., aqueous bark resin extract) from Calycophyllum spp. to be included in the composition featured herein can be bark resin extract (e.g., aqueous bark resin extract) from one or more species of the genus Calycophyllum (e.g., one or more species of Calycophyllum mentioned hereinabove). For example, bark resin extract (e.g., aqueous bark resin extract) from Calycophyllum spp. to be included in the composition featured herein can be bark resin extract (e.g., aqueous bark resin extract) from Calycophyllum spruceanum (common name: capirona). Calycophyllum spruceanum is a canopy tree belonging to the Gardenia Family (Rubiaceae) indigenous to the Amazon rainforest. The dried bark is used to treat fungus on the skin.

[0062] A person of ordinary skill in the art would be able to isolate any one of the extracts identified herein from parts of the corresponding plant by using any suitable method known in the art. In one non-limiting example, the plant (or any part of the plant such as the leaves, stems, bark, roots, fruit, flowers or flower buds, seeds, seed pods, sap, whole plant, etc.) can be disrupted by mechanical means which results in a puree. The puree may then be processed to remove impurities or undesired solids, e.g., to provide a solution substantially free of solids and impurities. The puree can then be poured into a shallow vessel and quickly exposed to low temperature, i.e., flash frozen, for example at -20° C or lower, preferably under a vacuum for removal of water content (lyophilization). The resultant extract can then be used in the compositions of the present invention.

[0063] In other aspects, aqueous, alcoholic, or oil-based extraction techniques, or combinations thereof, can be used on the whole plant or any part thereof (e.g., leaves, stems, bark, roots, fruit, flowers or flower buds, seeds, seed pods, sap, whole plant, etc.) to produce an extract. In such a process, the desired part of the plant or the whole plant is crushed up (e.g., blender) and then subjected to a desired solvent (e.g., water, alcohol, water / alcohol, or oil-based solvents) to obtain the desired extract. The extract can then be stored in liquid form, lyophilized, or subject to further processing techniques (e.g., heating, cooling, etc.). Extraction processes are well-known to those having ordinary skill in the extract field (e.g., maceration, infusion, percolation, digestion, decoction, hot continuous extraction, aqueous- alcoholic extract, counter current extract, micro wave assisted extraction, ultrasound extraction, supercritical fluid extracts, phytonic extract (e.g., with hydro-fluoro-carbon solvents).

[0064] In some embodiments, the composition is formulated as topical skin composition. The composition can be a lotion, a cream, a gel, a emulsion (e.g., oil-in-water, water-in-oil, silicone-in water, water-in-silicone, water-in-oil-in-water, , oil-in-water-in-oil, oil-in-water- in-silicone, etc.), solutions (e.g., aqueous or hydro-alcoholic solutions), anhydrous bases (e.g., lipstick or a powder), ointments, milk, paste, aerosol, solid forms, eye jellies, etc. The composition can be in the powdered form (e.g., dried, lyophilized, particulate, etc.). The composition can have a dermatologically acceptable vehicle or carrier for the plant, plant part, or extract thereof. The composition can further include a moisturizing agent, an antioxidant, a structuring or thickening agent, and / or an emulsifier (examples of each of these ingredients is provided below). The composition can further include a silicone containing compound and / or a sunscreen agent. The compositions of the present invention can also include any one of, any combination of, or all of the following additional ingredients: water, a preservative, a silicone containing compound, an essential oil, a structuring agent, a vitamin, a pharmaceutical ingredient, or an antioxidant, or any combination of such ingredients or mixtures of such ingredients. In certain aspects, the composition can include at least two, three, four, five, six, seven, eight, nine, ten, or all of these additional ingredients identified in the previous sentences. Non-limiting examples of these additional ingredients are identified throughout this specification and are incorporated into this section by reference. The amounts of such ingredients can range from 0.0001% to 99.9% by weight or volume of the composition, or any integer or range in between as disclosed in other sections of this specification, which are incorporated into this paragraph by reference.

[0065] In some embodiments, the composition may further include one or more emulsifiers. Emulsifiers can reduce the interfacial tension between phases and improve the formulation and stability of an emulsion. The emulsifier may include a non-ionic emulsifier, an anionic emulsifier, a cationic emulsifier, a zwitterionic emulsifier or a combination thereof. Nonlimiting examples of emulsifiers include esters of glycerin, esters of propylene glycol, fatty acid esters of polyethylene glycol, fatty acid esters of polypropylene glycol, esters of sorbitol, esters of sorbitan anhydrides, carboxylic acid copolymers, esters and ethers of glucose, ethoxylated ethers, ethoxylated alcohols, alkyl phosphates, polyoxyethylene fatty ether phosphates, fatty acid amides, acyl lactylates, soaps, TEA stearate, DEA oleth-3 phosphate, polyethylene glycol 20 sorbitan monolaurate (polysorbate 20), polyethylene glycol 5 soya sterol, Steareth-2, Steareth-20, Steareth-21, ceteareth-20. PPG-2 methylglucose ether distearate, ceteth 10, polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, polysorbate 60, glyceryl Stearate, PEG- 100 stearate, and mixtures thereof. In certain embodiments, the non-ionic emulsifier is cetearyl olivate or sorbitan olivate. In other embodiments, the emulsifier is present in an amount from about 0.1 wt % to about 4.0 wt %.

[0066] In some embodiments, the composition further includes a moisturizing agent. Nonlimiting examples of moisturizing agents that can be used with the compositions of the present invention include amino acids, chondroitin sulfate, diglycerin, erythritol, fructose, glucose, glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol, honey, hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysate, inositol, lactitol, maltitol, maltose, mannitol, natural moisturizing factor, PEG- 15 butanediol, poly glyceryl sorbitol, salts of pyrrolidone carboxylic acid, potassium PCA, propylene glycol, sodium glucuronate, sodium PCA, sorbitol, sucrose, trehalose, urea, and xylitol. In some embodiments, the moisturizing agent is glycerin. In other embodiments, the moisturizing agent is present in an amount of from about 0.5 wt % to about 6.0 wt %.

[0067] Other examples include acetylated lanolin, acetylated lanolin alcohol, alanine, algae extract, aloe barbadensis, aloe-barbadensis extract, aloe barbadensis gel, althea officinalis extract, apricot (prunus armeniaca) kernel oil, arginine, arginine aspartate, arnica montana extract, aspartic acid, avocado (persea gratis sima) oil, barrier sphingolipids, butyl alcohol, beeswax, behenyl alcohol, beta-sitosterol, birch (betula alba) bark extract, borage (borago officinalis) extract, butcherbroom (ruscus aculeatus) extract, butylene glycol, calendula officinalis extract, calendula officinalis oil, candelilla (euphorbia cerifera) wax, canola oil, caprylic / capric triglyceride, cardamon (elettaria cardamomum) oil, carnauba (copernicia cerifera) wax, carrot (daucus carota sativa) oil, castor (ricinus communis) oil, ceramides, ceresin, ceteareth-5, ceteareth-12, ceteareth-20, cetearyl octanoate, ceteth-20, ceteth-24, cetyl acetate, cetyl octanoate, cetyl palmitate, chamomile (anthemis nobilis) oil, cholesterol, cholesterol esters, cholesteryl hydroxystearate, citric acid, clary (salvia sclarea) oil, cocoa (theobroma cacao) butter, coco-caprylate / caprate, coconut (cocos nucifera) oil, collagen, collagen amino acids, corn (zea mays) oil, fatty acids, decyl oleate, dimethicone copolyol, dimethiconol, dioctyl adipate, dioctyl succinate, dipentaerythrityl hexacaprylate / hexacaprate, DNA, erythritol, ethoxydiglycol, ethyl linoleate, eucalyptus globulus oil, evening primrose (oenothera biennis) oil, fatty acids, geranium maculatum oil, glucosamine, glucose glutamate, glutamic acid, glycereth-26, glycerin, glycerol, glyceryl distearate, glyceryl hydroxystearate, glyceryl laurate, glyceryl linoleate, glyceryl myristate, glyceryl oleate, glyceryl stearate, glyceryl stearate SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycans, grape (vitis vinifera) seed oil, hazel (corylus americana) nut oil, hazel (corylus avellana) nut oil, hexylene glycol, hyaluronic acid, hybrid safflower (carthamus tinctorius) oil, hydrogenated castor oil, hydrogenated coco-glycerides, hydrogenated coconut oil, hydrogenated lanolin, hydrogenated lecithin, hydrogenated palm glyceride, hydrogenated palm kernel oil, hydrogenated soybean oil, hydrogenated tallow glyceride, hydrogenated vegetable oil, hydrolyzed collagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin, hydrolyzed soy protein, hydroxylated lanolin, hydroxyproline, isocetyl stearate, isocetyl stearoyl stearate, isodecyl oleate, isopropyl isostearate, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearamide DEA, isostearic acid, isostearyl lactate, isostearyl neopentanoate, jasmine (jasminum officinale) oil, jojoba (buxus chinensis) oil, kelp, kukui (aleurites moluccana) nut oil, lactamide MEA, laneth-16, laneth-10 acetate, lanolin, lanolin acid, lanolin alcohol, lanolin oil, lanolin wax, lavender (lavandula angustifolia) oil, lecithin, lemon (citrus medica limonum) oil, linoleic acid, linolenic acid, macadamia temifolia nut oil, maltitol, matricaria (chamomilla recutita) oil, methyl glucose sesquistearate, methylsilanol PCA, mineral oil, mink oil, mortierella oil, myristyl lactate, myristyl myristate, myristyl propionate, neopentyl glycol dicaprylate / dicaprate, octyldodecanol, octyldodecyl myristate, octyldodecyl stearoyl stearate, octyl hydroxystearate, octyl palmitate, octyl salicylate, octyl stearate, oleic acid, olive (olea europaea) oil, orange (citrus aurantium dulcis) oil, palm (elaeis guineensis) oil, palmitic acid, pantethine, panthenol, panthenyl ethyl ether, paraffin, PCA, peach (prunus persica) kernel oil, peanut (arachis hypogaea) oil.

[0068] Additional non-limiting examples of moisturizing agents may include PEG- 8 Cl 2- 18 ester, PEG- 15 cocamine, PEG- 150 distearate, PEG-60 glyceryl isostearate, PEG-5 glyceryl stearate, PEG-30 glyceryl stearate, PEG-7 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-20 methyl glucose sesquistearate, PEG40 sorbitan peroleate, PEG-5 soy sterol, PEG- 10 soy sterol, PEG-2 stearate, PEG-8 stearate, PEG-20 stearate, PEG-32 stearate, PEG40 stearate, PEG-50 stearate, PEG- 100 stearate, PEG- 150 stearate, pentadecalactone, peppermint (mentha piperita) oil, petrolatum, phospholipids, polyamino sugar condensate, poly glyceryl- 3 diisostearate, polyquatemium-24, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, potassium myristate, potassium palmitate, propylene glycol, propylene glycol dicaprylate / dicaprate, propylene glycol dioctanoate, propylene glycol dipelargonate, propylene glycol laurate, propylene glycol stearate, propylene glycol stearate SE, PVP, pyridoxine dipalmitate, retinol, retinol palmitate, rice (oryza sativa) bran oil, RNA, rosemary (rosmarinus officinalis) oil, rose oil, safflower (carthamus tinctorius) oil, sage (salvia officinalis) oil, sandalwood (santalum album) oil, serine, serum protein, sesame (sesamum indicum) oil, shea butter (butyro spermum parkii), silk powder, sodium chondroitin sulfate, sodium hyaluronate, sodium lactate, sodium palmitate, sodium PCA, sodium poly glutamate, soluble collagen, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitol, soybean (glycine soja) oil, sphingolipids, squalane, squalene, stearamide MEA- stearate, stearic acid, stearoxy dimethicone, stearoxytrimethylsilane, stearyl alcohol, stearyl glycyrrhetinate, stearyl heptanoate, stearyl stearate, sunflower (helianthus annuus) seed oil, sweet almond (prunus amygdalus dulcis) oil, synthetic beeswax, tocopherol, tocopheryl acetate, tocopheryl linoleate, tribehenin, tridecyl neopentanoate, tridecyl stearate, triethanolamine, tristearin, urea, vegetable oil, water, waxes, wheat (trificum vulgare) germ oil, and ylang ylang (cananga odorata) oil. In some embodiments, the moisturizing agent may be allantoin. In other embodiments, the moisturizing agent is present in the composition in an amount of from about 0.5 wt % to about 6.0 wt %.

[0069] In some embodiments, the composition may further include a thickening agent. Thickening agents, including thickener or gelling agents, include substances which that can increase the viscosity of a composition. Thickening agents include those that can increase the viscosity of a composition without substantially modifying the efficacy of the active ingredient within the composition. Thickening agents can also increase the stability of the compositions of the present invention. In certain aspects of the present invention, thickening agents include hydrogenated polyisobutene or trihydroxy stearin, or a mixture of both.

[0070] Non-limiting examples of additional thickening agents that can be used in the context of the present invention include carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, polysaccharides, and gums. Examples of carboxylic acid polymers include crosslinked compounds containing one or more monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of these acrylic acids and the substituted acrylic acids, wherein the crosslinking agent contains two or more carbon-carbon double bonds and is derived from a polyhydric alcohol (see CTFA International Cosmetic Ingredient Dictionary, Fourth Edition, 1991, pp. 12 and 80). Examples of commercially available carboxylic acid polymers include carbomers, which are homopolymers of acrylic acid crosslinked with allyl ethers of sucrose or pentaerythritol (e.g., Carbopol™ 900 series from B. F. Goodrich). Non-limiting examples of crosslinked polyacrylate polymers include cationic and nonionic polymers.

[0071] Non-limiting examples of polyacrylamide polymers (including nonionic polyacrylamide polymers including substituted branched or unbranched polymers) include polyacrylamide, isoparaffin and Laureth-7, multi-block copolymers of acrylamides and substituted acrylamides with acrylic acids and substituted acrylic acids. Non-limiting examples of polysaccharides include cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxy late, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulfate, and mixtures thereof. Another example is an alkyl substituted cellulose where the hydroxy groups of the cellulose polymer are hydroxy alkylated (preferably hydroxy ethylated or hydroxypropylated) to form a hydroxyalkylated cellulose which is then further modified with a C10-C30 straight chain or branched chain alkyl group through an ether linkage. Typically these polymers are ethers of C10-C30 straight or branched chain alcohols with hydroxyalkylcelluloses. Other useful polysaccharides include scleroglucans comprising a linear chain of (1-3) linked glucose units with a (1-6) linked glucose every three unit.

[0072] Non-limiting examples of gums that can be used with the present compositions include acacia, agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gelatin, gellan gum, guar gum, guar hydroxypropyltrimonium chloride, hectorite, hyaluroinic acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, locust bean gum, natto gum, potassium alginate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboyxmethyl dextran, sodium carrageenan, tragacanth gum, xanthan gum, and mixtures thereof. In some embodiments, the thickening agent is Chondrus crispus (carrageenan) extract. In other embodiments, the thickening agent is present in the composition in an amount of from about 0.1 wt % to about 4.5 wt %.

[0073] In some embodiments, the composition further includes an essential oil. Essential oils include oils derived from herbs, flowers, trees, and other plants. Such oils are typically present as tiny droplets between the plant's cells and can be extracted by several methods known to those of skill in the art (e.g., steam distilled, enfleurage (i.e., extraction by using fat), maceration, solvent extraction, or mechanical pressing). When these types of oils are exposed to air they tend to evaporate (i.e., a volatile oil). As a result, many essential oils are colorless, but with age, they can oxidize and become darker. Essential oils are insoluble in water and are soluble in alcohol, ether, fixed oils (vegetal), and other organic solvents. Typical physical characteristics found in essential oils include boiling points that vary from about 160° C to 240° C and densities ranging from about 0.759 to about 1.096.

[0074] Essential oils typically are named by the plant from which the oil is found. For example, rose oil or peppermint oil are derived from rose or peppermint plants, respectively. Non-limiting examples of essential oils that can be used in the context of the present invention include sesame oil, macadamia nut oil, tea tree oil, evening primrose oil, Spanish sage oil, Spanish rosemary oil, coriander oil, thyme oil, pimento berries oil, rose oil, anise oil, balsam oil, bergamot oil, rosewood oil, cedar oil, chamomile oil, sage oil, clary sage oil, clove oil, cypress oil, eucalyptus oil, fennel oil, sea fennel oil, frankincense oil, geranium oil, ginger oil, grapefruit oil, jasmine oil, juniper oil, lavender oil, lemon oil, lemongrass oil, lime oil, mandarin oil, marjoram oil, myrrh oil, neroli oil, orange oil, patchouli oil, pepper oil, black pepper oil, petitgrain oil, pine oil, rose otto oil, rosemary oil, sandalwood oil, spearmint oil, spikenard oil, vetiver oil, wintergreen oil, or ylang ylang. Other essential oils known to those of skill in the art are also contemplated as being useful within the context of the present invention. In some embodiments, the essential oil may be Copaifera officinalis (balsam copaiba) resin. In other embodiments, the essential oil component is present in an amount of from about 0.1 wt % to about 2.5 wt %.

[0075] In some embodiments, the composition may further include a preservative. Nonlimiting examples of preservatives may include quaternary ammonium preservatives such as polyquatemium- 1 and benzalkonium halides (e.g., benzalkonium chloride (“BAC”) and benzalkonium bromide), parabens (e.g., methylparabens and propylparabens), phenoxyethanol, ethylhexylglycerinbenzyl alcohol, chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof. In some embodiments, the preservative in the compositions is phenoxyethanol. In some embodiments, the preservative in the compositions is ethylhexylglycerin. In other embodiments, the preservative component is present in an amount of from about 0.1 wt % to about 1.0 wt %.

[0076] In some embodiments, the composition may also include an antioxidant. Non-limiting examples of antioxidants that can be used with the compositions of the present invention include acetyl cysteine, ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate, BHA, BHT, t-butyl hydroquinone, cysteine, cysteine HC1, diamylhydroquinone, di-t-butylhydroquinone, dicetyl thiodipropionate, dioleyl tocopheryl methylsilanol, disodium ascorbyl sulfate, distearyl thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate, erythorbic acid, esters of ascorbic acid, ethyl ferulate, ferulic acid, gallic acid esters, hydroquinone, isooctyl thioglycolate, kojic acid, magnesium ascorbate, magnesium ascorbyl phosphate, methylsilanol ascorbate, natural botanical anti-oxidants such as green tea or grape seed extracts, nordihydroguaiaretic acid, octyl gallate, phenylthioglycolic acid, potassium ascorbyl tocopheryl phosphate, potassium sulfite, propyl gallate, quinones, rosmarinic acid, sodium ascorbate, sodium bisulfite, sodium erythorbate, sodium metabisulfite, sodium sulfite, superoxide dismutase, sodium thioglycolate, sorbityl furfural, thiodiglycol, thiodiglycolamide, thiodiglycolic acid, thioglycolic acid, thiolactic acid, thiosalicylic acid, tocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18, tocophereth-50, tocopherol, tocophersolan, tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, and tris(nonylphenyl)phosphite. In some embodiments, the antioxidant is tocopherol. In other embodiments, the antioxidant component is present in an amount of from about 0.1 wt % to about 10 wt %.

[0077] In some embodiments, the composition may also include a structuring agent. Structuring agent, in certain aspects, assists in providing rheological characteristics to the composition to contribute to the composition's stability. In other aspects, structuring agents can also function as an emulsifier or surfactant. Non-limiting examples of structuring agents include stearic acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, stearic acid, palmitic acid, the polyethylene glycol ether of stearyl alcohol having an average of about 1 to about 21 ethylene oxide units, the polyethylene glycol ether of cetyl alcohol having an average of about 1 to about 5 ethylene oxide units, and mixtures thereof.

[0078] In some embodiments, the compositions may additionally include a triglyceride. Nonlimiting examples include small, medium, and large chain triglycerides. In certain aspects, the triglyceride is a medium chain triglyceride (e.g., caprylic / capric triglyceride).

[0079] In some embodiments, the compositions may also include a UV absorption agent. UV absorption agents that can be used in combination with the compositions of the present invention include chemical and physical sunblocks. Non-limiting examples of chemical sunblocks that can be used include para-aminobenzoic acid (PABA), PABA esters (glyceryl PABA, amyldimethyl PABA and octyldimethyl PABA), butyl PABA, ethyl PABA, ethyl dihydroxypropyl PABA, benzophenones (oxybenzone, sulisobenzone, benzophenone, and benzophenone- 1 through 12), cinnamates (octyl methoxycinnamate, isoamyl p- methoxycinnamate, octylmethoxy cinnamate, cinoxate, diisopropyl methyl cinnamate, DEA- methoxycinnamate, ethyl diisopropylcinnamate, glyceryl octanoate dimethoxycinnamate and ethyl methoxy cinnamate), cinnamate esters, salicylates (homomethyl salicylate, benzyl salicylate, glycol salicylate, isopropylbenzyl salicylate, etc.), anthranilates, ethyl urocanate, homosalate, octisalate, dibenzoylmethane derivatives (e.g., avobenzone), octocry lene, octyl triazone, digalloyl trioleate, glyceryl aminobenzoate, lawsone with dihydroxyacetone, ethylhexyl triazone, dioctyl butamido triazone, benzylidene malonate polysiloxane, terephthalylidene dicamphor sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate, diethylamino hydroxybenzoyl hexyl benzoate, bis diethylamino hydroxybenzoyl benzoate, bis benzoxazoylphenyl ethylhexylimino triazine, drometrizole trisiloxane, methylene bis- benzotriazolyl tetramethylbutylphenol, and bis-ethylhexyloxyphenol methoxyphenyltriazine, 4-methylbenzylidenecamphor, and isopentyl 4-methoxycinnamate. Non-limiting examples of physical sunblocks include kaolin, talc, petrolatum and metal oxides (e.g., titanium dioxide and zinc oxide).

[0080] In some embodiments, the composition may also include a cosmetic ingredient. A wide variety of non-limiting cosmetic ingredients described in the CTFA International Cosmetic Ingredient Dictionary and Handbook (2004 and 2008) can be used. Non-limiting examples of cosmetic ingredients include fragrances (artificial and natural), dyes and color ingredients (e.g., Blue 1, Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C green no. 5, D&C orange no. 4, D&C red no. 17, D&C red no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C yellow no. 11), adsorbents, lubricants, solvents, moisturizers (including, e.g., emollients, humectants, film formers, occlusive agents, and agents that affect the natural moisturization mechanisms of the skin), water-repellants, UV absorbers (physical and chemical absorbers such as paraminobenzoic acid (“PABA”) and corresponding PABA derivatives, titanium dioxide, zinc oxide, etc.), essential oils, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g. zinc, calcium and selenium), anti-irritants (e.g. steroids and nonsteroidal anti-inflammatories), botanical extracts (e.g., aloe vera, chamomile, cucumber extract, ginkgo biloba, ginseng, and rosemary), anti-microbial agents, antioxidants (e.g., BHT and tocopherol), chelating agents (e.g., disodium EDTA and tetrasodium EDTA), preservatives (e.g., methylparaben and propylparaben), pH adjusters (e.g., sodium hydroxide and citric acid), absorbents (e.g., aluminum starch octenylsuccinate, kaolin, corn starch, oat starch, cyclodextrin, talc, and zeolite), skin bleaching and lightening agents (e.g., hydroquinone and niacinamide lactate), humectants (e.g., sorbitol, urea, and mannitol), exfoliants, waterproofing agents (e.g., magnesium / aluminum hydroxide stearate), skin conditioning agents (e.g., aloe extracts, allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, and dipotassium glycyrrhizate).

[0081] In some embodiments, the compositions may further include a pharmaceutical active agent. Non-limiting examples of pharmaceutical active agents include anti-acne agents, agents used to treat rosacea, analgesics, anesthetics, anorectals, antihistamines, anti- inflammatory agents including non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antimicrobials, anti-cancer actives, scabicides, pediculicides, antineoplastics, antiperspirants, antipruritics, antipsoriatic agents, antiseborrheic agents, biologically active proteins and peptides, bum treatment agents, cauterizing agents, depigmenting agents, depilatories, diaper rash treatment agents, enzymes, hair growth stimulants, hair growth retardants including DFMO and its salts and analogs, hemostatics, kerotolytics, canker sore treatment agents, cold sore treatment agents, dental and periodontal treatment agents, photosensitizing actives, skin protectant / barrier agents, steroids including hormones and corticosteroids, sunburn treatment agents, sunscreens, transdermal actives, nasal actives, vaginal actives, wart treatment agents, wound treatment agents, wound healing agents, etc.

[0082] In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition is preferably administered as a pharmaceutical composition and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In certain embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (z.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration.

[0083] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0084] Methods of Treatment

[0085] Provided herein are methods of preventing or treating a disease comprising administering a composition described herein.

[0086] Wounds

[0087] Compositions featured herein may be used for treating wounds (e.g., dermal wounds) in a subject (e.g., a human subject or an animal model) in need thereof. The featured composition can be used for treating chronic wounds (e.g., chronic dermal wounds) and / or acute wounds (e.g., acute dermal wounds).

[0088] Chronic wounds

[0089] The compositions and methods described herein can be used for treating a chronic non-healing wound. A chronic wound (e.g., chronic dermal wound) that can be treated by the methods and composition described herein can be a wound that has failed to progress through the phases of healing in an orderly and timely fashion, does not improve after four weeks, and / or does not heal in eight weeks. Types of chronic wounds that can be treated by the compositions and methods described herein may include, but are not limited to venous ulcers, diabetic ulcers, pressure ulcers, non-healing surgical wounds, wounds related to metabolic diseases, wounds that repeatedly break down, and lesions and rashes associated with or caused by shingles, allergy (e.g., induced by irritants, such as certain chemical, plants, animals, etc.), and autoimmune diseases (e.g., psoriasis, dermatitis (e.g., atopic dermatitis (e.g., eczema), contact dermatitis, and seborrheic dermatitis), etc.). One or more chronic wounds (e.g., chronic dermal wounds) can be treated by the composition described herein.

[0090] Acute wounds The compositions and methods described herein can be used for treating an acute wound. An acute wound (e.g., acute dermal wound) that can be treated by the methods and composition described herein can be an injury to the skin that occurs suddenly rather than overtime and heals at a predictable and expected rate according to the normal wound healing process. Types of acute wounds that can be treated by the compositions and methods described herein may include, but are not limited to trauma wounds (e.g., abrasions, lacerations, crush wounds, penetrations and punctures), surgical wounds (e.g., clean surgical wounds (e.g., made in an operating room or in a sterile procedure environment), contaminated surgical wounds (e.g., surgical wound contaminated with bacteria but not yet infected), and dirty surgical wounds (e.g., surgical wound with a bacterial infection)), and bum wounds. One or more acute wounds (e.g., acute dermal wounds) can be treated by the composition described herein.

[0091] Cancer

[0092] In one aspect, disclosed herein is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein. In some embodiments, the pharmaceutical composition induces cytostasis in keratinocytes. Cytostasis is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Chemotherapy of cancer, treatment of skin diseases and treatment of infections are common use cases of cytostatic drugs. Active hygienic products generally contain cytostatic substances.

[0093] Cytostatic agents (e.g., the composition described herein) have been beneficial in fighting tumors with their ability to induce cell growth arrest. For example, nitric oxide (NO) is able to have a cytostatic effect on the human breast cancer cell line MDA-MB-231. Not only does nitric oxide stop cell growth, a study shows that it can also induce apoptosis after the cancer cells have been exposed to NO over 48 hours. Another example, long-chain polyunsaturated fatty acids inhibit cell division, cause cell cycle arrest, and can induce cell death in malignant epithelial cells from various tissue organs in vitro.

[0094] In some embodiments, the pharmaceutical composition described herein is administered with a cancer therapeutic, such as a chemotherapeutic agent. Examples of the chemotherapeutic agent may be thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, dynemicin, clodronate, esperamicin; neocarzinostatin chromophore, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, may tansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, PSK polysaccharide complex, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone;

[0095] 2,2',2"-trichlorotriethylamine, trichothecene, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, oxaliplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, RFS 2000, difluoromethylomithine, retinoic acid, or capecitabine.

[0096] In some embodiments, the cancer is hematological malignancy, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, chondrosarcoma, fibrosarcoma, lymphosarcoma, melano sarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, telangiectaltic sarcoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, skin cancer, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, plasmacytoma, colorectal cancer, rectal cancer, Merkel Cell carcinoma, salivary gland carcinoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0097] Formulations and carriers

[0098] In order to be administered to a subject (e.g., a human subject or an animal model), a composition described herein, can be formulated as a pharmaceutical composition. Pharmaceutical compositions or formulations contemplated herein with a pharmaceutically acceptable carrier, adjuvant or vehicle. A pharmaceutically acceptable carrier or excipient refers to a carrier (e.g., carrier, media, diluent, solvent, vehicle, etc.) which does not significantly interfere with the biological activity or effectiveness of the active ingredients) of a pharmaceutical composition and which is not excessively toxic to the host at the concentrations at which it is used or administered. Pharmaceutical compositions or formulations contemplated herein may include carriers (e.g., diluents, excipients and auxiliaries) that facilitate processing of the active components (e.g., active ingredients)) into a pharmaceutically acceptable formulation. Carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the inventive compositions may include time-delay or timerelease material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such: as LABRASOL®, GELUCIRE®, or the like, or formulators, such as CHIC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. GELUCIRE®, a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation. Other pharmaceutically acceptable ingredients can be present in the composition as well. Suitable substances and their use for the formulation of pharmaceutically active compounds are well-known in the art (see, for example, Remington: The Science and Practice of Pharmacy 22th edition (2012), for additional discussion of pharmaceutically acceptable substances and methods of preparing pharmaceutical compositions of various types).

[0099] If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of ointment, lotion, gel, cream, salve, liniment, paste, tonic, unguent, spray, soap, shampoo, lip balm, syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non- aqueous liquid suspension. Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin. The inventive compositions are prepared in unit- dosage form appropriate for the mode of administration, e.g., parenteral (e.g., topical) or oral administration.

[0100] To obtain a stable water-soluble dose form, the active components of the present invention may be dissolved in water, or an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. The active components may also be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like in concentrations ranging from 0-60% of the total volume. For example, an active component of the present invention can be dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

[0101] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions or formulations of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethyleneglycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, liposomes and wool fat. In some embodiments, the vehicle used for preparing the pharmaceutical composition or formulation featured herein is water. In particular, the pharmaceutical composition or formulation featured herein may contain at least 40% (e.g., at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or more) water. For example, the pharmaceutical composition or formulation featured herein, may contain at least 50% water. The composition of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism, or alter rate of excretion ( Pharmacokinetic Optimization in Drug Research, Testa, B. et al., 2001 , Wiley- VCH, VCHA).

[0102] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration. The pharmaceutical compositions of this invention may be administered parenterally (e.g., topically), orally, by inhalation spray, rectally, nasally, buccally, vaginally, or via an implanted reservoir, and are preferably administered topically. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The term “parenteral” or “parenterally” as used herein includes topical administration, injections (e.g., subcutaneous, intra-cutaneous, intra-venous, intra-muscular, intra-articular, intra-synovial, intra-stemal, intrathecal, intra-lesional and intracranial injection) or infusion techniques.

[0103] For topical application, a pharmaceutical composition may be formulated in a suitable ointment, lotion, gel, cream, salve, liniment, paste, tonic, unguent, spray, soap, shampoo, or lip balm containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers suitable for use in such compositions.

[0104] For administration by injection, pharmaceutical compositions of this invention can be formulated in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solutions. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. Pharmaceutically acceptable vehicles also include, but are not limited to, cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F- 12 medium). Formulation methods are known in the art, see e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (3rd ed.) Taylor & Francis Group, CRC Press (2015).

[0105] Pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the composition described herein with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0106] For administration by inhalation, pharmaceutical compositions of this invention may be formulated in the form of an aerosol spray from a pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, a fluorocarbon, or a nebulizer. Liquid or dry aerosol (e.g., dry powders, large porous particles, etc.) can also be used. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0107] For oral administration, agents can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as a powder, tablet, pill, capsule, lozenge, liquid, gel, syrup, slurry, suspension, and the like. It is recognized that some pharmaceutical compositions, if administered orally, must be protected from digestion. This is typically accomplished either by complexing the protein with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the protein in an appropriately resistant carrier such as a liposome. Suitable excipients for oral dosage forms include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrating agents may be added, for example, such as the cross linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Lubricating agents, such as magnesium stearate, are also typically added. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, and / or coloring agents may be added. Optionally the oral formulations may also be formulated in saline or buffers for neutralizing internal acid conditions or may be administered without any carriers.

[0108] Pharmaceutical compositions may also be prepared in microcapsules, such as hydroxylmethylcellulose or gelatin-microcapsule and poly-(methylmethacrylate) microcapsule. Pharmaceutical compositions may also be prepared in other drug delivery systems such as liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules. Such techniques are described in the art. The pharmaceutical compositions to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0109] Tropical Formulation

[0110] Described herein are method of making a tropical formulation. The Tropical formulation comprises an aqueous phase and a lipid phase that may be emulsified using emulsification wax. The emulsification wax may be about 0.1 %- 1 %, l%-2%, 2%-3%, 3%- 4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%-14%, or 14%-15% (w / v). In some embodiments, the aqueous phase comprises colloidal oatmeal and / or arrow root powder dissolved in deionized H2O. The colloidal oatmeal may be about 0.1%-1%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v). The arrow root powder may be about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v). The deionized H2O may be about 20%-30%, 30%-40%, 40%-50%, 50%-60%, or 60%-70% (w / v).

[0111] The method comprises adding bark resin extract from the plant of genus Calycophyllum (e.g., Calycophyllum spruceaniim) to the aqueous phase. The bark resin extract from the plant of genus Calycophyllum may be about 0.001%-50% (w / v), such as about 0.01%-l%, 1 %- 10%, 10%-20%, 20%-30%, 30%-40%, or 40%-50% (w / v), preferably about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v). The method may further comprise adding amiticide coconut, aspen bark, and / or lemon ferment. The amiticide coconut may be about 0.1%-1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%- 9%, or 9%-10% (w / v). The aspen bark may be about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v). The lemon ferment may be about 0.1%-1%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v). In some embodiments, the bark resin extract from the plant of genus Calycophyllum, amiticide coconut, aspen bark, and / or lemon ferment are allowed to dissolve at 25°C.

[0112] In some embodiments, the lipid phase comprises shea butter and / or emulsification wax. The shea butter may be about 0.1 %- 1 %, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%-14%, or 14%- 15% (w / v). The emulsification wax may be about 0.1%-1%, l%-2%, 2%-3%, 3%-4%, 4%- 5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%- 14%, or 14%- 15% (w / v). The method may further comprise heating shea butter and / or emulsification wax at 60°C until melted.

[0113] The method may further comprise adding oleoresin extract from the plant of genus Copaifera (e.g., Copaifera officinalis) to the lipid phase. The oleoresin extract from the plant of genus Copaifera (e.g., Copaifera officinalis) may be about 0.001%-50% (w / v), such as about 0.01%-l%, 1 %- 10%, 10%-20%, 20%-30%, 30%-40%, or 40%-50% (w / v), preferably about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v). The method may further comprise adding Carapa guianensis oil to the lipid phase. The Carapa guianensis oil may be about 0.1%-1%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v). In some embodiments, the oleoresin extract from the plant of genus Copaifera and the Carapa guianensis oil are combined before being added to the lipid phase.

[0114] The method may further comprise mixing the lipid phase with the aqueous phase. The method may further comprise blending the lipid phase and the aqueous phase with an immersion blender until the oil in water (o / w) emulsification has doubled in volume. The method may further comprise maintaining the pH at about 6.5 to 7.5, preferably 7.0. The method further comprises storing the formulation at about 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C.

[0115] Combination therapy

[0116] The composition described herein can be used as a monotherapy (e.g., the composition can be administered alone for treating wounds) or a combination therapy (e.g., the composition can be administered with one or more additional agents for treating wounds). In some embodiments, the composition described herein can be administered (e.g., topically) to a subject (e.g., a human subject or an animal model) as a combination therapy, e.g., along with one or more additional agents. Such additional agents may include, but are not limited to, one or more antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV- absorbing agents, and moisturizing agents.

[0117] In some embodiments, the additional agents (e.g., antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV-absorbing agents, and / or moisturizing agents) can be included in the pharmaceutical composition or formulation contemplated herein. For example, a combination therapy may include administering (e.g., topically) to a subject (e.g., a human subject or an animal model) the pharmaceutical composition or formulation, one or more pharmaceutically acceptable carriers, adjuvants or vehicles, and one or more additional agents (e.g., antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV-absorbing agents, and / or moisturizing agents).

[0118] In other embodiments, the additional agents (e.g., antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV-absorbing agents, and / or moisturizing agents) can be administered (e.g., parenterally (e.g., topically) or orally) as a separate composition (e.g., a separate pharmaceutical composition) prior to, concurrent with, or subsequent to administration (e.g., topical administration) of the composition (e.g., pharmaceutical composition or formulation) described herein. For example, a combination therapy may include administering (e.g., parenterally (e.g., topically) or orally) to a subject (e.g., a human subject or an animal model) one or more additional agents (e.g., antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV-absorbing agents, and / or moisturizing agents) prior to, concurrent with, or subsequent to administration (e.g., topical administration) of the pharmaceutical composition or formulation.

[0119] Antibiotic agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., antibiotic agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: mupirocin, bacitracin, polymyxin B, and neomycin.

[0120] Antiseptic agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., antiseptic agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: sodium hypochlorite, chlorhexidine, hexachlorophene, povidone iodine, ethanol, benzethonium chloride, triclosan, and benzalkonium chloride.

[0121] Antifungal agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., antifungal agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: Whitfield ointment (3% salicylic acid, 6% benzoic acid in petrolatum), Undecylenic alkanolamide, Ciclopirox olamine, Polyenes (e.g., Nystatin), Imidazoles (e.g., Bifonazole, Clotrimazole, Econazole, Efinaconazole, Ketoconazole, Luliconazole, Miconazole, Sulconazole, Tioconazole), Allylamine (e.g., Terbinafine), Thiocarbamates (e.g., Tolciclate, Tolnaftate), and Benzoxaborole (e.g., Tavaborole).

[0122] Antiviral agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., antiviral agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: acyclovir, and penciclovir.

[0123] Analgesic agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., analgesic agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: Benzocaine (Anbeso®, Cepacol®, others), Benzocaine / Butamben / Tetracaine (Cetacaine®), Benzyl Alcohol (Ulesfia; Zilactin), Capsaicin (various), Dibucaine (Nupercainal), Diclofenac (Elector ®, Pennsaid®, Voltaren®, others), Dyclonine (Dyclocaine®, Sucrets®), Ethyl Chloride, Hexylresorcinol (Sucrets®), Lidocaine (Akten, AneCream, Lidoderm, Xylocaine, others), Lidocaine / Prilocaine (EMLA®, Oraqix®), Lidocaine / Tetracaine (Synera®), Methyl alicylate / Menthol (BenGay®; Icy Hot®, others), Pramoxine (Itch-X, Proctofoam, others), Proparacaine (Flucaine), Tetracaine (Altacaine®, Pontocaine®, others), and Trolamine (Arthricream, Myoflex, others).

[0124] UV-absorbing agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., UV-absorbing agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: Phenyl ester of salicylate (Component: phenyl o- hydroxybenzoate); UV-absorber UV-P (Component: o-nitroaniline, p- cresol reaction products); UV-absorbing agent UV-0 (Component: 2,4-dihydroxybenzophenone); Ultraviolet absorber UV-9 (Component: 2-hydroxy-4-methoxybenzophenone); UV- absorbing agent UV- 531 (Component: 2-hydroxy-4-n-octoxybenzophenone); UV absorber UVP-327 (Component: 2-(2'- hydroxy-3 ', 5'-di-tert-phenyl)-5-chlorobenzotriazole); UV absorbers (Component: resorcinol monobenzoate); Light stabilizer AM- 101 (Composition: 2,2'-thiobis (4-t-octylphenoxy) nickel); Light stabilizer GW-540 (Component: tris (1 , 2, 2,6,6- pentamethylpiperidyl) phosphite); Light stabilizer 744 (Component: 4-benzoyloxy-2,2,6,6- tetramethylpiperidine); Light stabilizer HPT (Ingredients: hexamethylphosphoric triamide); titanium dioxide; and zinc oxide.

[0125] Moisturizing agents that can be used in combination therapy with a composition (e.g., pharmaceutical composition) described herein (e.g., moisturizing agents that can be included in a pharmaceutical composition described herein or administered prior to, concurrent with, or subsequent to administration of a pharmaceutical composition described herein) may be selected from: humectants (e.g., glycerol, sorbitol, glycerin, urea, lactic acid, and hyaluronic acid) and emollients (e.g., lanolin, paraffin, ceramides, and silicones).

[0126] Methods of treatment, their dosage levels and requirements featured herein may be selected by those of ordinary skill in the art from available methods and techniques.

[0127] It will be appreciated that the actual dosages of the composition (e.g., pharmaceutical composition) of this invention as a monotherapy or a combination therapy will vary according to the particular composition formulated, the mode of administration, the particular wound being treated, and the particular subject being treated. Those skilled in the art using conventional dosage-determination tests in view of the experimental data may ascertain optimal dosages for a given set of conditions. The course of treatment can be repeated (e.g., 1-12 times or more (e.g., 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, or more)) at appropriate intervals, e.g., every 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. The composition described herein may be administered to a subject in need thereof, for example, one or more times (e.g., 1-12 times or more) hourly, daily, weekly, biweekly, monthly, bimonthly, quarterly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The treatment may be continued for 5 years or less (e.g., 5 years, 4 years, 3 years, 2 years, 1 year, 6 months, 5 months, 4 months, 3 months, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or less). For example, a wound (e.g., chronic or acute) in a subject may be treated by administering (e.g., topically) to the subject the composition (e.g., pharmaceutical composition) as a monotherapy (e.g., the composition alone) or a combination therapy (e.g., the composition with one or more additional agents (e.g., antibiotic agents, antiseptic agents, antifungal agents, antiviral agents, analgesic agents, UV-absorbing agents, and / or moisturizing agents)) for 8 weeks or less (e.g., 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or less).

[0128] Upon improvement of a patient’s condition, a maintenance dose of a composition of this invention may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been reduced or alleviated to the desired level, treatment should cease, at least in principle. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of wound.

[0129] As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific composition used, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, the severity of the wound, the patient’s disposition to the wound and the judgment of the treating physician.

[0130] With respect to the composition of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

[0131] EXAMPLES

[0132] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0133] Example 1 : Materials and Methods

[0134] Pulverized Calycophyllum spruceanum bark is obtained from OK Natura in Iquitos, Peru. Copaifera officinalis oleoresin is obtained from Amazon Oil-The Rainforest Company, Ananindeua, Brazil. Andiroba oil, Carapa guianensis, is obtained from Beraca, Sao Paolo, Brazil. Bark extraction

[0135] All steps are carried out under aseptic conditions.

[0136] Pulverized Calycophyllum spruceanum bark is submerged in deionized water (dithO) at a ratio of 1:3 for 3 days. The bark and extracted aqueous components are centrifuged at 8000rmp for 15 minutes followed by depth filtration through graduated filtration membranes with molecular weight cut offs of lOOpM to 0.22pM. Filtration through the 0.22pM membrane is the sterilization step for extraction and the final % (w / v) is 33.0%.

[0137] Topical formulation

[0138] The topical formulation contains an aqueous phase and a lipid phase that are emulsified using 7.0% (w / v) emulsification wax. All measurements are performed in % (w / v). The aqueous phase consists of colloidal oatmeal (1.0%) and arrow root powder (1.0%) dissolved in deionized H2O (52.0%). Calycophyllum spruceanum (10.0%), amiticide coconut (3.0%), aspen bark (3.0%) and lemon ferment (2.0%) are weighed and added to the aqueous phase and allowed to dissolve at 25°C. The lipid phase consists of shea butter (7.0%) and emulsification wax (7.0%) heated and stirred at 60°C until melted. Once the lipid phase is completely melted, Copaifera officinalis oleoresin (7.0%) and Carapa guianensis oil (7.0%) are combined and added to the lipid phase. The lipid phase is then rapidly added to the aqueous phase and blended at high speeds with an immersion blender until the oil in water (o / w) emulsification has doubled in volume. pH is monitored at 7.0, microbial testing is performed, and batches are stored in sterile containers at 4°C.

[0139] Scratch assay

[0140] Primary adult human keratinocytes suspended in keratinocyte specific medium are plated on 6-well tissue culture plates at a density of 500,000 cells / mL. One mL of cell suspension is added to each well and allowed to grow to confluence. At confluence, each well is scored through the midline with the tip of a 20pL pipet tip. Wells are also left unscored as controls. Media is removed from each well to discard cellular debris and replaced with 2mL of either fresh keratinocyte specific medium, medium supplemented with 10.0%v / v Calycophyllum spruceanum aqueous bark extract (CSABE), medium supplemented with 7.0%v / v Copaifera officinalis oleoresin (CO) or medium supplemented with both 10.0%v / v CSABE and 7.0%v / v CO. Cell medium is replaced every 2 days and cells are monitored by microscopy at specific time points for up to 3 weeks. Controls include untreated cells or cells treated with 0.2%v / v dimethylsulfoxide (DMSO). Cells are treated after cellular wounding.

[0141] TNF-a ELISA

[0142] PBMC: Primary human peripheral blood mononuclear cells (PBMCs) are incubated in defined PBMC medium for 24 hours. Following 24 hours, PBMCs are stimulated with 1.0 ng / ml of lipopolysaccharides (LPS) and supplemented with either CSABE and CO individually or a combination thereof. Controls include untreated PBMCs and untreated LPS -stimulated PBMCs. Supernatant samples are collected and tested for the presence of TNF-a by Enzyme-Linked Immunosorbent Assay (ELISA).

[0143] Keratinocytes: Primary adult human keratinocytes are incubated in defined medium for 24 hours. Following 24 hours, keratinocytes are stimulated with 1.0 ng / ml LPS and supplemented with either CSABE and CO individually or a combination thereof. Controls include untreated, LPS stimulated and unstimulated cells and cells treated with 0.2% DMSO. Supernatant samples are collected and tested for the presence of TNF-a by ELISA.

[0144] TGF-P ELISA

[0145] Keratinocytes: Primary adult human keratinocytes are incubated in defined medium for 24 hours. Following 24 hours, keratinocytes are stimulated with 1.0 ng / ml LPS and supplemented with either CSABE and CO individually or a combination thereof. Controls include untreated, LPS stimulated and unstimulated cells and cells treated with 0.2% DMSO. Supernatant samples are collected and tested for the presence of TGF-P by ELISA.

[0146] Example 2: TNF ELISA & Scratch assay

[0147] In vitro assays show dose dependent inhibition of TNF-a release from LPS -stimulated adult human PBMCs with significant inhibition observed following exposure to concentrations of CSABE above 7.0% (w / v). Unstimulated adult human PBMCs do not release TNF-a (Figure 1). Cytostasis of adult human keratinocytes is observed following exposure to concentrations of CSABE between 0.1%-10.0% (w / v). (Figure 6)

[0148] In vitro assays show dose dependent inhibition of TNF-a release from LPS -stimulated adult human PBMCs with significant inhibition observed following exposure to concentrations of CSABE above 0.5% (w / v) (Figure 2). Although definitive percentages are different between figures 1 and 2, a trend of immune suppression is evident in both assays. Unstimulated adult human PBMCs do not release TNF-a. Cytostasis of adult human keratinocytes is observed following exposure to concentrations of CSABE at 10.0% (w / v) (Figure 7). Clusters of early keratinocytes are observed at day 16 following addition of fresh 10.0% CSABE at day 7 (yellow circles) (Figure 7).

[0149] To summarize the cytokine assay, the addition of CSABE to LPS-stimulated primary human PBMCs reduces PBMC release of TNF-a in a concentration dependent manner (Figures 1 and 2). This suggests potential inhibition of chronic inflammation that can be the result of persistent PBMC activation

[0150] In vitro assays show TNF-a release from control and EPS -stimulated keratinocytes when exposed to 10.0% (w / v) CSABE (Figure 3). Control keratinocytes and keratinocytes exposed to 0.2% DMSO do not release TNF-a. Cytostasis of adult human keratinocytes is observed following exposure to concentrations of CSABE at 0.1% and 10.0% (w / v) (Figures 8a-8d). When exposed to fresh 10.0% (w / v) CSABE on day 7, control cells, and cells previously exposed to 10% (w / v) CSABE show pockets of undifferentiated keratinocytes growing between differentiated cells (Figures 8a-8d). Cytostasis in the wound site remains undisturbed.

[0151] To summarize the cytokine assay, the addition of 10% (w / v) CSABE to control and LPS-distressed primary human adult keratinocytes stimulates release of TNF-a (Figure 3). Control cells and those treated with 0.2% DMSO show no significant release of TNFa during the 7-day culture period. This suggests immediate activation of an immune response from primary human keratinocytes with rapid resolution at day 3.

[0152] In vitro assays show that the addition of 10.0% (w / v) CSABE and 7.0% (w / v) CO to EPS-distressed primary human adult keratinocytes inhibits release of TNF-a (Figure 4). Control cells, cells treated with 0.2% DMSO and cells treated with 7.0% CO alone show similar release profiles of TNF-a during the 7-day culture period. As shown in Figure 3, CSABE alone appears to stimulate TNF-a release from adult human keratinocytes as compared to controls. The addition of CO to CSABE causes a polar response and significantly inhibits the release of this cytokine. Following wounding at day 7, cytostasis is again observed when cells are exposed to CSABE and CO but not CO alone (Figure 9b). Pockets of undifferentiated keratinocytes are shown growing between differentiated cells at 24 days in culture (Figure 9b, circles)

[0153] To summarize the cytokine assay, the novel combination of CSABE and CO causes unexpected inhibition of TNF-a release from EPS -stimulated adult human keratinocytes unlike cellular responses to CSABE and CO individually. This suggests that this unique combination may be capable of suppressing chronic inflammation in epithelial tissue.

[0154] In vitro assays show significant release of TGF-P from LPS-stimulated keratinocytes when exposed to 10.0% (w / v) CSABE as compared to control cells (Figure 5). TGF-P release from treated cells diametrically opposes that of untreated cells in that untreated cellular release increases by day 7. Addition of CSABE to control and LPS-distressed primary adult human keratinocytes induces release of TGF-P at 24 hours with a decrease by day 7 (Figure 5). Control keratinocytes and those treated with DMSO show increases in release of TGF-P by day 7.

[0155] To summarize the cytokine assay, the release of TGF-P and immediate increases in TNFa from CSABE-treated cells, as shown in Figure 3, suggests inflammatory modulation resulting in rapid wound resolution.

[0156] In vitro assays show adult human keratinocytes that have been treated with 0.1%- 10.0% (w / v) CSABE following the scratch assay appear to become cytostatic and do not migrate to close the wounded area (Figure 6). Control cells proliferate into the wounded area and begin to form a second layer of cells.

[0157] In vitro assays show adult human keratinocytes that have been treated with 10.0% (w / v) CSABE following the scratch assay appear to become cytostatic and do not migrate to close the wounded area (Figure 7). Additionally, cells remain in this cytostatic state and are viable following 3 weeks in culture. Control cells proliferate into the wounded area and begin to form a second layer of cells.

[0158] In vitro assays show the addition of CSABE to primary human adult keratinocytes induces cytostasis and maintains cell viability and morphology for over 2 weeks in culture (Figures 8a-8d). Keratinocytes are rescued from continuous EPS exposure by CSABE and pockets of early keratinocytes appear at day 16 (circles) suggesting potential cellular regeneration. Different batches of CSABE preparations show consistent results.

[0159] In vitro assays show the additions of 10.0% CSABE (w / v) and 7.0% CO (w / v) to previously LPS-stimulated and wounded primary human adult keratinocytes appear to rescue distressed primary adult keratinocytes up to day 24 in culture (Figure 9b). Cells remain viable and pockets (rings) of young keratinocytes are seen in cultures containing CO and CSABE combined with CO. Cytostasis is only observed with the combined extracts and not with CO alone. Together this data suggests that the combination of extracts modulates cell cycles in both mature and young keratinocytes by maintaining cytostasis in older cells and growth in younger populations.

[0160] INCORPORATION BY REFERENCE

[0161] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0162] EQUIVALENTS

[0163] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We claim:

1. A pharmaceutical composition comprising bark resin extract from a plant of genus Calycophyllum and oleoresin extract from a plant of genus Copaifera.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 0.001%-50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 0.001%-50% (w / v) oleoresin extract from the plant of genus Copaifera.

3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises about 0.01%- 1%, l%-10%, 10%-20%, 20%-30%, 30%-40%, or 40%- 50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 0.01%-l%,1 %- 10%, 10%-20%, 20%-30%, 30%-40%, or 40%-50% (w / v) oleoresin extract from the plant of genus Copaifera.

4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v) bark resin extract from the plant of genus Calycophyllum and about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (w / v) oleoresin extract from the plant of genus Copaifera.

5. The pharmaceutical composition of any one of claims 1-4, wherein ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is 1:1.

6. The pharmaceutical composition of any one of claims 1-4, wherein ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is more than 1:1 (e.g., 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11 :1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21: 1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37: 1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45: 1, 46: 1, 47: 1, 48: 1, 49:1, or 50:1) or less than 1:1 (e.g., 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25,1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50).

7. The pharmaceutical composition of any one of claims 1-4, wherein ratio of the bark resin extract from the plant of genus Calycophyllum to the oleoresin extract from the plant of genus Copaifera is 5:1, 10:1, 1:5, or 1:10.

8. The pharmaceutical composition of any one of claims 1-7, further comprising colloidal oatmeal, arrow root powder, amiticide coconut, aspen bark, or lemon ferment.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) colloidal oatmeal.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) arrow root powder.

11. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) amiticide coconut.

12. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) aspen bark.

13. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, or 9%-10% (w / v) lemon ferment.

14. The pharmaceutical composition of any one of claims 1-13, further comprising colloidal shea butter or emulsification wax.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%-14%, or 14%-15% (w / v) shea butter.

16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises about 0.1%-l%, l%-2%, 2%-3%, 3%-4%, 4%-5%, 5%-6%, 6%-7%, 7%-8%, 8%-9%, 9%-10%, 10%-l 1%, 11%-12%, 12%-13%, 13%-14%, or 14%-15% (w / v) emulsification wax.

17. The pharmaceutical composition of any one of claims 1-16, wherein the bark resin extract from the plant of genus Calycophyllum and the bark oleoresin extract from the plant of genus Copaifera are aqueous extracts.

18. The pharmaceutical composition of any one of claims 1-17, wherein the pharmaceutical composition comprises at least 50% (v / v) water.

19. The pharmaceutical composition of any one of claims 1-18, wherein the plant of genus Calycophyllum is Calycophyllum spruceanum.

20. The pharmaceutical composition of any one of claims 1-19, wherein the plant of genus Copaifera is Copaifera officinalis.

21. The pharmaceutical composition of any one of claims 1-20, further comprising a pharmaceutically acceptable carrier, excipient, or vehicle.

22. The pharmaceutical composition of any one of claims 1-21, further comprising one or more antibiotic agents.

23. The pharmaceutical composition of any one of claims 1-22, further comprising one or more antiseptic agents.

24. The pharmaceutical composition of any one of claims 1-23, further comprising one or more antifungal agents.

25. The pharmaceutical composition of any one of claims 1-24, further comprising one or more antiviral agents.

26. The pharmaceutical composition of any one of claims 1-25, further comprising one or more analgesic agents.

27. The pharmaceutical composition of any one of claims 1-26, further comprising an emulsifier, a moisturizing agent, an essential oil, a sunscreen, a pharmaceutically activeagent, a cosmetic ingredient, a triglyceride, a structuring agent, an antioxidant, a preservative, a gum, a polysaccharide, a polymer, a thickening agent, a gelling agent, or a vitamin.

28. The pharmaceutical composition of claim 27, wherein the emulsifier is cetearyl olivate or sorbitan olivate.

29. The pharmaceutical composition of claim 27, wherein the moisturizing agent is allantoin.

30. The pharmaceutical composition of any one of claims 1-29, further comprising an adjuvant.

31. The pharmaceutical composition of claim 30, wherein the adjuvant is shea butter, meadowfoam seed, tea tree oil, lemon grass oil, eucalyptus oil, lemon eucalyptus oil, sweet almond, arnica, argan, avocado, borage, calendula, calophyllum, carrot, wheat germ, jojoba, macadamia, St. John's wort, apricot, hazel, olive, rosehip, sunflower, cocoa butter, cottonseed oil, evening primrose, grapeseed oil, wheatgerm, hemp, tamanu, macadamia, olive or sesame.

32. The pharmaceutical composition of any one of claims 1-31, wherein the pharmaceutical composition is formulated as a topical formulation.

33. The pharmaceutical composition of any one of claims 1-32, further comprising one or more UV-absorbing agents.

34. The pharmaceutical composition of any one of claims 1-33, further comprising one or more moisturizing agents.

35. The pharmaceutical composition of any one of claims 1-34, wherein the pharmaceutical composition is formulated as an emulsion, a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, lip balm, a serum, or a solution.

36. A method of treating a skin condition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1-35.

37. The method of claim 36, wherein the skin condition is skin wound, dry skin, itchy skin, inflamed skin, erythema, sensitive skin, pruritus, blotches, fine lines or wrinkles, sundamaged skin, dermatitis, psoriasis, folliculitis, blemish, rosacea, acne, eczema, sunburns, burned skin, or skin inflammation.

38. The method of claim 37, wherein the skin wound is a chronic wound.

39. The method of claim 38, wherein the chronic wound is a venous ulcer, a diabetic ulcer, a pressure ulcer, or rash associated with shingles, psoriasis, allergy, or dermatitis.

40. The method of claim 37, wherein the wound is an acute wound.

41. The method of claim 40, wherein the acute wound is a trauma wound, a burn wound, or a surgical wound.

42. A method of treating pain or inflammation in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1-35.

43. A method of inhibiting scar formation in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1-35.

44. A method of improving wound healing in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1-35.

45. A method of treating cancer in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1-35.

46. The method of claim 45, wherein the cancer is skin cancer or premalignant skin lesions.

47. The method of any one of claims 36-46, wherein the pharmaceutical composition is administered to the subject topically.

48. The method of any one of claims 36-47, wherein the pharmaceutical composition is administered to the subject as a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, or lip balm.

49. The method of any one of claims 36-48, wherein the pharmaceutical composition is administered to the subject for 15 days or less.

50. The method of claim 49, wherein the pharmaceutical composition is administered to the subject for 10 days or less.

51. The method of claim 50, wherein the pharmaceutical composition is administered to the subject for 7 days or less.

52. The method of any one of claims 36-48, wherein the pharmaceutical composition is administered to the subject for 15 days or more.

53. The method of any one of claims 36-48, wherein the pharmaceutical composition is administered to the subject for the lifetime of the subject.

54. The method of any one of claims 36-53, wherein the pharmaceutical composition reduces inflammation.

55. The method of any one of claims 36-54, wherein the pharmaceutical composition induces wound contraction.

56. The method of any one of claims 36-55, wherein the pharmaceutical composition induces wound closure.

57. The method of any one of claims 36-56, wherein the pharmaceutical composition reduces release of TNF-a from peripheral blood mononuclear cells.

58. The method of any one of claims 36-57, wherein the pharmaceutical composition increases release of TNF-a from keratinocytes.

59. The method of any one of claims 36-58, wherein the pharmaceutical composition stimulates release of TGF-P from keratinocytes.

60. The method of any one of claims 36-59, wherein the pharmaceutical composition induces cytostasis in keratinocytes.

61. The method of any one of claims 36-60, wherein the pharmaceutical composition induces migration of epidermal keratinocytes.

62. The method of any one of claims 58-61, wherein the keratinocytes are adult human keratinocytes.

63. The method of any one of claims 58-62, wherein the keratinocytes are LPS- distressed keratinocytes.

64. The method of any one of claims 36-63, wherein the pharmaceutical composition is administered after skin cancer removal.

65. The method of any one of claims 36-60, wherein the subject is a human.

66. The method of any one of claims 36-60, wherein the subject is a non-human mammal.

67. The method of claim 66, wherein the non-human mammal is a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

68. A method of treating a skin condition in a subject in need thereof, comprising administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition of any one of claims 1-35.

69. The method of claim 68, wherein the skin condition is skin wound, dry skin, itchy skin, inflamed skin, erythema, sensitive skin, pruritus, blotches, fine lines or wrinkles, sun damaged skin, dermatitis, psoriasis, folliculitis, blemish, rosacea, acne, eczema, sunburns, burned skin, or skin inflammation.

70. The method of claim 69, wherein the skin wound is a chronic wound.

71. The method of claim 70, wherein the chronic wound is a venous ulcer, a diabetic ulcer, a pressure ulcer, or rash associated with shingles, psoriasis, allergy, or dermatitis.

72. The method of claim 69, wherein the wound is an acute wound.

73. The method of claim 72, wherein the acute wound is a trauma wound, a burn wound, or a surgical wound.

74. A method of treating pain or inflammation in a subject in need thereof, comprising administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition of any one of claims 1-35.

75. A method of inhibiting scar formation in a subject in need thereof, comprising administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition of any one of claims 1-35.

76. A method of improving wound healing in a subject in need thereof, comprising administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition of any one of claims 1-35.

77. A method of treating cancer in a subject in need thereof, comprising administering to the subject a bark resin extract from a plant of genus Calycophyllum then administering to the subject the pharmaceutical composition of any one of claims 1-35.

78. The method of claim 77, wherein the cancer is skin cancer or premalignant skin lesions.

79. The method of any one of claims 68-78, wherein the pharmaceutical composition is administered to the subject topically.

80. The method of any one of claims 68-78, wherein the pharmaceutical composition is administered to the subject as a lotion, cream, salve, liniment, ointment, gel, paste, tonic, unguent, spray, soap, shampoo, or lip balm.

81. The method of any one of claims 68-80, wherein the pharmaceutical composition is administered 1 to 7 days after the bark resin extract from a plant of genus Calycophyllum is administered.

82. The method of any one of claims 68-80, wherein the pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, or 7 days after the bark resin extract from a plant of genus Calycophyllum is administered.

83. The method of any one of claims 68-80, wherein the pharmaceutical composition is administered 1 to 24 hours after the bark resin extract from a plant of genus Calycophyllum is administered.

84. The method of any one of claims 68-80, wherein the pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after the bark resin extract from a plant of genus Calycophyllum is administered.

85. The method of any one of claims 68-84, wherein the pharmaceutical composition is administered to the subject for 15 days or less.

86. The method of claim 85, wherein the pharmaceutical composition is administered to the subject for 10 days or less.

87. The method of claim 86, wherein the pharmaceutical composition is administered to the subject for 7 days or less.

88. The method of any one of claims 68-84, wherein the pharmaceutical composition is administered to the subject for 15 days or more.

89. The method of any one of claims 68-84, wherein the pharmaceutical composition is administered to the subject for the lifetime of the subject.

90. The method of any one of claims 68-89, wherein the pharmaceutical composition reduces inflammation.

91. The method of any one of claims 68-90, wherein the pharmaceutical composition induces wound contraction.

92. The method of any one of claims 68-91, wherein the pharmaceutical composition induces wound closure.

93. The method of any one of claims 68-92, wherein the pharmaceutical composition reduces release of TNF-a from peripheral blood mononuclear cells.

94. The method of any one of claims 68-93, wherein the pharmaceutical composition increases release of TNF-a from keratinocytes.

95. The method of any one of claims 68-94, wherein the pharmaceutical composition stimulates release of TGF-P from keratinocytes.

96. The method of any one of claims 68-95, wherein the pharmaceutical composition induces cytostasis in keratinocytes.

97. The method of any one of claims 68-96, wherein the pharmaceutical composition induces migration of epidermal keratinocytes.

98. The method of any one of claims 94-97, wherein the keratinocytes are adult human keratinocytes.

99. The method of any one of claims 94-98, wherein the keratinocytes are LPS- distressed keratinocytes.

100. The method of any one of claims 68-99, wherein the pharmaceutical composition is administered after skin cancer removal.

101. The method of any one of claims 68-96, wherein the subject is a human.

102. The method of any one of claims 68-96, wherein the subject is a non-human mammal.

103. The method of claim 102, wherein the non-human mammal is a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

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