Topical preparations and drops, kits, methods, and uses thereof for the treatment of external wounds

Abstract

A topical formulation comprising one or more cannabinoids, one or more terpenes, and one or more flavonoids; and methods and uses thereof for treating external skin wounds, wherein the one or more cannabinoids comprise tetrahydrocannabinolic acid.

Description

[Technical Field]

[0001] This application relates, in general, to the treatment of external wounds (including chronic and acute wounds, both of which involve the skin membrane and mucous membranes), and more particularly to topical formulations and instillates, kits, and methods for treating external wounds, as well as to the use thereof. [Background technology]

[0002] Wound healing typically proceeds through a highly organized and controlled series of events mediated by multiple cell lines and associated growth factors. Hemostasis occurs after tissue damage caused by either a disease process or trauma. Subsequently, wound healing can generally be described as occurring in three overlapping stages: an inflammatory phase, a proliferation phase, and a reconstruction phase (Bielefeld et al. Cell. Mol. Life Sci. (2013) 70:2059~2081; and de Oliveira Gonzalez et al. An Bras Dermatol. 2016;91(5):614~20).

[0003] During the inflammatory phase, the wound is immobilized, swollen, and painful, preparing the wound site for healing. Vasodilation and phagocytosis also occur during the inflammatory phase, and histamine and serotonin are released.

[0004] The proliferative phase is characterized by the proliferation of epithelial cells at the wound edge and the repair of the underlying dermis or mesenchymal layer. This is accompanied by angiogenesis. This process usually occurs 2 days to 3 weeks after injury, and granulation tissue forms at the wound site.

[0005] Granulation tissue formation occurs during the proliferative phase and involves the following mechanisms: increased fibroblast proliferation; collagen and elastic biosynthesis forming a three-dimensional extracellular network of connective tissue; and production of chemotactic factors and IFN-beta by fibroblasts (de Oliveira Gonzalez et al.). Healthy granulation tissue is granular, has an uneven texture, is not prone to bleeding, and is pink / red in color.

[0006] In the final reconstruction stage, the main objective is the reconstruction of the dermal tissue to generate greater tensile strength, and the resulting formation of new collagen. The main cell type involved is fibroblasts. Collagen molecules begin to form and undergo further modification, and the molecules begin to form a characteristic triple helix structure. Overall, these changes lead to wound contraction and the formation of acellular scar tissue.

[0007] Figure 1 shows an exemplary sequence of typical wound healing: Upon tissue injury, hemostasis 101 occurs, possibly involving epinephrine, platelets, and transforming growth factor beta (TGF-β); inflammation 102 may follow hemostasis 101, potentially involving neutrophils, macrophages, reactive oxygen species, matrix metalloproteinases (MMPs), interleukins (ILs), tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), TGF-β, and platelet-derived growth factor (PDGF); inflammation 102 may develop into prolonged inflammation 103 that can lead to a chronic wound. Yes; Granulation tissue formation and angiogenesis 104 may follow inflammation 102, and fibroblasts, macrophages, endothelial cells, MMPs, IL, TNF, VEGF, TGF-β, PDGF, and keratinocyte growth factor (KGF) may be involved; re-epithelialization 105 may follow granulation tissue formation and angiogenesis 104, and keratinocytes, endothelial cells, epidermal growth factor, KGF, and MMPs may be involved; and tissue reconstruction 106 may follow re-epithelialization 105, and fibroblasts, collagen fiber crosslinking, TGF-β, and MMPs may be involved, and the wound may heal through these processes.

[0008] Numerous disease processes can affect a range of events involved in wound healing, potentially leading to chronically non-healed wounds. This may be due to a complex combination of local and systemic factors. The pathophysiology of a “stagnant” or “stopped” healing process may be characterized by a state of increased and prolonged inflammation.

[0009] In an exemplary chronic wound cycle, prolonged inflammation stimulates macrophages and neutrophils to the wound, leading to the release of pro-inflammatory cytokines such as TNFα and IL-1β; the release of these cytokines increases the expression of MMPs and decreases the expression of metalloproteinase tissue inhibitors, which contribute to the degradation of the extracellular matrix (leading to impaired cell migration and connective tissue deposition) and growth factors, thereby intensifying the prolonged inflammation. The effects of this exemplary chronic wound cycle may include delayed healing, repeated trauma, localized tissue ischemia, necrotic tissue, high bacterial load, and tissue destruction.

[0010] Chronic wounds, which are wounds that cannot heal regularly and in a timely manner, can cause significant pain, reduced quality of life, decreased productivity, limb loss, and a shorter lifespan, while consuming an increasing proportion of the world's healthcare budget. In the United States, more than $90 billion is spent annually on wound care as a whole, and this is growing faster than any other area of ​​healthcare, approaching 8% per year.

[0011] While there are local wound treatments and dressings available based on case experience, little or no data supporting their effectiveness in promoting wound healing has been published. Many advanced treatments exist, such as negative pressure occlusion and hyperbaric oxygen therapy, but these often require specialized equipment / devices or surgical procedures. For example, negative pressure occlusion requires controlled vacuum dressings, and hyperbaric oxygen therapy requires a hyperbaric oxygen chamber.

[0012] Overall wound care is recognized as one of the least managed areas in global healthcare. Therefore, there is a need for the development of wound treatments, dressings, and protocols that are effective in promoting wound healing and are easy for patients to administer. [Prior art documents] [Patent Documents]

[0013]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Document

[0014]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0015] In one aspect, (a) one or more cannabinoids at 0.1 mg / ml to 40 mg / ml; (b) one or more terpenes at 25 mg / ml to 1000 mg / ml; (c) one or more flavonoids at 10 mg / ml to 500 mg / ml; and (d) a liquid carrier A topical preparation containing, A topical formulation is provided which contains one or more cannabinoids, at least 0.1 mg / ml of tetrahydrocannabinolic acid.

[0016] In some embodiments of the topical formulations described herein, one or more cannabinoids further comprise cannabidiol or cannabidiolic acid.

[0017] In some embodiments of the topical formulations described herein, one or more terpenes include beta-caryophyllene, and the concentration of beta-caryophyllene is 50 mg / ml to 500 mg / ml.

[0018] In some embodiments of the topical formulations described herein, one or more terpenes further comprise linalool, with a concentration of linalool ranging from 25 mg / ml to 500 mg / ml.

[0019] In some embodiments of the topical formulations described herein, one or more flavonoids include at least one of diosmin, quercetin, and hesperidin.

[0020] In some embodiments of the topical formulations described herein, one or more flavonoids include diosmin, quercetin, and hesperidin.

[0021] In another embodiment, (a) One or more cannabinoids in a concentration of 0.1 mg / ml to 40 mg / ml; (b) One or more terpenes in a concentration of 25 mg / ml to 1000 mg / ml; and (c) One or more flavonoids in a concentration of 10 mg / ml to 500 mg / ml; A topical formulation for direct application to external wounds, including, A topical formulation is provided which contains one or more cannabinoids, at least 0.1 mg / ml of tetrahydrocannabinolic acid.

[0022] In some embodiments of the topical formulations described herein, one or more cannabinoids further comprise cannabidiol or cannabidiolic acid.

[0023] In some embodiments of the topical formulations described herein, one or more terpenes include beta-caryophyllene, and the concentration of beta-caryophyllene is 50 mg / ml to 500 mg / ml.

[0024] In some embodiments of the topical formulations described herein, one or more terpenes further comprise linalool, with a concentration of linalool ranging from 25 mg / ml to 500 mg / ml.

[0025] In some embodiments of the topical formulations described herein, one or more flavonoids include at least one of diosmin, quercetin, and hesperidin.

[0026] In some embodiments of the topical formulations described herein, one or more flavonoids include diosmin, quercetin, and hesperidin.

[0027] In some embodiments of the topical formulations described herein, the topical formulation further comprises a liquid carrier selected for the application of the topical formulation onto a cutaneous wound.

[0028] In another embodiment, a use is provided of a first topical formulation for the treatment of a target cutaneous wound, wherein the first topical formulation comprises one or more cannabinoids; one or more terpenes; and one or more flavonoids, and is for application to a cutaneous wound, wherein the one or more cannabinoids comprises at least 0.1 mg / ml of tetrahydrocannabinolic acid.

[0029] In some embodiments of the use described herein, the use further comprises the use of a second topical formulation comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids, the second topical formulation being for application on the peri-wound area surrounding the cutaneous wound.

[0030] In some embodiments of use described herein, the first topical formulation comprises aloe vera gel and hyaluronic acid gel, and the second topical formulation comprises Pluronic® lecithin organogel or a transdermal base containing a liposome component.

[0031] In some embodiments of use described herein, the first topical formulation and / or the second topical formulation are the topical formulations described herein.

[0032] In some embodiments of the use described herein, the use further includes the use of an oral formulation comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids.

[0033] In some embodiments of use described herein, the cutaneous wound is caused by a skin disease or condition, which is skin cancer (e.g., primary tumor, metastatic tumor, or Bowen's disease), vascular ulcers and erosions (e.g., sickle cell disease, Maltrell's ulcer, uremic calciphylaxis, nonuremic calciphylaxis, venous lower extremity ulcer, or arterial ulcer), cutaneous ulcers and erosions caused by microorganisms (e.g., bacteria, fungi, viruses, or mycobacterium), diabetes-related ulcers and erosions (e.g., diabetic foot ulcer, diabetic lipoid necrosis, or diabetic skin disorder), vesicular skin Ulcers and erosions caused by skin conditions (e.g., epidermolysis bullosa, pemphigus, or bullous pemphigoid), autoimmune diseases (e.g., pyoderma gangrenosum, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or Morphea), vasculitic ulcers and erosions (e.g., cutaneous vasculitis, leukocytosis-destroying vasculitis, cutaneous polyarteritis nodosa, or microscopic polyangiitis), or other combined diseases (e.g., hidradenitis suppurativa, chronic lichen simplex, lichen sclerosing, lichen planus, Wegener's granulomatosis, cryoglobulinemia, Behçet's disease, cryofibrinogenemia, antiphospholipid syndrome, allergic dermatitis, psoriasis, or porokeratosis).

[0034] Other aspects, features, and embodiments of this disclosure will become apparent to those skilled in the art by examining the following descriptions of specific embodiments in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0035] [Figure 1] This diagram shows an exemplary normal wound healing sequence. [Figure 2](a) A schematic cross-sectional view of a portion of normal tissue with intact skin. (b) A schematic fragment of wound tissue with the wound bed exposed. (c) A schematic cross-sectional view of the wound in Figure 2b during treatment, showing a treatment process according to an embodiment disclosed herein. (d) A schematic cross-sectional view of the wound in Figure 2b during treatment, showing a treatment process according to an embodiment disclosed herein. (e) A schematic cross-sectional view of the wound in Figure 2b during treatment, showing a treatment process according to an embodiment disclosed herein. (f) A schematic cross-sectional view of the wound in Figure 2b during treatment, showing a treatment process according to an embodiment disclosed herein. (g) A schematic cross-sectional view of the wound in Figure 2b during treatment, showing a treatment process according to an embodiment disclosed herein. [Figure 3a] A representative analysis performed on day 15 in Example 2 is shown. [Figure 3b] A representative analysis performed on day 41 in Example 2 is shown. [Figure 3c] A representative analysis performed on day 87 in Example 2 is shown. [Figure 4] This shows the trend of wound healing, expressed as granulation tissue formation and epithelial tissue density within the wound area. Evaluation of epithelial tissue began around day 30, when significant epithelial proliferation started. [Figure 5-1] (A) Shows the wound size measured at the longest length. [Figure 5-2] (B) Shows the wound size measured at the widest width. (C) Shows the wound size as the upper limit estimate of the total wound area, measured as the product of the longest length and widest width. [Figure 6] This is a schematic block diagram showing an exemplary kit according to one embodiment of the present disclosure. [Figure 7] The images show wounds on the right (column A) and left (column B) lateral ankles of a sickle cell disease patient described in the case report of Example 4, on day 97 (i.e., day 0 of the second treatment; top image) and day 150 (i.e., day 53 of the second treatment; bottom image). [Figure 8-1](A) Regarding the treatment of NUC patient A as described in the case report of Example 4. Figure 8A shows representative images of the wound area of ​​patient A on days 0, 27, 54, and 74. [Figure 8-2] (B) Regarding the treatment of NUC patient A as described in the case report of Example 4. Figure 8B shows the results of wound area tracking over the duration of treatment. The wound closed completely on day 74. When fitted to a linear regression model, the predicted wound closure day is 77.0 days. (C) Regarding the treatment of NUC patient A as described in the case report of Example 4. Figure 8C shows the results of wound composition analysis showing the relative wound area of ​​granulation tissue versus reepithelialization tissue. [Figure 9-1] (A) Regarding the treatment of NUC patient B as described in the case report of Example 4. Representative images of the wound area of ​​patient A's left leg (Figure 9A) on days 0, 27, 55, and 81 (2 days after closure) are shown. [Figure 9-2] (B) Regarding the treatment of NUC patient B as described in the case report of Example 4. Representative images of the wound area of ​​patient A's right leg (Figure 9B) on days 0, 27, 55, and 76 are shown. [Figure 9-3] (C) Regarding the treatment of NUC patient B as described in the case report of Example 4. Figure 9C shows the results of tracking wound healing over the duration of treatment on both legs. Complete wound closure was confirmed on day 79 and day 76, respectively. When fitted to a linear regression model, the predicted closure dates are 100 days and 77 days, respectively. (D) Regarding the treatment of NUC patient B as described in the case report of Example 4. Figure 9D shows the results of wound composition analysis showing the relative area of ​​granulation tissue versus re-epithelialized tissue for the left and right legs. [Figure 9-4] (E) Regarding the treatment of NUC patient B as described in the case report of Example 4. Figure 9E shows the results of wound composition analysis showing the relative area of ​​granulation tissue versus re-epithelialized tissue for the left and right legs. [Figure 10]This concerns the treatment of arterial-venous ulcers complicated with porokeratosis, as described in the case report of Example 4. A reduction in wound size (cm2) during the treatment period is shown, and the best-fit line (dotted line) is plotted. [Modes for carrying out the invention]

[0036] Selected combinations of cannabinoids, terpenes, and flavonoids have been found to produce healing effects when applied directly to the wound bed of cutaneous wounds. Surprisingly, the inventors discovered that the non-psychotoxic tetrahydrocannabinol (THCa) produced better wound healing effects than the psychotoxic decarboxylated tetrahydrocannabinol (TCC). Therefore, the topical formulations disclosed herein are substantially free from any psychotoxic effects. Without being limited by any particular theory, THCa is expected to contribute to the downregulation of inflammation, as well as to the improvement of angiogenesis, granulation tissue formation, and epithelial differentiation, by activating the PPAR family, NF-κB, and other nuclear receptors.

[0037] As used herein, “skin” refers to the outer protective layer (both the skin membrane and mucous membrane of an organism), and the term “skin wound” refers to the destruction and loss of at least a portion of the skin, such as the outermost sublayer (i.e., epithelium), and optionally, the destruction of deeper tissues (e.g., dermis, fat, fascia, connective tissue, and often muscle and bone). Skin wounds may include wounds commonly referred to as open wounds (also known as wound beds), in which the damaged area of ​​body exposes the dermis of the skin or tissue, and the structures beneath the dermis of the skin (e.g., fat, muscle, fascia, and bone), to the air. As can be understood by those skilled in the art, the skin has two main layers: (i) an outer layer (referred to as the epithelium) that functions as a barrier to the external environment, and (ii) an inner layer (referred to as the dermis) composed of connective tissue that gives the skin some of its mechanical properties.

[0038] In one embodiment, treatment of an external wound includes topically delivering selected cannabinoids, terpenes, and flavonoids as a dropper solution to the external wound and optionally to the surrounding peri-wound area.

[0039] Therefore, certain embodiments of the present disclosure provide topical formulations comprising selected compositions of cannabinoids, terpenes, and flavonoids at concentrations within specific ranges, formulated for direct application to an external wound and, optionally, to the peri-wound area surrounding such external wound.

[0040] For example, in certain embodiments, the formulation may be a topical drop solution, which comprises: (a) 5 mg / ml to 30 mg / ml of cannabidiol or cannabidiolic acid, and 2 mg / ml to 10 mg / ml of tetrahydrocannabinol or tetrahydrocannabiolic acid; (b) 30 mg / ml to 60 mg / ml of beta-caryophyllene, and 10 mg / ml to 30 mg / ml of linalool; (c) 10 mg / ml to 30 mg / ml of diosmin, and 10 mg / ml to 30 mg / ml of quercetin; and (d) aloe vera gel and optionally hyaluronic acid gel.

[0041] Another specific embodiment of this formulation may be a topical drop solution comprising: (a) 0.1 mg / ml to 20 mg / ml of cannabidiol or cannabidiolic acid, and 0 mg / ml to 5 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid; (b) 50 mg / ml to 500 mg / ml of beta-caryophyllene, and 10 mg / ml to 150 mg / ml of linalool; (c) 0 mg / ml to 50 mg / ml of diosmin, and 10 mg / ml to 50 mg / ml of quercetin; and (d) aloe vera gel and optionally hyaluronic acid gel.

[0042] In another specific embodiment, the formulation may be a topical drop solution comprising: (a) 2.3 mg / ml of cannabidiol or cannabidiolic acid and 1.0 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid; (b) 81.5 mg / ml of beta-caryophyllene and 28.4 mg / ml of linalool; (c) 16.7 mg / ml of microparticle diosmin and 16.7 mg / ml of microparticle quercetin; and (d) aloe vera gel and hyaluronic acid gel.

[0043] In another specific embodiment, the formulation may be a topical drop solution comprising: (a) 2.6 mg / ml of cannabidiol or cannabidiolic acid; (b) 118 mg / ml of beta-caryophyllene; (c) 19.6 mg / ml of microparticle diosmin, 21.7 mg / ml of microparticle quercetin, and 2.2 mg / ml of hesperidin; and (d) aloe vera gel and hyaluronic acid gel.

[0044] Unless otherwise indicated, the concentrations described herein are based on the total volume of the formulation and the dry mass of each activator.

[0045] Examples of this formulation include solutions or colloids, and this formulation is formulated for direct application to the wound bed of an external wound by drop, for example, by dropping, spraying, diffusing, dispersing, spraying, or spreading it on the external wound bed to promote wound healing.

[0046] Further embodiments of the present disclosure relate to methods for treating external wounds. In a particular method, the method includes directly applying a topical formulation containing cannabinoids, terpenes, and flavonoids to an external wound and optionally to the peri-wound area surrounding the external wound.

[0047] Further embodiments of this disclosure relate to the use of selected topical formulations disclosed herein for the treatment of cutaneous wounds.

[0048] The selected topical formulations disclosed herein may also have one or more other beneficial effects, such as pain management (e.g., baseline pain and breakdown pain), analgesic effect, anti-inflammatory effect, antipruritic effect, opioid-saving effect, antimicrobial activity, or similar effects.

[0049] Topical preparations The term “topical formulation” is generally understood to mean a mixture of substances suitable for application to a specific site on or within the body. A topical formulation may be a solution in which one or more solutes are uniformly dispersed in a solvent, or a colloid in which some substances are not dissolved in another substance but are suspended throughout the other substance. A topical formulation may exist in any phase or in a combination of phases. In connection with this disclosure, preferred forms of topical formulations for application to skin wounds may include solutions, lotions, creams, ointments, gels, emulsions, liposomes, foams, powders, impregnated gauze sheets, tulles, vapors, and pastes, and preferred forms of topical formulations for application to mucosal wounds may include aerosolized sprays for nasal and oral application, and suppositories for rectal and vaginal application.

[0050] In one embodiment, the topical formulation may comprise one or more cannabinoids, one or more terpenes, one or more flavonoids, and a liquid carrier selected for application of the topical formulation onto a cutaneous wound.

[0051] The term "cannabinoid" is generally understood to include any compound that acts on cannabinoid receptors. Examples of cannabinoids include: cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabichromanone (CBCN), cannabiersoin (CBE), canbifuran (CBF), tetrahydrocannabinol (THC), cannabicyclol (CBL), cannabitriol (CBT), cannabivarin (CBV), cannabidivarin (CBDV), cannabiclomevalin (CBCV), cannabigerovalin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerol acid, cannabidiolic acid (CBDa), cannabinodiol (CBND), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCa), tetrahydrocannabivaric acid (THCVa), and their derivatives. Further examples of cannabinoids are discussed in International Publication No. 2017 / 190249 and U.S. Patent Application Publication No. 2014 / 0271940.

[0052] Cannabinoids can exist in acidic or non-acidic forms, and the non-acidic form is also referred to as the decarboxylated form, as it can be produced by decarboxylation of the acidic form. Where a particular cannabinoid is referred to in this disclosure, that cannabinoid may exist in its acidic or non-acidic form, or as a mixture of both acidic and non-acidic forms.

[0053] In some embodiments, the topical formulations provided herein may contain cannabidiol (CBD). CBD is expected to relieve convulsions, inflammation, anxiety, and nausea, rather than being psychoactive. In some embodiments, CBD may be completely replaced by CBDa.

[0054] The term "cannabidiol", "CBD", or "cannabidiols" is generally understood to refer to one or more of the following compounds, and includes the compound "Δ 2 -cannabidiol" unless a specific other stereoisomer is designated. These compounds are as follows: (1) Δ 5 -cannabidiol (2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (2) Δ 4 -cannabidiol (2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (3) Δ 3 -cannabidiol (2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (4) Δ 3,7 -cannabidiol (2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol); (5) Δ 2 -cannabidiol (2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (6) Δ 1 -cannabidiol (2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); and (7) Δ 6 -cannabidiol (2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol).

[0055] These compounds have one or more chiral centers and two or more stereoisomers, as described below: (1) Δ 5 -cannabidiol has two chiral centers and four stereoisomers; (2) Δ 4 -cannabidiol has three chiral centers and eight stereoisomers; (3) Δ 3 -cannabidiol has two chiral centers and four stereoisomers; (4) Δ 3,7-Cannabidiol has two chiral centers and four stereoisomers; (5)Δ 2 -Cannabidiol has two chiral centers and four stereoisomers; (6)Δ 1 -Cannabidiol has two chiral centers and four stereoisomers; (7)Δ 6 -Cannabidiol has one chiral center and two stereoisomers.

[0056] In some embodiments, the topical formulations provided herein are Δ 2 - May contain cannabidiol

[0057] Unless otherwise specified, any reference to "cannabidiol," "CBD," or "cannabidiols," or to any of the specific cannabidiol compounds (1) to (7) mentioned above, includes all possible stereoisomers of all compounds included by that reference. For example, "Δ 2 -Cannabidiol is a compound found in plants or their extracts (e.g., cannabis (Cannabis sativa), Indian cannabis (Cannabis indica), or other plants of the genus Cannabis). 2 -It may be a mixture of cannabidiol stereoisomers; "Δ 2 -Cannabidiol is a compound found in plants or their extracts (e.g., cannabis (Cannabis sativa), Indian cannabis (Cannabis indica), or other plants of the genus Cannabis). 2 -It may be a mixture of cannabidiol stereoisomers, where the mixture of stereoisomers is in a ratio of naturally occurring isomers or approximately such a ratio; 2 "-Cannabidiol" can have a single stereoisomer.

[0058] In some embodiments, the topical formulations provided herein may contain, in addition to CBD, one or more cannabinoids (e.g., cannabinol, cannabigerol, cannabichromene, and tetrahydrocannabivarin). The combination of CBD and CBN may be particularly useful for managing burn pain.

[0059] In some embodiments, the topical formulations provided herein may also contain THC. In other embodiments, the topical formulations provided herein may not contain THC. THC is psychoactive only in its decarboxylated form. Delta-9-tetrahydrocannabinol (Δ9-THC) and delta-8-tetrahydrocannabinol (Δ8-THC) produce cannabis-related effects by binding to CB1 cannabinoid receptors in the brain. THC is expected to relieve moderate pain (analgesic), be neuroprotective, reduce neuroinflammation, and potentially stimulate neurogenesis. In some embodiments, THC may be completely replaced by THCV. The carboxylic acid form (THCa) is non-psychoactive.

[0060] In some embodiments, the topical formulations provided herein may contain both THC and THCa. In some embodiments, the topical formulations provided herein may contain THCa but not THC.

[0061] In some embodiments, the topical formulations provided herein may contain cannabinoids in concentrations of 0.1 mg / ml to 40 mg / ml. For example, the topical formulations provided herein may contain concentrations of 0.1 mg / ml to 30 mg / ml, 0.5 mg / ml to 30 mg / ml, 1 mg / ml to 30 mg / ml, 0.1 mg / ml to 25 mg / ml, 0.5 mg / ml to 25 mg / ml, 1 mg / ml to 25 mg / ml, 0.1 mg / ml to 20 mg / ml, 0.5 mg / ml to 20 mg / ml, 1 mg / ml to 20 mg / ml, and 0.1 mg / ml to 40 mg / ml. 15mg / ml, 0.5mg / ml~15mg / ml, 1mg / ml~15mg / ml, 0.1mg / ml~10mg / ml, 0.5mg / ml~10mg / ml, 1mg / ml~10mg / ml , 0.1mg / ml~5mg / ml, 0.5mg / ml~5mg / ml, 1mg / ml~5mg / ml, 0.1mg / ml~2mg / ml, 0.5mg / ml~2mg / ml, 1mg / ml~2m g / ml, 2mg / ml~40mg / ml, 2mg / ml~30mg / ml, 2mg / ml~25mg / ml, 2mg / ml~20mg / ml, 2mg / ml~15mg / ml, 2mg / ml~1 0mg / ml, 2mg / ml~5mg / ml, 5mg / ml~40mg / ml, 5mg / ml~30mg / ml, 5mg / ml~25mg / ml, 5mg / ml~20mg / ml, 5mg / ml~ 15mg / ml, 5mg / ml~10mg / ml, 10mg / ml~40mg / ml, 10mg / ml~30mg / ml, 10mg / ml~25mg / ml, 10mg / ml~20mg / ml, 1 0mg / ml~15mg / ml, 15mg / ml~40mg / ml, 15mg / ml~30mg / ml, 15mg / ml~25mg / ml, 15mg / ml~20mg / ml, 20mg / ml~40 mg / ml, 20mg / ml to 30mg / ml, 20mg / ml to 25mg / ml, 25mg / ml to 40mg / ml, 25mg / ml to 30mg / ml, or 30mg / ml to 40mg / ml of cannabinoids.

[0062] In some embodiments, the topical formulations provided herein may contain 0.1 mg / ml to 10 mg / ml of THCa. For example, the topical formulations provided herein may contain 0.1 mg / ml to 5 mg / ml, 0.5 mg / ml to 5 mg / ml, 1 mg / ml to 5 mg / ml, 2 mg / ml to 5 mg / ml, 0.1 mg / ml to 4 mg / ml, 0.5 mg / ml to 4 mg / ml, 1 mg / ml to 4 mg / ml, 2 mg / ml to 4 mg / ml, 0.1 mg / ml to 3 mg / ml, 0.5 mg / ml to 3 mg / ml, 1 mg / ml to 3 mg / ml, 2 mg / ml to 3 mg / ml, 0.1 mg / ml to 2 mg / ml, 0.5 mg / ml to 2 mg / ml, 1 mg / ml to 2 mg / ml, 0.1 mg / ml to 1 mg / ml, or 0.5 mg / ml to 1 mg / ml of THCa.

[0063] In some embodiments, the topical formulations provided herein contain at least 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, and 18 mg / ml. It may contain cannabinoids in amounts of 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, or 39 mg / ml.

[0064] In some embodiments, the topical formulations provided herein are 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / It may contain cannabinoids in amounts of ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, or 40 mg / ml.

[0065] In some embodiments, the concentration of cannabinoids in the topical formulations provided herein may be adjusted according to the stage of wound healing. For example, during the inflammatory stage, higher levels of the THC and CBD mixture (e.g., 5 mg / ml to 20 mg / ml of cannabidiol and 2 mg / ml to 10 mg / ml of tetrahydrocannabinol) may be advantageous because wound pain is most severe at this stage, and higher levels of THC and CBD may help manage this pain. In contrast, during the re-epithelialization and reconstruction stages, lower concentrations of THC (e.g., 0 mg / ml to 5 mg / ml) may be desirable because preclinical studies suggest that THC may inhibit keratinocyte differentiation, allowing CBD concentrations to remain relatively high (e.g., 0.1 mg / ml to 20 mg / ml).

[0066] The term "terpene" is generally understood to include any organic compound biosynthetically derived from isoprene units, while the term "terpenoid" generally refers to terpenes that have been chemically modified (e.g., by oxidation). As used herein, terpene includes terpenoids. Terpenes can be classified in various ways (e.g., by their size). For example, suitable terpenes may include monoterpenes, sesquiterpenes, or triterpenes. At least some terpenes are expected to interact with cannabinoids to enhance their activity.

[0067] Examples of terpenes known to be extractable from cannabis include: aromadendren, bergamotin, bergamonotol, bisabolene, borneol, 4-3-carene, beta-caryophyllene, cineole / eucalyptol, p-cymene, dihydrojasmone, elemene, farnesene, fencol, geranyl acetate, guaiol, humulene, isopulegol, limonene, linalool, menthone, menthol, mentofuran, myrcene, neryl acetate, neomentyl acetate, ocimene, periryl alcohol, phellandrene, pinene, pulegone, sabinene, terpinene, terpineol, terpinen-4-ol, terpinolene, and their derivatives.

[0068] Additional examples of terpenes include: nerolidol, phytol, geraniol, alpha-bisabolol, thymol, genipine, astragaloside, asiaticoside, camphene, beta-amyrin, thujone, citronellol, 1,8-cineole, cycloartenol, and their derivatives. Further examples of terpenes are discussed in U.S. Patent Application Publication No. 2016 / 0250270.

[0069] In some embodiments, the topical formulations provided herein may comprise at least one of beta-caryophyllene, linalool, thymol, alpha-bisabolol, myrcene, limonene, and pinene. In some embodiments, the topical formulations provided herein may comprise beta-caryophyllene and a monoterpene (e.g., linalool, thymol, alpha-bisabolol, alpha-terpineol, and genipine) or a triterpene (e.g., astragaloside and asiaticoside). In some embodiments, the topical formulations provided herein may comprise beta-caryophyllene, linalool, or both.

[0070] Commercially available cannabinoid oils often contain trace amounts of various terpenes. In some embodiments, the topical formulations provided herein may have a higher total terpene concentration compared to the total terpene concentration found in commercially available cannabinoid oils.

[0071] For example, in some embodiments, the topical formulations provided herein may contain terpenes in concentrations of 10 mg / ml to 1000 mg / ml. More specifically, the total terpene concentrations in the topical formulations provided herein may range from 10 mg / ml to 1000 mg / ml, 10 mg / ml to 500 mg / ml, 10 mg / ml to 400 mg / ml, 10 mg / ml to 300 mg / ml, 10 mg / ml to 250 mg / ml, 10 mg / ml to 200 mg / ml, 10 mg / ml to 180 mg / ml, 10 mg / ml to 160 mg / ml, 10 mg / ml to 140 mg / ml, 10 mg / ml to 120 mg / ml, 10 mg / ml to 100 mg / ml, and 10 mg / ml to 80 mg / ml. l, 10mg / ml~60mg / ml, 10mg / ml~40mg / ml, 10mg / ml~25mg / ml, 10mg / ml~20mg / ml, 10mg / ml~15mg / ml, 15mg / ml~1000mg / ml, 15mg / ml~500mg / ml, 15mg / ml~400mg / ml, 15mg / ml~300mg / ml, 15mg / ml~250mg / ml, 15mg / ml~200mg / ml, 15mg / ml~180mg / ml, 15mg / ml~160mg / ml, 15mg / ml~140mg / ml , 15mg / ml~120mg / ml, 15mg / ml~100mg / ml, 15mg / ml~80mg / ml, 15mg / ml~60mg / ml, 15mg / ml~40mg / ml, 15mg / ml~25mg / ml, 15mg / ml~20mg / ml, 20 mg / ml~1000mg / ml, 20mg / ml~500mg / ml, 20mg / ml~400mg / ml, 20mg / ml~300mg / ml, 20mg / ml~250mg / ml, 20mg / ml~200mg / ml, 20mg / ml~180mg / ml, 20mg / ml~160mg / ml, 20mg / ml~140mg / ml, 20mg / ml~120mg / ml, 20mg / ml~100mg / ml, 20mg / ml~80mg / ml, 20mg / ml~60mg / ml, 20mg / ml~40mg / ml, 2 0mg / ml~25mg / ml, 25mg / ml~1000mg / ml, 25mg / ml~500mg / ml, 25mg / ml~400mg / ml, 25mg / ml~300mg / ml, 25mg / ml~250mg / ml, 25mg / ml~200mg / ml,25mg / ml~180mg / ml、25mg / ml~160mg / ml、25mg / ml~140mg / ml、25mg / ml~120mg / ml、25mg / ml~100mg / ml、25mg / ml~80mg / ml、25mg / ml~60mg / ml、25mg / ml~40mg / ml、40mg / ml~1000mg / ml、40mg / ml~500mg / ml、40mg / ml~400mg / ml、40mg / ml~300mg / ml、40mg / ml~250mg / ml、40mg / ml~200mg / ml、40mg / ml~180mg / ml、40mg / ml~160mg / ml、40mg / ml~140mg / ml、40mg / ml~120mg / ml、40mg / ml~100mg / ml、40mg / ml~90mg / ml、40mg / ml~80mg / ml、40mg / ml~60mg / ml、60mg / ml~1000mg / ml、60mg / ml~500mg / ml、60mg / ml~400mg / ml、60mg / ml~300mg / ml、60mg / ml~250mg / ml、60mg / ml~200mg / ml、60mg / ml~180mg / ml、60mg / ml~160mg / ml、60mg / ml~140mg / ml、60mg / ml~120mg / ml、60mg / ml~100mg / ml、60mg / ml~80mg / ml、80mg / ml~1000mg / ml、80mg / ml~500mg / ml、80mg / ml~400mg / ml、80mg / ml~300mg / ml、80mg / ml~250mg / ml、80mg / ml~200mg / ml、80mg / ml~180mg / ml、80mg / ml~160mg / ml、80mg / ml~140mg / ml、80mg / ml~120mg / ml、80mg / ml~100mg / ml、100mg / ml~1000mg / ml、100mg / ml~500mg / ml、100mg / ml~400mg / ml、100mg / ml~300mg / ml、100mg / ml~250mg / ml、100mg / ml~200mg / ml、100mg / ml~180mg / ml、100mg / ml~160mg / ml、100mg / ml~140mg / ml、100mg / ml~120mg / ml、120mg / ml~1000mg / ml、120mg / ml~500mg / ml、120mg / ml~400mg / ml、It can be 120 mg / ml to 300 mg / ml, 120 mg / ml to 250 mg / ml, 120 mg / ml to 200 mg / ml, 120 mg / ml to 180 mg / ml, 120 mg / ml to 160 mg / ml, 120 mg / ml to 140 mg / ml, 140 mg / ml to 1000 mg / ml, 140 mg / ml to 500 mg / ml, 140 mg / ml to 400 mg / ml, 140 mg / ml to 300 mg / ml, 140 mg / ml to 250 mg / ml, 140 mg / ml to 200 mg / ml, 140 mg / ml to 180 mg / ml, 140 mg / ml to 160 mg / ml, 160 mg / ml to 1000 mg / ml, 160 mg / ml to 500 mg / ml, 160 mg / ml to 400 mg / ml, 160 mg / ml to 300 mg / ml, 160 mg / ml to 250 mg / ml, 160 mg / ml to 200 mg / ml, 160 mg / ml to 180 mg / ml, 180 mg / ml to 1000 mg / ml, 180 mg / ml to 500 mg / ml, 180 mg / ml to 400 mg / ml, 180 mg / ml to 300 mg / ml, 180 mg / ml to 250 mg / ml, 180 mg / ml to 200 mg / ml, 200 mg / ml to 1000 mg / ml, 200 mg / ml to 500 mg / ml, 200 mg / ml to 400 mg / ml, 200 mg / ml to 300 mg / ml, or 200 mg / ml to 250 mg / ml.

[0072] In some embodiments, the total terpene concentration in the topical formulations provided herein is at least 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, and 120 mg / ml. g / ml, 130mg / ml, 140mg / ml, 150mg / ml, 160mg / ml, 170mg / ml, 180mg / ml, 190mg / ml, 200mg / ml, 210mg / ml, 220mg / ml, 2 It can be 30mg / ml, 240mg / ml, 250mg / ml, 300mg / ml, 400mg / ml, 500mg / ml, 600mg / ml, 700mg / ml, 800mg / ml, or 900mg / ml.

[0073] In some embodiments, the total terpene concentrations in the topical formulations provided herein are 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml ml, 130mg / ml, 140mg / ml, 150mg / ml, 160mg / ml, 170mg / ml, 180mg / ml, 190mg / ml, 200mg / ml, 210mg / ml, 220mg / ml, 23 It can be 0 mg / ml, 240 mg / ml, 250 mg / ml, 300 mg / ml, 400 mg / ml, 500 mg / ml, 600 mg / ml, 700 mg / ml, 800 mg / ml, or 900 mg / ml.

[0074] In some embodiments, the concentration of terpenes in the topical formulations provided herein may be adjusted according to the stage of wound healing. For example, since beta-caryophyllene is a potent agonist of the CB2 receptor of the endogenous cannabinoid system, it has been found that high levels of beta-caryophyllene (e.g., 50 mg / ml to 500 mg / ml) may be desirable during the re-epithelialization and reconstruction stages.

[0075] The term "flavonoid" is generally understood to include all secondary plant metabolites that have a common 15-carbon skeletal structure consisting of two phenyl rings and a heterocycle. Flavonoids are generally classified into subclasses based on their oxidation state and C2-C3 substitution patterns, including flavanones, flavonols, flavones, anthocyanidins, chalcones, dihydrochalcones, aurones, flavanols, dihydroflavanols, proanthocyanidins (flavan-3,4-diols), isoflavones, and neoflavones. Specific examples of flavonoids include cannaflavin, kaempferol (3,4',5,7-tetrahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), chrysin, diosmin, hesperidin, luteolin, rutin, and quercetin.

[0076] In some embodiments, the topical formulations provided herein may contain quercetin. In some embodiments, the topical formulations provided herein may contain diosmin, quercetin, hesperidin, or a combination thereof. In some embodiments, the topical formulations provided herein may contain diosmin and hesperidin in a ratio of about 9:1. In some embodiments, the topical formulations provided herein may contain quercetin, kaempferol, apigenin, or a combination thereof. Diosmin and quercetin, or each or both, may be micronized and optionally in the form of a dry powder.

[0077] Commercially available cannabinoid oils often contain trace amounts of various flavonoids. In some embodiments, the topical formulations provided herein may have a higher total flavonoid concentration compared to the total concentration of flavonoids found in commercially available cannabinoid oils.

[0078] In some embodiments, the total flavonoid concentration in the topical formulations provided herein may range from 10 mg / ml to 500 mg / ml. For example, this total flavonoid concentration may range from 10 mg / ml to 400 mg / ml, 10 mg / ml to 300 mg / ml, 10 mg / ml to 200 mg / ml, 10 mg / ml to 150 mg / ml, 10 mg / ml to 100 mg / ml, 10 mg / ml to 90 mg / ml, 10 mg / ml to 80 mg / ml, 10 mg / ml to 70 mg / ml, 10 mg / ml to 60 mg / ml, 10 mg / ml to 50 mg / ml, 10 mg / ml to 40 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml, and 10 mg / ml~20mg / ml, 10mg / ml~15mg / ml, 15mg / ml~500mg / ml, 15mg / ml~400mg / ml, 15mg / ml~300mg / ml, 15mg / ml~200mg / ml, 15mg / ml~150mg / ml, 15mg / ml~100mg / ml, 15mg / ml~90mg / ml, 15mg / ml~80mg / ml, 15mg / ml~70mg / ml, 15mg / ml~60mg / ml, 15mg / ml~50mg / ml, 15mg / ml~40mg / ml, 15mg / ml~3 0mg / ml, 15mg / ml~25mg / ml, 15mg / ml~20mg / ml, 20mg / ml~500mg / ml, 20mg / ml~400mg / ml, 20mg / ml~300mg / ml, 20mg / ml~200mg / ml, 20mg / ml~15 0mg / ml, 20mg / ml~100mg / ml, 20mg / ml~90mg / ml, 20mg / ml~80mg / ml, 20mg / ml~70mg / ml, 20mg / ml~60mg / ml, 20mg / ml~50mg / ml, 20mg / ml~40mg / ml, 20mg / ml~30mg / ml, 40mg / ml~500mg / ml, 40mg / ml~400mg / ml, 40mg / ml~300mg / ml, 40mg / ml~200mg / ml, 40mg / ml~150mg / ml, 40mg / ml~100mg / ml, 40mg / ml~90mg / ml, 40mg / ml~80mg / ml, 40mg / ml~70mg / ml, 40mg / ml~60mg / ml, 40mg / ml~50mg / ml, 50mg / ml~500mg / ml, 50mg / ml~400mg / ml,50mg / ml~300mg / ml、50mg / ml~200mg / ml、50mg / ml~150mg / ml、50mg / ml~100mg / ml、50mg / ml~90mg / ml、50mg / ml~80mg / ml、50mg / ml~70mg / ml、50mg / ml~60mg / ml、60mg / ml~500mg / ml、60mg / ml~400mg / ml、60mg / ml~300mg / ml、60mg / ml~200m g / ml、60mg / ml~150mg / ml、60mg / ml~100mg / ml、60mg / ml~90mg / ml、60mg / ml~80mg / ml、60mg / ml~70mg / ml、80mg / ml~50 0mg / ml、80mg / ml~400mg / ml、80mg / ml~300mg / ml、80mg / ml~200mg / ml、80mg / ml~150mg / ml、80mg / ml~100mg / ml、80mg / m l~90mg / ml、90mg / ml~500mg / ml、90mg / ml~400mg / ml、90mg / ml~300mg / ml、90mg / ml~200mg / ml、90mg / ml~150mg / ml、90 mg / ml~100mg / ml、100mg / ml~500mg / ml、100mg / ml~400mg / ml、100mg / ml~300mg / ml、100mg / ml~200mg / ml、100mg / ml~15 0mg / ml, 150mg / ml~500mg / ml, 150mg / ml~400mg / ml, 150mg / ml~300mg / ml, 150mg / ml~200mg / ml, 200mg / ml~500mg / ml, 200mg / ml~400mg / ml, 200mg / ml~300mg / ml, 300mg / ml~500mg / ml, 300mg / ml~400mg / ml, 400mg / ml~500mg / ml.

[0079] In some embodiments, the total flavonoid concentration in the topical formulations provided herein may be at least 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml, 130 mg / ml, 140 mg / ml, 150 mg / ml, 160 mg / ml, 170 mg / ml, 180 mg / ml, 190 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 350 mg / ml, 400 mg / ml, or 450 mg / ml.

[0080] In some embodiments, the total flavonoid concentration in the localized area provided herein may be 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml, 130 mg / ml, 140 mg / ml, 150 mg / ml, 160 mg / ml, 170 mg / ml, 180 mg / ml, 190 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 350 mg / ml, 400 mg / ml, 450 mg / ml, or 500 mg / ml.

[0081] In some embodiments, the concentration of flavonoids in the topical formulations provided herein may be adjusted according to the stage of wound healing. For example, it has been found that high levels of quercetin (e.g., 10 mg / ml to 50 mg / ml) may be desirable during the granulation stage due to their effects on VEGF and TGF-beta. In contrast, the level of diosmin may remain high (e.g., 10 mg / ml to 50 mg / ml) throughout all stages of the healing cascade.

[0082] The cannabinoids, terpenes, and flavonoids used in the topical formulations provided herein may be extracted from natural plants or genetically modified host cells (e.g., yeast cells), or synthesized. Terpenes or flavonoids may be extracted from non-cannabis plants such as fruits and vegetables. When cannabinoids, terpenes, or flavonoids are extracted from a source, the amount of solvent in the extract, or the concentration of cannabinoids, terpenes, or flavonoids in the extract, may vary. For example, the extract may contain one or more solvents (e.g., oil or medium-chain triglycerides), or it may contain substantially no solvent (i.e., the solvent present is undetectable). In another example, the extract may be substantially pure (e.g., the concentration of cannabinoids, terpenes, or flavonoids in this extract is greater than 99 wt%).

[0083] In some embodiments, the topical formulations provided herein may include a liquid carrier selected for the application of the topical formulation to an external wound, the peri-wound area surrounding the external wound, or both. The term “liquid carrier” is generally understood to include any carrier that is liquid at ambient temperature and on which one or more activators are carried, dispersed, or dissolved. The liquid carrier may be in the form of a viscous liquid, paste, emulsion, or gel. As will be understood by those skilled in the art, the liquid carrier should be safe for direct application to an external wound and should avoid or limit irritation or inflammation or an increase in pain levels. For example, an alcohol-based carrier would not be suitable for the application of the topical formulations provided herein to a wound bed, as it is expected to cause necrosis, pain, and irritation at the wound site.

[0084] In relation to this disclosure, the term “dropping” refers to the stepwise application or administration of a topical formulation onto a target wound bed. The dropping of topical formulations provided herein may be carried out by modes of application including, but not limited to, dripping, spraying, diffusing, dispersing, spraying, or spreading.

[0085] In some embodiments, suitable liquid carriers may include: aloe vera gel, ointment, or cream; hyaluronic acid gel, ointment, or cream; vegetable oils (e.g., olive oil or sunflower oil); medium-chain triglycerides; pluronic lecithin organogel (PLO); transdermal bases containing liposome components; physiological saline; or mixtures or combinations thereof. In some embodiments, the liquid carrier may be aloe vera gel. In some embodiments, the liquid carrier may include a mixture or combination of aloe vera gel and hyaluronic acid gel, for example, in a 1:1 ratio. In some embodiments, the liquid carrier may be sunflower oil.

[0086] In some embodiments, the liquid carrier may be a transdermal base containing liposome components. An example of a transdermal base containing liposome components is LIPODERM®, a family of transdermal bases exclusively available from Professional Compounding Centers of America (PCCA). LIPODERM® is an elegant alternative to conventional pluronic lecithin organogels (PLOs) and contains unique liposome components to enhance the permeability of various active pharmaceutical ingredients (APIs).

[0087] Medium-chain triglycerides are triglycerides that consist of a glycerol backbone and numerous fatty acids, two or three of which have an aliphatic tail of 6 to 12 carbon atoms.

[0088] In addition to cannabinoids, terpenes, and flavonoids, which can be considered activators, the topical formulations provided herein may, in some embodiments, include one or more additional activators. The term “activator” is generally understood to mean the active pharmaceutical ingredient.

[0089] Examples of active agents include: active herbal extracts, analgesics, topical anesthetics, anticonvulsants, anti-allergics, antibacterials, antibiotics, antiburns, anticancers, antidermatitis agents, anti-edema agents, antihistamines, antihelmintic agents, antihyperkeratolyte agents, anti-inflammatory agents, antistimulants, antibacterial agents, antifungal agents, antiproliferative agents, antioxidants, antipruritics, psoriasis treatments, antirosacea agents, antiseborrheic agents, antiseptics, and antiswelling agents. Agents, antiviral agents, antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, bactericides, disinfectants, hormones, hydroxy acids, immunosuppressants, immunomodulators, insecticides, insecticides, keratolytic agents, lactams, metals, metal oxides, acaricides, neuropeptides, non-hythroid anti-inflammatory agents, oxidizing agents, lice killers, photodynamic agents, retinoids, sanatives, scabies insecticides, vasoconstrictors, vasodilators, vitamins (e.g., vitamin C) and related derivatives, minerals, wound healing agents, and wart removers.

[0090] In some embodiments, the topical formulations provided herein may further comprise one or more of the following: anti-inflammatory agents, wound healing agents, antioxidants, and antimicrobial agents.

[0091] The topical formulations provided herein may further include at least one additive that does not interfere with the efficacy or biological activity of the activator and is nontoxic to the subject to which the topical formulation provided herein is applied.

[0092] Suitable additives may include: preservatives; thickeners; buffering agents; isotonic agents; wetting agents, solubilizers, and emulsifiers; acidifying agents; alkalizing agents; transporters; chelating agents; complexing agents; solvents; suspending agents or thickeners; oils; penetration enhancers; polymers; curing agents; proteins; carbohydrates; and fillers.

[0093] Preparation method An exemplary method for preparing a topical formulation provided herein includes the steps of: gently pouring the liquid carrier described herein into a vessel such as a container; sequentially adding one or more flavonoids, one or more cannabinoids, and one or more terpenes to the liquid carrier; and mixing the one or more flavonoids, one or more cannabinoids, and one or more terpenes in the liquid carrier, for example by shaking the vessel. This method may be carried out in a sterile environment using aseptic techniques and apparatus. This method may also be carried out in a dark environment (e.g., by covering the container with dark tape) to protect the topical formulation from light.

[0094] The topical formulations provided herein may also be prepared by mixing the materials of the kit provided herein in accordance with the instructions for use included in the kit. For example, one or more flavonoids may be pre-mixed with a liquid carrier and placed in one container of the kit in accordance with the instructions for use, and one or more cannabinoids and one or more terpenes may be added separately to constitute the topical formulation.

[0095] wound dressing Many topical wound dressings are known for use in the treatment of wounds or other openings at physiologically targeted sites on the human or animal body from which blood or other bodily fluids seep. For example, wound dressings can be selected from those described in Dhivya S. et al. Biomedicine (Taipei) 2015 Dec; 5(4):24-28.

[0096] In some embodiments disclosed herein, a wound dressing, or a selected set of wound dressings, may be used in conjunction with or after the application of a topical formulation to an external wound. Preferred wound dressings may include a wound contact layer. Wound dressings may take the form of gauze, bandages, pads, foam dressings, film dressings, patches, or the like. In some embodiments, the wound contact layer may be a material or layer sold under the trademarks JELONET® or PROFORE WCL®. JELONET® is a sterile paraffin tulle gras dressing made from coarse gauze and has connecting threads that minimize fraying when the dressing is cut and shaped. PROFORE WCL® is a 14 cm × 20 cm (5 1 / 2" × 8") dressing made from knitted viscose rayon.

[0097] In some embodiments, the wound dressing described above may be used separately from the formulations described herein. For example, the formulation and the wound dressing may be applied sequentially to an external wound. In some embodiments, the wound dressing described above may be used simultaneously with the formulations described herein. For example, the formulation may be integrated with the contact layer of the wound dressing before use, so that the formulation can be released from the contact layer at a suitable rate after the wound dressing has been applied to the external wound.

[0098] How to use The topical formulations and wound dressings provided herein may be useful for treating the target cutaneous wounds. Without being limited by any particular theory, the topical formulations described herein are expected to promote wound healing by synergistically stimulating granulation tissue proliferation and promoting epithelialization through one or more epigenetic mechanisms, such as interactions with the endogenous cannabinoid system.

[0099] The endocannabinoid system (ECS) is ubiquitous throughout the human body, and in recent years, it has been found to be significantly present throughout the cutaneous system (both skin membranes and mucous membranes). The ECS mainly consists of cannabinoid receptors (CB1 and CB2), endogenous ligands (AEA and 2-AG), biosynthetic pathways (NAPE and DAGL), and degradation pathways (FAAH and MAGL). The ECS signaling pathway also involves other G protein-coupled cannabinoid receptors, ion channel receptors (TRPV, TRPA, TRPM), nuclear receptors (PPARγ, PPARα, PPARδ, NF-κB), and non-cannabinoid targets (5-HT, GlyR, A2A, α2R). Both cannabinoids and non-cannabinoids (e.g., terpenes and flavonoids) are capable of complex, direct, and indirect interactions with the cutaneous ECS.

[0100] The terms “to treat,” “to treat,” or “treatment of” are used herein in these broad senses unless otherwise specifically indicated in a particular context, and the results of treatment may generally include reversal, reduction, or inhibition of the progression of the indicated disorder or condition, or one or more symptoms of such disorder or condition.

[0101] As used herein, the terms “individual” or “subject” mean an animal, and for example, a mammal such as a human. Other mammals include livestock, sports animals, companion animals, primates, horses, dogs, cats, mice, and rats.

[0102] In some embodiments, a method for treating an external wound may include the step of dropping a topical formulation (e.g., a solution or colloid) provided herein onto the external wound in question. The dropping may be carried out by dripping, spraying, diffusing, dispersing, spraying, or spreading the topical formulation. An applicator may be used for dropping. Examples of applicators include droppers, nebulizers, impregnated gauze sheets, syringes, and cotton swabs. After dropping, the topical formulation may cover one or more areas within the external wound, or the entire external wound (including the wound margin), or the entire external wound and areas adjacent to the margin of the external wound (e.g., peri-wound areas).

[0103] In some embodiments, a method for treating an epidermal wound may include the step of applying a topical formulation (e.g., a solution or colloid) provided herein to both the epidermal wound in question and the peri-wound area surrounding the epidermal wound. The peri-wound area is typically limited to the epidermis surrounding an open wound within about 4 cm from the wound margin, but may extend beyond the 4 cm limit depending on the extent of the damage present. For example, as can be understood by those skilled in the art, the peri-wound area may be proportional to the size of the open wound and may cover any area of ​​skin at risk of further destruction. It is understood that tissue within the peri-wound area may exhibit pathophysiological features such as inflammation, edema, vasoconstriction, lymphatic occlusion, decreased oxygen pressure, and acidosis ("leukocyte capture") from reduced cell chemotaxis.

[0104] In some embodiments, topical formulations suitable for application to the peri-wound area surrounding a target external wound may include a liquid carrier having the ability to penetrate intact skin, for example, a Pluronic lecithin organogel and a transdermal base containing liposome components. Such topical formulations are also suitable for application to external wounds. Therefore, a method for treating an external wound may include applying the same topical formulation (for example, formulated in either PLP or liposome form) to both the target external wound and the peri-wound area surrounding the external wound.

[0105] In some embodiments, topical formulations suitable for application to a cutaneous wound may contain a different liquid carrier than those suitable for application to the peri-wound area surrounding the cutaneous wound, in order to achieve better localization of the activator in the cutaneous wound. For example, for application to a cutaneous wound of interest, the topical formulations provided herein may be formulated in petrolatum, paraffin, aloe vera gel, hyaluronic acid gel, or a mixture thereof, and for application to the peri-wound area surrounding the cutaneous wound, the topical formulations provided herein may be formulated in PLO or liposomes.

[0106] Treatment by applying the topical formulations provided herein to both the target external wound and the surrounding peri-wound area may promote vasodilation and / or oxygen supply. Furthermore, treatment of the peri-wound area is expected to promote wound closure and healing, and further prevent deterioration or spread of tissue within the peri-wound area.

[0107] In some embodiments, a wound dressing or a selected set of wound dressings may be applied to the cutaneous wound after the application of a topical formulation provided herein. This wound dressing may include a wound contact layer comprising materials or layers sold under the trademarks JELONET® or PROFORE WCL®. This wound dressing may be a foam dressing or a film dressing.

[0108] In some embodiments, a topical formulation disclosed herein may be applied first to a wound dressing, which is then applied to the target cutaneous wound.

[0109] In some embodiments, the topical formulations provided herein are used for the treatment of a target external wound. The topical formulations provided herein may be dropped onto the external wound and optionally onto the peri-wound area surrounding the external wound. Dropping may be carried out by dripping, spraying, diffusing, dispersing, spraying, or spreading the formulation. In some embodiments, the use of the topical formulations provided herein further includes the use of oral formulations comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids.

[0110] In some embodiments, after the topical formulation provided herein is first applied to the external wound, a wound dressing or a selected set of wound dressings is used for application on the external wound. This wound dressing may include a wound contact layer comprising materials or layers sold under the trademarks JELONET® or PROFORE WCL®. This wound dressing may be a foam dressing or a film dressing.

[0111] In some embodiments, the topical formulations provided herein are used in combination with existing treatments for wound healing. For example, the topical formulations provided herein may be dropped onto a target cutaneous wound during negative pressure wound occlusion (NPWT). In some embodiments, the topical formulations provided herein, containing saline as a liquid carrier, are delivered to the cutaneous wound via an NPWT foam dressing. This formulation can be removed from the cutaneous wound along with the exudate. Unused formulations can be dropped onto the cutaneous wound using an NPWT canister and subsequently removed periodically along with the exudate.

[0112] Surprisingly, the inventors have discovered that certain combination therapies can exhibit synergistic effects. For example, it has been found that combining the topical formulations provided herein with electrical stimulation therapy (EST) results in better healing effects. Without being limited by any particular theory, the cannabinoids and non-cannabinoids contained in the topical formulations provided herein bind to extracellular receptors on the membranes of intact cells in a cutaneous wound, but it is expected that EST facilitates the process of "electroporation" (i.e., creation of openings within the cell membrane), thereby enabling the cannabinoids and non-cannabinoids to enter the cell and interact with the intracellular binding sites of cannabinoid receptors (it is expected that both extracellular and intracellular binding will continue after the electroporation is reversed). In some embodiments, a combination therapy is provided comprising the steps of applying the topical formulations provided herein to a cutaneous wound, and then applying electrical pulses generated by an electrical stimulation generator to this cutaneous wound (e.g., by electrodes attached to the skin surrounding the wound).

[0113] In some embodiments, the topical formulations provided herein may be used in combination with existing intravenous treatments for non-uremic calciphylaxis such as intravenous pamidronate, zoledronate, and STS.

[0114] The external wounds treated may be acute and may include, for example, tears, lacerations, abrasions, postoperative trauma, and burns. Alternatively, the external wounds treated may be chronic, stagnant, refractory, or a combination thereof. For example, external wounds may be caused by skin ulcers, burns (radiation burns, chemical burns, thermal burns, or sunburns), or traumatic abrasions or lacerations. Possible skin ulcers include diabetic ulcers (e.g., neuroischemic diabetic foot ulcers, or diabetic dermatoses such as diabetic lipoid necrotosis), pressure injury ulcers, arterial leg ulcers, venous leg ulcers, or arterial ulcers (e.g., arterial ulcers with severe ischemia).

[0115] Skin wounds may be iatrogenic (drug-induced) or caused by skin diseases or systemic conditions. For example, skin diseases or conditions include skin cancer (e.g., primary tumors, metastatic tumors, or Bowen's disease), vascular ulcers and erosions (e.g., sickle cell disease, Maltrell's ulcer, uremic calciphylaxis, non-uremic calciphylaxis, venous lower extremity ulcers, or arterial ulcers), skin ulcers and erosions caused by microorganisms (e.g., bacteria, fungi, viruses, or Mycobacterium), ulcers and erosions caused by diabetes (e.g., diabetic foot ulcers, diabetic lipoid necrosis, or diabetic skin disorders), and vesicular skin conditions (e.g., epidermolysis bullosa, necrotic skin conditions). It may be ulcers and erosions caused by smallpox or bullous pemphigoid, autoimmune diseases (e.g., pyoderma gangrenosum, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or Morphea), vasculitic ulcers and erosions (e.g., cutaneous vasculitis, leukocytosis-destroying vasculitis, cutaneous polyarteritis nodosa, or microscopic polyangiitis), or other combined diseases (e.g., hidradenitis suppurativa, chronic lichen simplex, lichen sclerosing, lichen planus, Wegener's granulomatosis, cryoglobulinemia, Behçet's disease, cryofibrinogenemia, antiphospholipid syndrome, allergic dermatitis, psoriasis, or porokeratosis).

[0116] The treatment can be administered to humans or animals.

[0117] In some embodiments, treatment of an external wound may simultaneously or separately provide analgesia, opioid-saving effects, antimicrobial activity, and relief of scar tissue.

[0118] In some embodiments, treatment of an external wound can stimulate the proliferation of granulation tissue. For example, studies have shown that at least 33% of external wounds may form granulation tissue within 7 days after application of the topical formulations provided herein, or at least 66% of external wounds may form granulation tissue within 14 days after application of the topical formulations disclosed herein.

[0119] In some embodiments, treatment of an external wound can prevent scar formation (e.g., keloid formation) and / or completely close the wound.

[0120] In certain embodiments, an external wound may be treated as described below, with reference to Figure 2.

[0121] Figure 2a shows an intact wound including the epithelium 201, dermis 202, subcutaneous tissue 203, and superficial fascia 204.

[0122] As shown in Figure 2b, in treatment step 1, the cutaneous wound 205 is evaluated for treatment. Based on this evaluation, the initial formulation is prepared or obtained. This initial formulation may be one of the formulations described herein that have been adjusted based on the evaluation. For example, if the wound to be treated is in the inflammatory stage, the concentrations of the cannabinoids may be adjusted as follows, using a combination of THC and CBD as an example: 2 mg / ml to 10 mg / ml of THC and 5 mg / ml to 20 mg / ml of CBD.

[0123] In the first stage, the wound bed of the external wound 205 and optionally the surrounding area of ​​the wound are prepared for treatment. The wound bed may be prepared by any preferred method or by any appropriate technique. For example, the wound bed may be prepared by gently washing it with sterile saline. Other examples of wound preparation techniques are provided in Sibbald RG. et al., Journal of Cutaneous Medicine and Surgery, 2013, Vol. 17, 4th edition, suppl. pp. S12-S22.

[0124] In the second stage, the initial formulation 206 is dropped directly onto the wound bed and the peri-wound area of ​​the optional epidermal wound 205. As shown in Figure 2c, a layer of formulation 206 is applied to the upper surface of the subcutaneous tissue of the open wound forming the wound bed and to the peri-wound area. The application of this formulation can be carried out according to its form. For example, if the initial formulation is oil-based, it can be dropped or spread onto the wound bed. If the initial formulation is gel, it can be spread onto the wound bed, for example, with an applicator with a sterile cotton tip.

[0125] As an alternative embodiment, the initial formulation 206 may be replaced with a first formulation and a second formulation. The first formulation is applied to the wound bed, and the second formulation is applied to the area surrounding the wound. The second formulation may be applied to a cuff with a radius of 4-6 cm in the area surrounding the wound. The first and second formulations may be the same or different.

[0126] In the third stage shown in Figure 2d, a wound dressing including a wound contact layer 207 is applied on top of the formulation layer 206. As can be understood, in some cases, a selected series of wound dressings are applied to the wound to cover the applied formulation. The wound contact layer may be JELONET or PROFORE WCL. The contact layer 207 may optionally contain a selected formulation as described herein, which is integrated with the contact layer in such a manner that the formulation can be released onto the wound bed of the epidermal wound 205 when the contact layer 207 is in contact with the wound bed.

[0127] In the optional fourth step shown in Figure 2e, if necessary, a wound void filler 208 (e.g., calcium alginate or hydrofiber) may be used to fill the voids on the wound dressing.

[0128] In the optional fifth step shown in Figure 2f, an absorbent layer 209 (such as MESORB® or foam, or similar) may be applied over the wound dressing and the optional void filler.

[0129] In the optional sixth stage shown in Figure 2g, compression therapy 210 may be optionally performed. This compression therapy may be elastic or non-elastic compression therapy. The compression therapy may be a spiral bandage. Possible compression therapy materials include gauze kling rolls, Comprilan®, or Easifix®, or a combination thereof.

[0130] This preparation may be applied 1 to 4 times a day for a period of several days to several weeks or months, or until wound healing is complete.

[0131] The wound may be re-evaluated periodically during the treatment period, and the formulation applied to the wound may be adjusted as the wound healing process progresses.

[0132] For example, if a treated wound progresses to the proliferative phase and continues to the reconstruction phase, a subsequent formulation may be prepared or obtained in which the concentration of cannabinoids is decreased and the concentration of terpenes (particularly terpenes that are CB2 receptor agonists) is increased. In some embodiments, the topical formulations provided herein contain beta-caryophyllene, the concentration of which may be 30 mg / ml to 60 mg / ml when the formulation is used in the inflammatory phase, and thereafter may be increased to 50 mg / ml to 500 mg / ml when the inflammatory phase of wound healing is completed. The subsequent formulation may be applied directly to the wound bed 1 to 4 times a day for a period of time such as several days to several weeks or months, or until wound healing is complete. The subsequent formulation may be used throughout the proliferative and reconstruction phases until the wound is completely healed.

[0133] In another embodiment, treatment with the topical formulations described herein may be applied at one or two stages of the wound healing process. For example, treatment may be initiated at the proliferation stage rather than the inflammatory stage.

[0134] Generally, the contents of a topical formulation, or the adjustments to a selected wound dressing, can be selected according to the nature of the cutaneous wound, or as the cutaneous wound progresses through various stages of wound healing. For example, higher concentrations of THC and / or THCa in the initial formulation may be beneficial for pain management during the inflammatory phase and / or may be desirable for wounds with low oxygen levels. However, after the inflammatory phase, the concentration of psychoactive THC can be reduced to avoid inhibition of keratinocyte differentiation. In another example, terpenes, which are CB2 receptor agonists, may be beneficially included in formulations applied to wounds after the inflammatory phase is complete, or the concentration of such terpenes in the formulation may increase during the proliferation and reconstruction phase, because such terpenes can promote re-epithelialization and reconstruction.

[0135] This formulation may also be adjusted depending on the nature of the wound and the condition of one or more of the target being treated.

[0136] In a specific example, the base topical formulation is: (a) 2.3 mg / ml of cannabidiol (CBD), 1.0 mg / ml of tetrahydrocannabinol (THC), and at least 0.1 mg / ml of tetrahydrocannabinolic acid (THCa); (b) 81.5 mg / ml of beta-caryophyllene and 28.4 mg / ml of linalool; and (c) 16.7 mg / ml of microparticle diosmin and 16.7 mg / ml of microparticle quercetin It may include.

[0137] From this base formulation, formulations for use in wound healing at various stages of treatment and for various targets during treatment can be prepared as follows.

[0138] If the patient has a significant level of venous lymphedema in the lower extremities during treatment, the diosmin concentration should be increased to 10 mg / ml to 50 mg / ml.

[0139] During the inflammatory phase of wound healing, the THC concentration is increased to 2 mg / ml to 10 mg / ml, and the CBD concentration is decreased to 5 mg / ml to 20 mg / ml, because wound pain is expected to be most severe during this phase, and increased CBD and THC may help reduce pain.

[0140] During the re-epithelialization and reconstruction phase, THC concentrations are maintained within the range of 0 mg / ml to 5 mg / ml, CBD concentrations within the range of 0.1 mg / ml to 20 mg / ml, and beta-caryophyllene concentrations within the range of 50 mg / ml to 500 mg / ml. This avoids inhibition of keratinocyte differentiation and promotes re-epithelialization and reconstruction. During the granulation phase, quercetin concentrations rise to 10 mg / ml to 50 mg / ml, which is expected to have an effect on both VEGF and TGF-beta.

[0141] This base formulation can be further modified in several embodiments. For example, linalool can be replaced with another monoterpene (e.g., alpha-bisabolol, thymol, alpha-terpineol, and genipine) or triterpene (e.g., astragaloside and asiaticoside). THC can be completely replaced with THCV. THC, CBD, and THCV may be decarboxylated or replaced with their respective non-carboxylated natural acid forms.

[0142] kit In some embodiments, a kit may be provided comprising a container containing a topical formulation disclosed herein, or several containers containing materials for preparing a topical formulation. The kit may also include instructions for use for treating an external wound using the topical formulation, such as dosage and method of application or infusion of the formulation to a wound bed. If the kit includes other containers, depending on the contents of these containers, the kit may also include instructions for use for preparing topical formulations with different concentrations of the active ingredient from the materials included in the kit and optionally other materials (e.g., liquid carriers or other additives). The kit may also include liquid carriers as described elsewhere in this specification. The kit may further include an applicator for applying the topical formulation to a wound bed and may include specific instructions for use regarding the method of using the applicator.

[0143] In one embodiment, a topical formulation can be prepared from or obtained from a kit comprising (a) one or more cannabinoids; (b) one or more terpenes; (c) one or more flavonoids; (d) a liquid carrier selected for application of the topical formulation to an external wound; and (e) instructions for use, wherein at least one of (a), (b), and (c) is not mixed with (d) in the kit, and the instructions for use include information enabling the mixing of all of (a), (b), and (c) with (d) at selected concentrations disclosed herein. The kit may include separate containers (see Kit 601 shown in Figure 6, for example, a first container 602 containing (a), a second container 603 containing (b), a third container 604 containing (c), a fourth container 605 containing (d), and a fourth container 602 containing (e)), or instructions for use to provide or prepare multiple pieces of information, including various concentrations of one or more of (a), (b), and (c).

[0144] In some embodiments, the kit may include a container containing a dropper solution or formulation provided herein. This formulation may be in the form of an oil, gel, paste, or the like as described above. Depending on the physical form of the formulation, the container may be, for example, a liquid bottle or a paste tube. In other embodiments, the kit may include a plurality of containers containing materials for forming a dropper solution or formulation provided herein. The kit may further include at least one of the following: instructions for direct application of the dropper solution or formulation to the wound bed and optionally the peri-wound area surrounding the external wound; instructions for using the dropper solution or formulation to treat the external wound according to the methods or uses provided herein; and instructions for using the materials in the plurality of containers to prepare the dropper solution or formulation according to the preparation methods provided herein. Optional components of the kit may include one or more applicators (e.g., droppers, sprays, gauze sheets, and cotton-tipped applicators) for applying the dropper solution or formulation to the open wound bed and the peri-wound area surrounding the external wound, as well as one or more wound dressings as described herein. One or more applicators may be sterilized and placed in a sealed sterile package.

[0145] Embodiment Specific embodiments of the present invention include, but are not limited to, the following: 1. (a) One or more cannabinoids in a concentration of 0.1 mg / ml to 40 mg / ml; (b) One or more terpenes in a concentration of 25 mg / ml to 1000 mg / ml; and (c) One or more flavonoids in concentrations of 10 mg / ml to 500 mg / ml A topical preparation containing [the specified ingredient].

[0146] 2. The topical preparation according to paragraph 1, comprising one or more cannabinoids, cannabidiol or cannabidiolic acid.

[0147] 3. The topical preparation according to paragraph 2, wherein the one or more cannabinoids further comprises at least one of cannabinol, cannabigerol, cannabichromene, and tetrahydrocannabivarin.

[0148] 4. The topical formulation according to paragraph 2 or 3, wherein the one or more cannabinoids further comprises at least 0.1 mg / ml of tetrahydrocannabinolic acid (e.g., 1 mg / ml to 5 mg / ml) and optionally tetrahydrocannabinol.

[0149] 5. The topical formulation according to paragraph 2 or 3, wherein the one or more cannabinoids do not include tetrahydrocannabinol.

[0150] 6. The topical formulation according to paragraph 1, wherein the one or more cannabinoids do not include tetrahydrocannabinol.

[0151] 7. The topical formulation according to any one of paragraphs 1 to 6, wherein the one or more terpenes include beta-caryophyllene.

[0152] 8. The topical formulation according to any one of paragraphs 1 to 7, wherein the one or more terpenes further comprise linalool.

[0153] 9. The topical formulation according to any one of paragraphs 1 to 8, wherein the one or more terpenes comprises beta-caryophyllene and a monoterpene (e.g., linalool, thymol, alpha-bisabolol, alpha-terpineol, and genipine) or a triterpene (e.g., astragaloside and asiaticoside).

[0154] 10. A topical preparation according to any one of paragraphs 1 to 9, wherein the one or more flavonoids include quercetin.

[0155] 11. The topical preparation according to any one of paragraphs 1 to 9, wherein the one or more flavonoids comprises at least one of diosmin, quercetin, and hesperidin, or comprises at least one of kaempferol, apigenin, and quercetin, or comprises kaempferol, apigenin, diosmin, hesperidin, and quercetin.

[0156] 12. The topical preparation according to any one of paragraphs 1 to 9, wherein the one or more flavonoids include diosmin, quercetin, and hesperidin.

[0157] 13. The topical preparation according to any one of paragraphs 1 to 12, wherein the one or more cannabinoids, terpenes, or flavonoids are extracted from plants or genetically modified host cells, or are synthesized.

[0158] 14. A topical preparation according to any one of paragraphs 1 to 13, comprising 0.1 mg / ml to 20 mg / ml of cannabidiol or cannabidiolic acid, and 0 mg / ml to 5 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid.

[0159] 15. A topical preparation according to any one of paragraphs 1 to 13, comprising 5 mg / ml to 20 mg / ml of cannabidiol or cannabidiolic acid, and 2 mg / ml to 10 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid.

[0160] 16. The topical formulation described in paragraph 14 or 15, wherein tetrahydrocannabinol is replaced with tetrahydrocannabivarin.

[0161] 17. A topical preparation according to any one of paragraphs 1 to 16, comprising one or more of the above terpenes in an amount of 50 mg / ml to 500 mg / ml.

[0162] 18. A topical preparation according to any one of paragraphs 1 to 16, wherein the concentration of beta-caryophyllene is 50 mg / ml to 500 mg / ml.

[0163] 19. A topical preparation described in any one of paragraphs 1 to 16, wherein the concentration of linalool is 25 mg / ml to 500 mg / ml.

[0164] 20. A topical preparation according to any one of paragraphs 1 to 19, comprising one or more of the aforementioned flavonoids in an amount of 20 mg / ml to 200 mg / ml.

[0165] 21. A topical preparation according to any one of paragraphs 1 to 20, comprising 30 mg / ml to 60 mg / ml of beta-caryophyllene and 10 mg / ml to 30 mg / ml of linalool.

[0166] 22. A topical preparation according to any one of paragraphs 1 to 20, comprising 50 mg / ml to 500 mg / ml of beta-caryophyllene and 10 mg / ml to 150 mg / ml of linalool.

[0167] 23. The topical formulation according to paragraph 21 or 22, wherein linalool is replaced with a monoterpene (e.g., linalool, thymol, alpha-bisabolol, alpha-terpineol, and genipine) or a triterpene (e.g., astragaloside and asiaticoside).

[0168] 24. A topical preparation according to any one of paragraphs 1 to 23, comprising 10 mg / ml to 50 mg / ml of diosmin and 10 mg / ml to 50 mg / ml of quercetin.

[0169] 25. A topical formulation according to any one of paragraphs 1 to 24, wherein one or more of the flavonoids are micronized.

[0170] 26. The topical preparation according to any one of paragraphs 1 to 25, wherein one or more flavonoids are in the form of a dry powder.

[0171] 27. A topical preparation according to paragraph 1, comprising (a) 10 mg / ml to 20 mg / ml of cannabidiol or cannabidiolic acid, and at least one of cannabinol, cannabigerol, cannabichromene, and tetrahydrocannabivarin; (b) 0.1 mg / ml to 0.2 mg / ml of at least one of linalool, thymol, alpha-bisabolol, and myrcene; and (c) 100 mg / ml to 200 mg / ml of at least one of kaempferol, apigenin, diosmin, hesperidin, and quercetin.

[0172] 28. The topical preparation according to paragraph 1, comprising (a) 5 mg / ml to 30 mg / ml of cannabidiol or cannabidiolic acid, and 2 mg / ml to 10 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid; (b) 30 mg / ml to 60 mg / ml of beta-caryophyllene, and 10 mg / ml to 30 mg / ml of linalool; and (c) 10 mg / ml to 30 mg / ml of diosmin, and 10 mg / ml to 30 mg / ml of quercetin.

[0173] 29. A topical preparation according to paragraph 1, comprising (a) 0.1 mg / ml to 20 mg / ml of cannabidiol or cannabidiolic acid, and 0 mg / ml to 5 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid; (b) 50 mg / ml to 500 mg / ml of beta-caryophyllene, and 10 mg / ml to 150 mg / ml of linalool; and (c) 0 mg / ml to 50 mg / ml of diosmin, and 10 mg / ml to 50 mg / ml of quercetin.

[0174] 30. A topical preparation according to paragraph 1, comprising (a) 2.3 mg / ml of cannabidiol or cannabidiolic acid and 1.0 mg / ml of tetrahydrocannabinol or tetrahydrocannabinolic acid; (b) 81.5 mg / ml of beta-caryophyllene and 28.4 mg / ml of linalool; and (c) 16.7 mg / ml of microparticle diosmin and 16.7 mg / ml of microparticle quercetin.

[0175] 31. The topical preparation according to paragraph 1, comprising (a) 2.6 mg / ml of cannabidiol or cannabidiolic acid; (b) 118 mg / ml of beta-caryophyllene; (c) 19.6 mg / ml of microparticle diosmin, 21.7 mg / ml of microparticle quercetin, and 2.2 mg / ml of hesperidin; and (d) aloe vera gel and hyaluronic acid gel.

[0176] 32. A topical preparation described in any one of paragraphs 1 to 31, for direct application to an external wound.

[0177] 33. A topical preparation according to any one of paragraphs 1 to 32, which is in the form of a solution, lotion, cream, ointment, gel, emulsion, liposome, foam, powder, impregnated gauze sheet, tulle, vapor, or paste for application to a skin wound, or in the form of an aerosolized spray for nasal or oral application to a skin wound, or in the form of a suppository for rectal or vaginal application to a skin wound.

[0178] 34. A topical preparation according to any one of paragraphs 1 to 32, which is a solution or colloid.

[0179] 35. The topical formulation according to paragraph 34, further comprising a liquid carrier selected for dropping the solution or colloid onto an external wound.

[0180] 36. The topical formulation according to paragraph 35, wherein the liquid carrier comprises an aloe vera gel, a hyaluronic acid gel, a vegetable oil, a medium-chain triglyceride, a pluronic acid lecithin organogel, a liposome component, or a physiological saline solution.

[0181] 37. The topical preparation according to paragraph 36, wherein the vegetable oil is olive oil or sunflower oil.

[0182] 38. The topical formulation according to paragraph 35, wherein the liquid carrier is sunflower oil.

[0183] 39. The topical formulation according to paragraph 35, wherein the liquid carrier is a pluronic lecithin organogel or a transdermal base containing a liposome component.

[0184] 40. A topical preparation described in paragraph 39, in the form of a cream.

[0185] 41. The topical formulation according to paragraph 35, wherein the liquid carrier comprises aloe vera gel.

[0186] 42. The topical formulation according to paragraph 35, wherein the liquid carrier comprises aloe vera gel and hyaluronic acid gel.

[0187] 43. A topical preparation according to any one of paragraphs 1 to 42, further comprising one or more additional activators.

[0188] 44. The topical formulation according to paragraph 43, wherein the one or more active agents include at least one of an anti-inflammatory agent, a wound healing agent, an antioxidant, and an antimicrobial agent.

[0189] 45. A topical preparation according to any one of paragraphs 1 to 44, further comprising an excipient.

[0190] 46. ​​A wound dressing comprising a wound contact layer and a topical formulation according to any one of paragraphs 1 to 41, which is integrated with the contact layer.

[0191] 47. The wound dressing according to paragraph 46, wherein the wound contact layer includes a paraffin gauze dressing or a dressing made of knitted viscose rayon.

[0192] 48. A wound dressing according to paragraph 46 or 47, which is a foam dressing.

[0193] 49. A wound dressing according to paragraph 46 or 47, which is a film dressing.

[0194] 50. A method comprising the step of applying a topical preparation described in any one of paragraphs 1 to 45 to a target skin wound.

[0195] 51. The method according to paragraph 50, wherein the dripping step covers a portion of the skin wound.

[0196] 52. The method according to paragraph 50, wherein the dripping step covers the entire surface wound.

[0197] 53. The method according to paragraph 50, wherein the dripping step covers the entire exocutaneous wound and the area adjacent to the edge of the exocutaneous wound.

[0198] 54. The method according to paragraph 53, wherein the region adjacent to the edge of the exoskeleton wound is the wound periphery surrounding the exoskeleton wound.

[0199] 55. A method comprising the step of dropping a topical preparation described in any one of paragraphs 1 to 45 onto a target skin wound and the surrounding wound area.

[0200] 56. A method comprising the steps of dropping the topical preparation described in paragraph 41 or 42 onto a target skin wound, and dropping the topical preparation described in paragraph 39 onto the wound periphery surrounding the skin wound.

[0201] 57. The method according to any one of paragraphs 50 to 56, wherein the dropping step includes dripping, spraying, diffusing, dispersing, spraying, or spreading the formulation.

[0202] 58. The method according to any one of paragraphs 50 to 57, further comprising the step of preparing a formulation for oral administration comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids.

[0203] 59. The method according to any one of paragraphs 50 to 58, further comprising the step of applying a wound dressing, including a wound contact layer, to the external wound after the topical preparation has been dropped.

[0204] 60. The method according to paragraph 59, wherein the wound contact layer includes a paraffin gauze dressing or a dressing made of knitted viscose rayon.

[0205] 61. The method according to paragraph 59 or 60, wherein the wound dressing is a foam dressing.

[0206] 62. The method according to paragraph 59 or 60, wherein the wound dressing is a film dressing.

[0207] 63. A method comprising the step of applying a wound dressing according to any one of paragraphs 46 to 49 to a target external wound and an optional peripheral wound area surrounding the external wound.

[0208] 64. The method according to any one of paragraphs 50 to 63, wherein the skin wound is acute, chronic, stagnant, refractory, or a combination thereof.

[0209] 65. The method according to any one of paragraphs 50 to 64, wherein the skin wound is caused by a skin ulcer, burn, or traumatic abrasion or laceration.

[0210] 66. The method according to paragraph 65, wherein the skin ulcer is a diabetic ulcer, a pressure ulcer, an arterial leg ulcer, a venous leg ulcer, or an arterial ulcer.

[0211] 67. The method according to any one of paragraphs 50 to 66, wherein the external wound is caused by a skin disease or condition.

[0212] 68. The aforementioned skin diseases or conditions include skin cancer (e.g., primary tumors, metastatic tumors, or Bowen's disease), vascular ulcers and erosions (e.g., sickle cell disease, Maltorell's ulcer, uremic calciphylaxis, nonuremic calciphylaxis, venous lower extremity ulcers, or arterial ulcers), epithelial ulcers and erosions caused by microorganisms (e.g., bacteria, fungi, viruses, or Mycobacterium), ulcers and erosions caused by diabetes (e.g., diabetic foot ulcers, diabetic lipoid necrosis, or diabetic skin disorders), and vesicular skin conditions (e.g., epidermolysis bullosa, pemphigus, or bullous pemphigoid). The method according to paragraph 67, wherein the ulcers and erosions are caused by autoimmune diseases (e.g., pyoderma gangrenosum, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or Morphea), vasculitic ulcers and erosions (e.g., cutaneous vasculitis, leukocytosis vasculitis, cutaneous polyarteritis nodosa, or microscopic polyangiitis), or other combined diseases (e.g., hidradenitis suppurativa, chronic lichen simplex, lichen sclerosing, lichen planus, Wegener's granulomatosis, cryoglobulinemia, Behçet's disease, cryofibrinogenemia, antiphospholipid syndrome, allergic dermatitis, psoriasis, or porokeratosis).

[0213] 69. The method described in any one of paragraphs 50 to 68, wherein the subject is a human.

[0214] 70. The method according to any one of paragraphs 50 to 68, wherein the subject is an animal.

[0215] 71. The method according to any one of paragraphs 50 to 70, having an analgesic effect, an anti-inflammatory effect, an antimicrobial effect, or an antipruritic effect.

[0216] 72. The method according to any one of paragraphs 50 to 71 having an opioid-saving effect.

[0217] 73. A method according to any one of paragraphs 50 to 72 for stimulating the growth of granulation tissue.

[0218] 74. The method according to paragraph 73, wherein at least 33% of the above-mentioned exocutaneous wounds form granulation tissue within 7 days.

[0219] 75. The method according to paragraph 73, wherein at least 66% of the exocutaneous wounds form granulation tissue within 14 days.

[0220] 76. The method according to any one of paragraphs 50 to 75, wherein the topical preparation is effective in reducing scar formation.

[0221] 77. The method according to any one of paragraphs 50 to 76, further comprising the step of adjusting the topical preparation in accordance with the nature of the external wound or as the external wound progresses through various stages of wound healing.

[0222] 78. The method according to paragraph 77, wherein the step of preparing the topical preparation includes a step of reducing the concentration of one or more cannabinoids in the topical preparation when the inflammatory stage of wound healing is completed.

[0223] 79. The method according to paragraph 78, wherein, if the topical preparation contains cannabidiol and tetrahydrocannabinol, the concentration of cannabidiol is 5 mg / ml to 20 mg / ml before adjustment and decreases to 0.1 mg / ml to 20 mg / ml after the inflammatory stage of wound healing is completed, and the concentration of tetrahydrocannabinol is 2 mg / ml to 10 mg / ml before adjustment and decreases to 0 mg / ml to 5 mg / ml after the inflammatory stage of wound healing is completed.

[0224] 80. The method according to paragraph 77, wherein the step of preparing the topical formulation includes increasing the concentration of one or more terpenes in the topical formulation when the inflammatory stage of wound healing is completed.

[0225] 81. The method according to paragraph 80, wherein the topical preparation contains beta-caryophyllene, the concentration of beta-caryophyllene is 30 mg / ml to 60 mg / ml before adjustment, and increases to 50 mg / ml to 500 mg / ml when the inflammatory stage of wound healing is completed.

[0226] 82. The method according to paragraph 77, wherein the step of preparing the topical preparation includes increasing the concentration of one or more flavonoids in the topical preparation when the wound healing is in the granulation tissue formation stage.

[0227] 83. The method according to paragraph 82, wherein the topical preparation contains 10 mg / ml to 50 mg / ml of quercetin when the wound healing is in the granulation tissue formation stage.

[0228] 84. The method according to any one of paragraphs 50 to 83, further comprising the step of treating the exocutaneous wound with an additional treatment for wound healing.

[0229] 85. The method according to paragraph 84, wherein the additional treatment method is negative pressure wound occlusion.

[0230] 86. The method according to paragraph 84, wherein the additional treatment is electrical stimulation therapy.

[0231] 87. Use of any one of the topical preparations described in paragraphs 1 to 45 for the treatment of the target external wound.

[0232] 88. The use of the topical preparation as described in paragraph 87, for application to the exocutaneous wound and, optionally, to the peri-wound area surrounding the exocutaneous wound.

[0233] 89. Use of the topical preparation described in paragraph 41 or 42 in combination with the topical preparation described in paragraph 39 for the treatment of an external wound, wherein the topical preparation described in paragraph 41 or 42 is for infusion onto the external wound, and the topical preparation described in paragraph 39 is for infusion onto the peripheral area surrounding the external wound.

[0234] 90. The use according to paragraph 89 or 90, wherein the dropping includes dropping, spraying, diffusing, dispersing, spraying, or spreading the topical formulation.

[0235] 91. Use according to any one of paragraphs 87 to 90, further comprising the use of an oral formulation comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids.

[0236] 92. The use described in paragraph 91, in which the oral preparation is taken once or twice a day.

[0237] 93. The use according to any one of paragraphs 87 to 92, further comprising the use of a wound dressing comprising a wound contact layer, wherein the wound dressing is for application onto the exocutaneous wound after the topical formulation.

[0238] 94. The use described in paragraph 93, wherein the wound contact layer includes a paraffin gauze dressing or a dressing made of knitted viscose rayon.

[0239] 95. The use described in paragraph 93 or 94, wherein the material of the wound dressing is a foam dressing.

[0240] 96. The use described in paragraph 93 or 94, wherein the material of the wound dressing is a film dressing.

[0241] 97. Use of any one of the wound dressings described in paragraphs 46 to 49 for the treatment of the target external wound.

[0242] 98. The use described in any one of paragraphs 87 to 97, wherein the skin wound is acute, chronic, stagnant, refractory, or a combination thereof.

[0243] 99. The use described in paragraph 98, wherein the external wound is caused by a skin ulcer, burn, or traumatic abrasion or laceration.

[0244] 100. The use described in paragraph 99, wherein the skin ulcer is a diabetic ulcer, a pressure injury ulcer, an arterial leg ulcer, a venous leg ulcer, or an arterial ulcer.

[0245] 101. The use described in any one of paragraphs 87 to 98, wherein the external wound is caused by a disease or condition of the skin.

[0246] 102. The aforementioned skin diseases or conditions include skin cancer (e.g., primary tumor, metastatic tumor, or Bowen's disease), vascular ulcers and erosions (e.g., sickle cell disease, Maltorell's ulcer, uremic calciphylaxis, nonuremic calciphylaxis, venous lower extremity ulcers, or arterial ulcers), epithelial ulcers and erosions caused by microorganisms (e.g., bacteria, fungi, viruses, or mycobacterium), ulcers and erosions caused by diabetes (e.g., diabetic foot ulcers, diabetic lipoid necrosis, or diabetic skin disorders), and vesicular skin conditions (e.g., epidermolysis bullosa, pemphigus, or bullous pemphigoid). The use described in paragraph 101, which is for ulcers and erosions caused by autoimmune diseases (e.g., pyoderma gangrenosum, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or Morphea), vasculitic ulcers and erosions (e.g., cutaneous vasculitis, leukocytosis vasculitis, cutaneous polyarteritis nodosa, or microscopic polyangiitis), or other combined diseases (e.g., hidradenitis suppurativa, chronic lichen simplex, lichen sclerosing, lichen planus, Wegener's granulomatosis, cryoglobulinemia, Behçet's disease, cryofibrinogenemia, antiphospholipid syndrome, allergic dermatitis, psoriasis, or porokeratosis).

[0247] 103. The use described in any one of paragraphs 87 to 102, wherein the subject is a human.

[0248] 104. The use described in any one of paragraphs 87 to 103, wherein the subject is an animal.

[0249] 105. Use according to any one of paragraphs 87 to 104 having an analgesic effect, an anti-inflammatory effect, an anti-microbial effect, or an anti-itching effect.

[0250] 106. Use according to any one of paragraphs 87 to 105 having an opioid-saving effect.

[0251] 107. Use according to any one of paragraphs 87 to 106 that stimulates the growth of granulation tissue.

[0252] 108. Use according to paragraph 107, wherein at least 33% of the skin wound is granulated within 7 days.

[0253] 109. Use according to paragraph 107, wherein at least 66% of the skin wound is granulated within 14 days.

[0254] 110. Use according to any one of paragraphs 87 to 109 for preventing scar formation.

[0255] 111. Use according to any one of paragraphs 87 to 110 for promoting vasodilation and / or oxygen supply.

[0256] 112. Use according to any one of paragraphs 87 to 111 including the step of adjusting the topical formulation according to the nature of the skin wound or as the skin wound progresses through various stages of wound healing.

[0257] 113. Use according to paragraph 112, wherein the step of adjusting the topical formulation includes the step of reducing the concentration of one or more cannabinoids in the topical formulation when the inflammatory stage of the wound healing is completed.

[0258] 114. The use described in paragraph 113, wherein the topical preparation contains cannabidiol and tetrahydrocannabinol, the concentration of cannabidiol is 5 mg / ml to 20 mg / ml before adjustment and decreases to 0.1 mg / ml to 20 mg / ml after the inflammatory stage of wound healing is completed, and the concentration of tetrahydrocannabinol is 2 mg / ml to 10 mg / ml before adjustment and decreases to 0 mg / ml to 5 mg / ml after the inflammatory stage of wound healing is completed.

[0259] 115. The use according to paragraph 112, wherein the step of preparing the topical preparation includes increasing the concentration of one or more terpenes in the topical preparation when the inflammatory stage of wound healing is completed.

[0260] 116. The use described in paragraph 115, wherein the topical preparation contains beta-caryophyllene, the concentration of beta-caryophyllene is 30 mg / ml to 60 mg / ml before adjustment, and increases to 50 mg / ml to 500 mg / ml when the inflammatory stage of wound healing is completed.

[0261] 117. The use according to paragraph 112, wherein the step of preparing the preparation includes increasing the concentration of one or more flavonoids in the topical preparation when the wound healing is in the granulation tissue formation stage.

[0262] 118. The use of the topical preparation as described in paragraph 117, wherein the topical preparation contains 10 mg / ml to 50 mg / ml of quercetin when the wound healing is in the granulation tissue formation stage.

[0263] 119. Uses described in any one of paragraphs 87 to 118, further including additional treatments for wound healing.

[0264] 120. The additional treatment method is negative pressure wound occlusion, as described in paragraph 119.

[0265] 121. The additional treatment method is electrical stimulation therapy, as described in paragraph 119.

[0266] 122. A container containing a topical preparation described in any one of paragraphs 1 to 45, or a kit comprising a plurality of containers containing materials for forming a topical preparation described in any one of paragraphs 1 to 45.

[0267] 123. The kit according to paragraph 122, further comprising instructions for direct application of the topical preparation to an external wound and an optional peri-wound area surrounding the external wound.

[0268] 124. The kit according to paragraph 122 or 123, further comprising instructions for use of the topical preparation for treating an external wound in accordance with the method described in any one of paragraphs 50 to 86.

[0269] 125. A kit according to any one of paragraphs 122 to 124, further comprising instructions for use of the materials in the plurality of containers for preparing the topical formulation.

[0270] 126. The kit according to any one of paragraphs 122 to 125, further comprising one or more applicators for applying the topical preparation to a wound bed.

[0271] 127. A kit according to any one of paragraphs 122 to 126, further comprising one or more wound dressings described in any one of paragraphs 46 to 49.

[0272] 128. A method comprising the step of dropping a topical formulation containing cannabidiol or cannabidiolic acid and a liquid carrier onto a target skin wound and an optionally selected area surrounding the skin wound.

[0273] 129. The method according to paragraph 128, wherein the topical preparation comprises cannabidiol or cannabidiolic acid and a liquid carrier.

[0274] 130. The method according to paragraph 128 or 129, wherein the topical preparation is dropped onto an external wound.

[0275] 131. The method according to any one of paragraphs 128 to 130, wherein the liquid carrier comprises a transdermal base containing aloe vera gel, hyaluronic acid gel, vegetable oil, medium-chain triglyceride, pluronic lecithin organogel, or liposome component.

[0276] 132. The method according to paragraph 131, wherein the liquid carrier comprises aloe vera gel or hyaluronic acid gel.

[0277] 133. The method according to any one of paragraphs 50 to 86, wherein the treatment period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or until wound healing is complete.

[0278] 134. The use according to any one of paragraphs 128 to 132, wherein the treatment period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or until wound healing is complete.

Example

[0279] (Example 1: Preparation of a topical formulation of cannabinoids, terpenes, and flavonoids) This formulation was prepared in 30 ml aliquots using aseptic techniques. 10 ml of aloe vera gel (purchased under the trade name "Aloe Gel" from Realaloe Canada, British Columbia, Canada) and 10 ml of hyaluronic acid gel (containing 8 mg / ml of hyaluronic acid; purchased under the trade name "PRO HA + C" from Naka Professional, Toronto, Canada M9W 5S2) were gently poured into a sterile container. To this gel mixture, diosmin in dry powder form (purchased under the trade name "Diovasc" from Xymogen, 32819 USA) and quercetin (purchased under the trade name "Quercetin Capsules" from Alpha Science Laboratories, Toronto, Canada) (equivalent to 500 mg each) were added. Next, 1.5 ml of THC oil (containing 20 mg / ml of THC; purchased from Tweed, Smiths Falls, Ontario, Canada, under the brand name "Red Cannabis Oil") and 3.5 ml of CBD oil (containing 20 mg / ml of CBD; purchased from Tweed, Smiths Falls, Ontario, Canada, under the brand name "Yellow Cannabis Oil") were added. Finally, 3 ml of beta-caryophyllene (containing 814.5 mg / ml of beta-caryophyllene; purchased from True Terpenes, 2416 N Hayden Island Drive, Portland, Oregon, USA, 97217) and 1 ml of linalool (containing 852.9 mg / ml of linalool; purchased from True Terpenes, 2416 N Hayden Island Drive, Portland, Oregon, USA, 97217) were added. The container was then closed and shaken for 30 seconds. This mixing container was covered with dark tape to block out light.The prepared formulation contained (a) 2.3 mg / ml of cannabidiol and 1.0 mg / ml of tetrahydrocannabinol; (b) 81.5 mg / ml of beta-caryophyllene and 28.4 mg / ml of linalool; and (c) 16.7 mg / ml of micronized diosmin and 16.7 mg / ml of micronized quercetin.

[0280] (Example 2: Case report of topical formulations of cannabinoids, terpenes, and flavonoids in wound healing) This example demonstrates the efficacy of the topical formulation prepared in Example 1, which was applied topically to the wound bed of a chronic, refractory wound. This treatment was found to promote the healing of chronic, refractory wounds.

[0281] A mixture containing cannabinoids, terpenes, and flavonoids was topically administered to the wound bed of an 85-year-old woman with a large chronic wound on her right leg, which had been present since 2013. This patient also suffered from CHF, atrial fibrillation, and osteoarthritis. The wound presented with clinical symptoms of idiopathic pyoderma gangrenosum, as identified by histopathological and immunofluorescence features. The patient had refused conventional medications such as prednisone, Imuran, cyclosporine, and infliximab.

[0282] Treatment was initiated on November 1, 2017. In highly heterogeneous wounds, rapid granulation tissue formation and subsequent epithelial proliferation were observed within the original necrotic area, along with a significant reduction in the wound area over 90 days. In addition to granulation tissue formation at the wound, this patient also reported experiencing a reduction in wound-related pain and exudation.

[0283] During the treatment period for this patient, color photographs of the wound were taken routinely at the patient's residence. Alternatively, the longest length and widest width of the wound were manually recorded.

[0284] Between November 1, 2017 and January 30, 2018 (total: 90 days), the patient was visited 35 times (average frequency: 2.6 days / visit). 119 images (average: 3.4 images / visit) were analyzed. Due to the large surface area of ​​the wound that could not be captured within the field of view (FOV) of a single camera, multiple images were taken at each visit.

[0285] In each image, the contour of the wound boundary was manually drawn. From this contour, the wound was extracted using a polygonal region mask defined by contour points. This region was defined as the Region of Interest (ROI). The images were subjected to a color space conversion from Red-Green-Blue (RGV) space to Hue-Saturation-Value (HSV) space. HSV space (or other similar approaches) is commonly used to perform segmentation of different objects, such as skin, due to the much higher contrast between semantically different objects. Hue space values ​​are generally represented as dimensionless values ​​from 0 to 360, with the lowest value being used. 0 and 360 represent red, green is 120, and blue is 240. Since the target color is near the red wavelength, various periods within the hue interval from -180 to 180 were taken. As a result, 0 and 120 remained red and green, respectively, but blue shifted by one period to (240-360)=-120. Most importantly, all red pixels were adjacent to each other for histogram analysis, enabling more convenient binning. Finally, for interoperability between different software platforms where different ranges of hue intervals can be selected, the range (-180,180) was normalized to (-0.5,0.5) (for example, the hue range could be chosen to be 0-255 to fit conventional 8-bit data structures). All pixels in the hue channel within the ROI were counted in the histogram. Empirical thresholds were applied to classify pixels in the wound into "necrotic," "granulation tissue," "epithelial," and "unlabeled."

[0286] Assuming that the necrotic, granulation, and epithelial regions are somewhat contiguous, morphological manipulations were performed to improve the accuracy of classification. First, appropriate-sized image erosion structuring elements were applied to eliminate small misclassified regions. Then, an extended filter using the same structuring elements was applied to reconstruct the precise size of the classified regions.

[0287] For visualization, a small extended structuring element was applied to each region, and then this region was subtracted. This series of operations made it possible to draw the outer contours of the classified regions. Regions with different classifications were depicted with different contour colors.

[0288] Finally, the percentage of each pixel classification within the wound was calculated and interpreted as the percentage of the area within the wound that was the labeled type of tissue. Granulation tissue % = Number of "granulation tissue" pixels / Total number of pixels in the wound Epithelial % = Number of "epithelial" pixels / Total number of pixels in the wound

[0289] The entire analysis pipeline was implemented in the Python programming language using the OpenCV computer vision library.

[0290] In addition to image analysis, the upper limit of the wound area is estimated from the measured maximum width and longest length: wound area ≈ longest length × maximum width.

[0291] Statistical analysis was performed using Python (version 3.6.2, SciPy version 0.19.1) and MATLAB (registered trademark, version R2016a).

[0292] Representative images and their analysis for days 15, 41, and 87 are shown in Figures 3a-3c. The upper left image in each figure was taken with the outlined and classified region (dark gray: granulation tissue, white: epithelial tissue). The upper right image in each figure shows the hue channel (region enclosed by a solid line) calculated from each image. The graph below each figure shows the hue value histogram within the wound area. Note that the peak is significantly higher and narrower from days 15 to 41 due to the increase in the proportion of granulation tissue, and slightly wider on day 87 due to the increase in the amount of epithelial tissue. Wound healing can be distinguished into two distinct stages: Stage 1 before day 30, when the tissue begins rapid granulation before day 30, and Stage 2 after day 30, when the granulation process is nearly saturated and epithelial proliferation begins. This division can be clearly observed in the statistical summary shown in Figure 4.

[0293] As discussed in the background section, the initial stage of granulation tissue formation is characterized by a narrowing of the histogram peak and a widening of the peak. In the second stage of healing, when granulation tissue formation is saturated and epithelial tissue begins to form, the histogram gradually becomes a yellow region, and the peak becomes smaller, indicating that the granulation tissue is changing into epithelial tissue.

[0294] The fluorescence of wound size and the proportion of granulation tissue and epithelial tissue is shown in Figures 5a-5c and Figure 4, respectively. In Figures 5a-5c, the linear regression line for all data points, represented by "X", is shown as a dotted line in each figure. The equation of the linear regression line in Figure 5a is y = -0.106x + 19.6, and the coefficient of determination (R) is 2 The coefficient of determination (R) is 0.774, and the equation of the linear regression line in Figure 5b is y = -0.059x + 9.6, and the coefficient of determination (R) is 0.774. 2 The coefficient of determination (R) is 0.930, and the equation of the linear regression line in Figure 5c is y = -1.545x + 175.8, and the coefficient of determination (R) is 0.930. 2 ) is 0.903.

[0295] It is important to note that the two indicators measure different quantities; Figures 5a-5c consider the total size of the wound, while Figure 4 considers the tissue inside the wound. This difference is due to the product of length and width being R2 This is shown in Figure 5c, where the value is =0.903, indicating a strong linear decrease. In contrast, Figure 4 shows rapid early granulation tissue formation and epithelial proliferation, as well as proliferation saturation after several days. This suggests that observing these two metrics together is best for a full understanding of the wound healing process.

[0296] The dramatic wound healing results observed in this study suggest the enhancement and synergistic effects of cannabinoids, terpenes, and flavonoids.

[0297] (Example 3: Open-label test) The Open-Lanbell trial was initiated in a cohort of stagnant, refractory wounds, consisting of chronic cases with an average duration of more than two years, and treated with the topical formulation of the present invention. This topical formulation was applied directly to the wound bed, and in some cases, directly to the wound bed and surrounding area. All cases had already received all available evidence-based medical treatment in accordance with topical best practices and wound bed pretreatment principles. All patients provided informed consent to receive experimental treatment.

[0298] The patient recruitment guidelines are summarized below: ● "Complex wounds" affect "complicated patients" ● 33 patients with 42 cases of refractory wounds ○ 31 patients with wounds accompanied by a skin membrane ○ Two patients with wounds involving mucous membranes ● Wound diagnosis: ○ Venous lower extremity ulcers (16 cases of wounds) ○ Autoimmune diseases (including pyoderma gangrenosum, rheumatoid arthritis, microscopic polyangiitis, and polyarteritis nodosa) (10 wound cases) ○ Non-uremic calciphylaxis (3 cases of wounds) ○ Uremic calciphylaxis (2 cases of wounds) ○ Diabetic foot ulcer (1 case of wound) ○ Pressure ulcers (2 cases of wounds) ○ Postoperative wounds (2 cases of wounds) ○ Sickle cell disease (3 cases of wounds) ○ Malignant wound (1 case of wound) ○ Mucous membranes (including the membranes around the vagina and anus) (2 cases of wounds) ● Duration of wound: More than 6 months (ranging from 6 months to 12 years) ○ Gender ■ 24 out of 33 cases: Female ■ 9 out of 33 cases: Male ○ Age ■ Average age = 70.5 years old ■ Range: 28.5~90.5 ○ General condition: (Score of 100% for a perfectly healthy person) ■ Average=70.0% ■ Range: 30%~100% ○ M3 Multiple Illness Index (score of 0 for a perfectly healthy person) ■ Average=3.16 ■ Range: 0.12~6.91

[0299] Identify the topical preparation used in the treatment using the table below (Table 1).

[0300] [Table 1A]

[0301] [Table 1B]

[0302] Of the 33 patients studied, complete wound closure was observed in 23, progressive wound closure in 7, and significant wound closure was not observed in 2 (one had severe diabetic Charcot foot and osteomyelitis, and the other was diagnosed with a malignant tumor). One patient with two wounds was not followed up. All patients except the one who was not followed up experienced clinically adequate pain relief within 5–7 days. A decrease in opioid analgesic use and systemic antibiotic use was also observed, and no systemic or local adverse reactions were observed. No patients underwent amputation.

[0303] (Example 4: Further testing of topical formulations of cannabinoids, terpenes, and flavonoids) Topical formulations were prepared in aliquots using the following proportions: For F21, F22, and F27-F30, the specified amounts of CBD and THCa were supplied in 2 ml of total oil; for F23 and F24, the specified amount of THCa was supplied in 2 ml of total oil and the specified amount of CBD in 4 ml of total oil; and for F25 and F26, the specified amount of CBD was supplied in 3 ml of total oil.

[0304] [Table 2]

[0305] Nine refractory wounds were treated with formulations F21-F30. Formulations F21, F23, F25, F27, and F29, which are mixtures of hyaluronic acid and aloe vera gel, were applied to the wound bed. Formulations F22, F24, F26, F28, and F30, which are formulated with a liposome base, were applied to the area surrounding the wound.

[0306] The nine patients suffered from the following diseases: ● Vascular disease ○ Pyoderma necrotizing (2 patients treated with F23 and F24 - 3 wounds; 1 patient treated with F27 and F28) ● Vascular diseases ○ Uremic calciphylaxis (one patient treated with F25 and F26; two legs with multiple wounds; see subsequent case reports for this example) ○ Non-uremic calciphylaxis (two patients treated with F25 and F26; three legs with multiple wounds; see subsequent case reports for this example) ○ Sickle cell disease (one patient treated with F21 and F22; two legs with three wounds; see subsequent case reports for this example) ○ Leukocytosis-destroying vasculitis (one patient treated with F28 and F29) ○ Porekeratosis (One patient treated with F29 and F30: See subsequent case reports for details.)

[0307] The following therapeutic benefits were observed. ● Relief of wound-related pain (WRP): Clinically significant pain relief (over 30% on an 11-point pain scale) was observed within 5-10 minutes of topical application, and systemic opioid use decreased by 30-50%; ● Promotion of wound closure and wound healing / maturation; and ● Reduced scar tissue formation and reduced skin fibrosis: No hypertrophic scars were formed, no induration was observed, and the treatment showed excellent cosmetic effects without the occurrence of bevel defects.

[0308] When wound bed preparations and surrounding wound preparations were used in combination, wounds closed an average of 1.3 times (1.2 to 1.5 times) faster compared to when wound bed preparations were used alone (cm²). 2 ( / day). Furthermore, with the use of THCa, wounds closed an average of 5.3 times (2 to 7 times) faster compared to when THCa was not used (cm). 2 ( / day). Furthermore, with the use of linalool, wounds closed an average of 3.8 times (3.2 to 4.3 times) faster compared to wounds not using linalool (cm). 2 / day).

[0309] Treatment of sickle cell disease lower leg ulcers This case report of a patient with sickle cell disease demonstrates the efficacy of the topical formulation disclosed in this example. This treatment was found to promote wound closure of refractory, non-healing wounds that had persisted for more than 6 months and had failed to respond to all available best-practice treatments.

[0310] A 44-year-old woman was a chronic disease patient with a 12-year history of recurrent chronic ulcers, including both lateral ankles and the left medial ankle. She had a Palliative Performance Scale score of 60% (compared to 100% for healthy individuals) and an M3 Multimorbidity Index score of 3.35 (compared to two-thirds of people in the typical population scoring zero). This patient also had right heart failure and peripheral vascular disease, with hemoglobin levels ranging from 65 to 75 g / L and oxygen saturation consistently below 90%.

[0311] This patient was treated with daily topical application of F21 and F22 to three wound sites located on her right lateral ankle, left medial ankle, and left lateral ankle. For each wound site, she first applied F21 to the wound bed and F22 to a 4-6 cm radius cuff of the pericutaneous skin. She then applied one layer of Jelonet® and one layer of Mesorb® on top, followed by spiral bandaging of the lower limb using gauze cling rolls, Comprilan, and Easifix in sequence. Wound size was estimated by taking daily photographs with a smartphone.

[0312] On day 0 of treatment, the size of the wounds on the patient's right lateral, left medial, and left lateral sides was 11.0 cm each. 2 1.8cm 2 , and 5.4cm 2 It was estimated that the wound on the left medial ankle closed completely on day 24. On day 45, the wounds on the right lateral and left lateral ankles closed 97% and 98.5%, respectively. Using a linear regression model, the wound closure rate was estimated to be 0.30 cm for the wounds on the right lateral, left medial, and left lateral ankles, respectively. 2 / day, 0.062cm 2 / day, and 0.15cm 2 The rate was per day. Expressed as a percentage, the three wounds closed at rates of 2.7% / day, 3.5% / day, and 2.8% / day, respectively.

[0313] After 45 days, the patient discontinued treatment and was lost to follow-up until day 97, when she was hospitalized with sepsis due to cholecystitis. Her wounds on the right and left lateral ankles measured 11.14 cm. 2and 7.46cm 2 The condition had worsened to the point where it was larger than the size of the wound on day 0. Her left medial wound remained closed. The patient agreed to resume the same daily topical application of F21 and F22 to the remaining two wound sites.

[0314] Fifty-three days after admission, both remaining wounds had completely closed. The wound closure rate for the right and left lateral ankles was 0.22 cm. 2 / day (or 1.9% / day) and 0.13cm 2 The rate was / day (or 1.7% / day). The progress of the treatment is shown in Figure 7.

[0315] Treatment of refractory non-uremic calciphylaxis (NUC) lower leg ulcers This study included two elderly Caucasian women with refractory NUC lower leg ulcers lasting more than 6 months. F25 and F26 were applied daily to both the wound bed and surrounding tissue until complete wound closure was achieved. Wounds were photographed regularly, and the digital images were subjected to area measurement analysis to objectively quantify the degree of granulation and epithelialization. The use of analgesics as a surrogate / substitute for pain scores was also tracked. The cohort had a mean M3 multi-illness index of 3.31. Complete wound closure was achieved in a mean of 76.3 days. In addition, analgesics were not required after a mean of 63 days. This treatment was well-tolerated with no adverse reactions.

[0316] method Two female patients with painful, non-healing lower leg ulcers lasting more than six months were referred to a community consultation wound management clinic in Toronto, Canada. Both patients had failed to follow all available best practices, including WBP (Wound-Based Blistering). Topical preparations F25 and F26 were applied daily to the wound bed and surrounding tissue.

[0317] F25 and F26 are chemically equivalent, but are formulated in separate vehicles that promote absorption through the wound bed and intact skin, respectively. Daily treatment was continued until the wound bed was 100% epithelialized, which is defined as complete wound closure.

[0318] At the initial consultation, the degree of overall medical complexity was calculated using the M3 Multi-Disease Index tool. In addition, both patients consented to 4 cm punch biopsy of the wound for histopathological and immunofluorescence evaluation, and NUC was confirmed. After gentle irrigation with sterile saline, a uniform thin layer of F25 was applied daily to the wound bed of each patient, and a uniform thin layer of F26 was applied daily to the 4-6 cm radius cuff of the peripheral epithelium. The tissue was then covered with one layer each of Jelonet and Mesorb, and subsequently the lower extremity was spirally bandaged using gauze cling rolls, Comprilan, and Easifix sequentially at the level of the metatarsophalangeal joint and between the knee cavity.

[0319] To track treatment outcomes and perform statistical analysis, wound images were acquired using smartphone cameras (iPhone® 6 and XS, Apple Inc.). Using simple area measurement wound image analysis techniques, the contours of the wound area in each image were manually drawn, and relative changes in wound area and relative changes in wound composition were calculated in terms of granulation tissue formation and re-epithelialization. The data were also fitted to a linear regression model to report overall trends and estimated time for complete wound closure. Daily use of opioid analgesics was pre-documented as a surrogate / substitute for monitoring and measuring pain severity. The examination results for each patient, described below, are shown in the table (Table 3) below.

[0320] [Table 3]

[0321] Patient A An 85-year-old Caucasian woman presented with a 6-month history of a painful ulcer on her right leg. Her medical history included chronic congestive heart failure, valvular heart disease, pulmonary hypertension, moderate dementia, type 2 diabetes mellitus, atrial fibrillation (Xarelto 2.5 mg bid), systemic hypertension, osteoarthritis, surgically fused right ankle, and hyperlipidemia. Her M3 comorbidity index was 3.59. Patient A was unable to express her pain level on a numerical rating scale. However, her caregiver stated that at the start of this study, the patient had never experienced a similar level of distress. Her caregiver shared a suspected history of "allergy" to potent opioids, and therefore chose to use only TYLENOL and codeine No. 3 tablets, USP (300 mg / 30 mg) to relieve pain.

[0322] During clinical examination, patient A had five necrotizing ulcers, including one on the anterolateral aspect of her right leg. Mild venous lymphedema was observed.

[0323] Twenty-seven high-quality images of this wound area, taken over 74 days, were available for analysis, and representative images at different stages of treatment are shown in Figure 8A. This wound area was 50% closed on day 37 and completely closed on day 74 (2.5 months). According to the linear regression model, the wound was predicted to close in 77.0 days (fitted slope = -1.4% / day), as shown in Figure 8B.

[0324] Area-based wound image analysis was used to evaluate the overall phenotypic changes in the wound bed during the treatment phase, and the results are shown in Figure 8C. The following characteristic two-stage wound closure process was observed: In the first half of the treatment, granulation tissue formation dominated the wound healing process, and the reduction in total wound area was relatively small (slope of granulation tissue formation over the first 34 days = +1.8% / day). In the second half of the treatment, the re-epithelialization process rapidly caught up by replacing granulation tissue and rapidly shrinking the wound area, achieving final wound closure (slope of re-epithelialization from day 34 to closure = +1.8% / day).

[0325] Regarding pain management, Patient A initially required 10 TYLENOL and Codeine No. 3 tablets per day. By day 18, the amount of analgesia needed had decreased by 33%, which was comparable to a clinically significant degree of analgesia. By day 57 of treatment, the patient no longer required TYLENOL and Codeine No. 3 tablets for pain relief.

[0326] patient B A 69-year-old Caucasian woman presented with an 8-month history of painful ulcers on her right leg and a 4-month history of ulcers on her left leg. Her medical history included type 2 diabetes mellitus, rheumatoid arthritis, systemic hypertension, osteoarthritis, and hyperlipidemia. Her M3 comorbidity index was 3.02. For three weeks prior to the start of the study, Patient B was completely bedridden due to severe pain and relied on others for personal care.

[0327] Clinical examination revealed that patient B had numerous necrotizing ulcers on both legs, which were spread circumferentially. Mild venous lymphedema was also observed.

[0328] Approximately 44 high-quality images of the posterior lateral aspects of both legs, taken over 81 days, were included in the analysis for each leg and are shown in Figures 9A and 9B, respectively. As shown in Figure 9C, the wound area on the left leg was found to be 50% closed at approximately 36-41 days and completely closed at 79 days (2.6 months) (fitted slope = -0.8% / day). The wound on the right leg healed somewhat faster overall (Figure 9D). It was 50% closed at approximately 32-36 days and completely closed at 74 days (2.4 months) (fitted slope = -1.2% / day).

[0329] Area-measured wound image analysis revealed a two-layered wound healing response very similar to that of patient A described above, as shown in Figure 9E. The first half of the treatment was characterized by an increase in granulation tissue (gradient of granulation formation over the first 25 days: left leg = +2.3% / day, right leg = +1.1% / day), while the second half was characterized by rapid re-epithelialization and wound closure (gradient of re-epithelialization from day 25 to closure: left leg = +1.5% / day, right leg = +1.8% / day).

[0330] Patient B initially required 188 mg of oral morphine sulfate equivalent per day. By day 19, her analgesic needs had decreased by 33%, which was comparable to clinically significant analgesia. By day 21, she began walking with assistance, and by day 54, she was fully mobile and independent. By day 68 of treatment, she no longer required any analgesics.

[0331] Throughout this trial, no patients experienced any significant systemic, local, or localized side effects.

[0332] Treatment of uremic calciphylaxis lower leg ulcers This case report of a patient with uremic calciphylaxis lower leg ulcer further demonstrates the efficacy of the topical formulation disclosed in this example. This treatment was found to promote wound healing in patients with high levels of comorbidities suffering from refractory, non-healing wounds.

[0333] A 74-year-old woman with bilateral leg ulcers lasting more than 12 months presented with large necrotic wounds on both legs that were excised in this study. Biopsy confirmed the diagnosis of uremic calciphylaxis. The patient also suffered from end-stage heart failure and peripheral vascular disease, and was undergoing hemodialysis for end-stage diabetic nephropathy. She was extremely frail, sarcopenic, had a palliative performance scale score of 50% (compared to a healthy control score of 100%), and an M3 multi-illness index of 4.79 (compared to a score of zero for two-thirds of people from the typical population). Throughout the course of her treatment in this study, her mean hemoglobin was 91 g / L, and her oxygen saturation was consistently below 90%. The patient had medical contraindications to other available experimental treatments.

[0334] This patient was treated with daily topical application of F25 and F26 to two wound sites located on the lower part of her left and right legs. For each wound site, she first applied F25 to the wound bed and F26 to a cuff with a radius of 4-6 cm around the perivascular skin. She then applied one layer of Jelonet® and one layer of Mesorb® on top, followed by spiral bandaging of her lower limbs using gauze cling rolls, Comprilan®, and Easifix® in sequence. The patient died before the completion of treatment due to cardiac conditions, resulting in a total treatment period of 21 days. Due to her three hemodialysis sessions per week, the application of the preparations over the 21-day period was limited to only 11 times. Digital images were taken on days 0, 7, and 21 of treatment to estimate wound size. The images were analyzed using area measurement image analysis.

[0335] Retrospective review of images showed a 9% and 5% reduction in overall wound size in the left and right legs, respectively, by the end of the 3-week treatment period. A significant increase in tissue granulation in the wound bed was also observed, with granulation forming on day 21 for 59% and 78% of the total wound size in the left and right legs, respectively. Throughout the course of this treatment, the patient experienced no local or systemic adverse reactions.

[0336] Treatment of chronic arterial and venous ulcers complicated by porokeratosis A 90-year-old male presented with a refractory circumferential right leg ulcer that had persisted for more than two years. Due to the chronicity of his arterial-venous ulcer, the patient developed extensive porokeratosis. The wound was treated with daily topical application of formulation F29 to the wound bed and daily topical application of F30 to the peri-wound area. The wound was photographed regularly, and the digital images were subjected to area metric analysis to quantify the degree of epithelialization. The initial size of this wound was approximately 176 cm². 2 This was estimated. Using a linear regression model, the wound closure rate over this treatment period was 1.57 cm. 2 The rate was either per day or 0.87% per day as a percentage of the total wound area (Figure 10).

[0337] (Example 5: Case report of medical cannabis for the alleviation of malignant wounds) A 44-year-old male with an lateral proliferative (mycelial) wound on his right cheek had been diagnosed with squamous cell carcinoma of the right buccal cavity three years prior. He had undergone surgical removal of the tumor and subsequently received external beam radiation therapy and chemotherapy. Despite this appropriate cancer treatment, he developed a recurrence in his cheek, which eventually eroded the cheek, resulting in an oral-cutaneous fistula and associated lateral proliferative lesions. For two years prior to treatment with medical cannabis (MC), he chose to opt for treatment primarily through natural therapies, moving away from further conventional cancer treatments. Despite the use of high doses of hydromorphone, pregabalin, and dexamethasone, he continued to experience persistent (unremarkable) generalized right hemifacial pain, along with voluntary incidental pain associated with changes in wound dressings (wound-related procedural pain). He rated his average daily pain score as 9 out of 10. In addition, he also reported analgesic side effects such as constipation and drowsiness. He also reported suffering from severe aesthetic distress due to facial deformity, along with difficulty opening his mouth on the right side, depression, insomnia, nausea, and loss of appetite.

[0338] At the outset, he was proposed to test TWEED's vaporized MC (ARGYLE®; THC 7.25% + CBD 8.21%) delivered via a certified Volcano® vaporizer unit. A specific system was strategically selected to maximize the analgesic effects of the THC and CBD therapy, and furthermore, to mitigate the analgesic and psychotropic side effects commonly experienced with high-dose THC systems.

[0339] At his second consultation, he reported a significant reduction in baseline and voluntary incidental pain management. He stated he was using 0.5–1.0 g of dried cannabis per day, vaporizing it every 2–4 hours and every 15 minutes before changing his wound dressings daily. His pain relief was so remarkable that it allowed him to discontinue pregabalin and dexamethasone, and even reduce hydromorphone to about 25% of the pre-MC dose. He also reported reduced trismus and nausea, as well as improved appetite, sleep, and efficacy. Importantly, he reported no adverse effects from MC. Furthermore, his overall general condition and symptom control were good enough to allow him to reschedule his work as a healthcare professional.

[0340] During his third and fourth visits, his malignant wound was observed to have increased in size, his general condition had only slightly deteriorated, his average daily pain score remained within an acceptable range, and his required daily opioid use had even slightly increased. Unfortunately, his limited mouth opening and oral-cutaneous fistula made the continued use of vaporized MC technically difficult.

[0341] Having experienced such positive results with MC therapy, the patient was eager to continue through an alternative delivery system. Therefore, we suggested he try topical MC formulated with non-genetically modified organic sunflower oil (TWEED's ARGYLE THC 5.24% + CBD 8.02%). He was instructed to apply 1-2cc of MC oil digitally to the entire malignant wound, both externally and intracheekly. He was also advised to swirl and swallow any remaining oil in his mouth.

[0342] At his fifth consultation, he reported consistently using topical MC four times a day. He stated that pain relief began 10-15 minutes after application and lasted up to 2 hours after application. He did not report any negative experiences with the use of topical MC. Between his fourth and fifth consultations, his condition began to worsen overall, and he requested to double his daily opioid use. Interestingly, the size of his malignant wound decreased by approximately 5% over a 4-week interval.

[0343] Four weeks after his last medical examination, he was admitted to an acute general hospital due to hypovolemia. As a result, he became unreachable, and the use of MC was discontinued upon his admission. He died three weeks later.

[0344] Table 1 (Table 4) summarizes the clinical course of his treatment with MC over a five-month period.

[0345] [Table 4]

[0346] This case report suggests that MC may provide effective pain and symptom management in malignant wound settings. The rapid onset of analgesia after local placement suggests that the effect was mediated through the absorption of THC and CBD cannabinoids, which subsequently interact with peripheral nociceptors, immune cells, and cancer cells. Post-application analgesia may be due to gastrointestinal absorption of ingested residual MC oil.

[0347] (Example 6: Three case reports of topical medical cannabis in the treatment of patients with pyoderma gangrenosum) Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic skin disease. 50–70% of cases occur in the context of inflammatory arthritis, inflammatory bowel disease, hematological disorders, and solid neoplasms, while the remainder are idiopathic. Classically, it presents as a skin ulcer, most commonly occurring on the lower extremities. PG presents significant challenges from both a diagnostic and therapeutic standpoint. PG is often misdiagnosed as cellulitis, venous lower extremity ulcers, and arterial ulcers. Pain is a common symptom of PG, with most patients suffering from high levels of pain that is often resistant to high-dose systemically administered opioid analgesics. Because PG lesions are chronic and prone to recurrence, they can significantly impair quality of life over the long term.

[0348] method Prior to initiating topical medical cannabis (TMC), all patients underwent a complete medical examination and submitted informed consent regarding the use of this experimental procedure. All patients also underwent wound biopsies for histopathological and immunofluorescence examinations to rule out other medical conditions. For all three cases, patients reported a mean daily pain score based on an 11-point numerical rating scale (0-10), and the mean daily opioid use (morphine sulfate equivalents in mg / day) was assessed before and after initiating TMC treatment. A paired t-test was used to compare the mean daily pain score before TMC with the mean value after TMC for all three cases. The percentage reduction in mean daily pain score after initiating TMC was also determined for each case. For mean daily opioid intake, a paired t-test was used to compare the mean morphine sulfate equivalents (MSE) used before TMC with the mean value after TMC for cases 1 and 2 only. In Case 3, the mean MSE used was zero both before and after the start of TMC treatment, making a paired t-test comparison impossible. For all hypothesis tests, a P-value < 0.05 was considered significant, and a reduction in mean pain score of 30% or more was considered clinically significant. All statistical analyses were performed using GraphPad QuickCalcs Software (GraphPad Software, La Jolla, CA).

[0349] Case 1 A 50-year-old woman presented with a painful left medial lower leg ulcer that had lasted for at least 12 months. This prostatic pressure (PG) overlapped with an area of ​​sclerosing dermatoderma resulting from postphlebitis syndrome in the context of factor V Leiden deficiency. She was initially treated with systemic corticosteroids, intralesional corticosteroids, opioid analgesics, and an inelastic compression system. Given her persistent high levels of pain, she consented to a trial of topical MC oil (ARGYLE® THC 5 mg / mL + CBD 6 mg / mL) from TWEED (Ontario, Canada). One milliliter of TMC was applied to the wound bed daily, followed by the application of an inelastic compression bandage. The use of a multi-layer inelastic compression system eliminated the need for TMC for the disastrous pain in this case. After the initiation of TMC, she did not require further corticosteroids.

[0350] Case 2 A 76-year-old male with no complications presented with a first onset of a painful right lateral ankle ulcer. He was prescribed opioid analgesics and systemic corticosteroids both before and after the initiation of TMC. Prior to the initiation of TMC, he was also administered intrafocal corticosteroids. He continued to experience high levels of pain, and therefore he agreed to a trial of Bedrocan's MC oil (Bedrolite® THC 7 mg / mL + CBD 9 mg / mL). Due to the catastrophic pain, he applied 0.5–1.0 mL of MC oil to the wound bed twice daily, and then 1–3 times daily. The wound was covered with a non-adhesive dressing.

[0351] Case 3 A 60-year-old woman with systemic lupus erythematosus presented with a recurrent, painful right lower leg ulcer. She was prescribed systemic corticosteroids both before and after the initiation of TMC. She had a history of side effects from opioid analgesics and therefore refused their use. She used acetaminophen 325–650 mg every 6 hours as needed for pain. Given her high level of pain, she agreed to a trial of Bedrocan's MC oil (Bedrolite® THC 7 mg / mL + CBD 9 mg / mL). Due to the breaking pain, she applied 0.5–1.0 mL of MC oil to the wound bed twice daily, and then 1–3 times daily. The wound was covered with a non-adhesive dressing.

[0352] result The data collected in advance in Tables 2 (Table 5) and 3 (Table 6) reflect clinical observations of 17, 21, and 23 weeks, respectively, for cases 1-3 before TMC, and 33, 9, and 21 weeks, respectively, for cases 1-3 after TMS. Each of the three patients reported consistently experiencing the onset of analgesia within 3-5 minutes of each application. After the initiation of TMC treatment, the mean 1-day pain score for cases 1 and 2 decreased statistically significantly (P<0.05) (Table 2 (Table 5)). In addition, all cases showed "clinically significant" pain reduction exceeding the generally accepted threshold of 30% cited in international pain studies (Younger et al., Curr. Pain Headache Rep. 2009;13:39-43). In Case 1, the mean pain score decreased from 8.25 to 2.76, a clinically and statistically significant (P=0.0007) decrease of 66.5%. In Case 2, the mean pain score before TMC was 8.75, and it decreased to 2.33, a clinically and statistically significant (P=0.0006) decrease of 73.4%. Finally, in Case 3, the mean pain score decreased from 4.29 to 1.50, a clinically significant but not fully statistically significant (P=0.0720) decrease of 65%. The mean daily opioid dose, measured as MSE (mg), decreased statistically significantly after the initiation of TMC (Table 3 (Table 6)). In Case 1, the mean MSE decreased from 26.00 to 0.24 mg, a statistically significant difference (P=0.0013). In Case 2, the mean MSE decreased from 27.33 mg to 12.50 mg, which was also a statistically significant decrease (P=0.0001).

[0353] This series of cases suggests that TMC may provide opioid-saving and effective analgesia in PG contexts. The rapid onset of analgesia after topical application suggests that the effect was mediated through the absorption of cannabinoids THC and CBD, which subsequently interact with cannabinoid receptors expressed on peripheral nociceptors and immune cells.

[0354] [Table 5]

[0355] [Table 6]

[0356] (Example 7: Oral formulation for wound management) The oral formulations shown in the table below (Table 7), when used alone or in combination with the topical formulations of the present invention, promote wound healing and / or reduce wound-related pain.

[0357] [Table 7]

[0358] The use of F31 and F32 was associated with a 30–50% reduction in patient-reported analgesic use, which is a surrogate or proxy indicator of patient-reported pain scores. The use of F31 and F32 improved wound closure time by 25–50%.

[0359] Although the aforementioned invention has been described in some detail as an example and illustration to clarify its meaning, it will be readily apparent to those skilled in the art that certain modifications and alterations can be made in light of the teachings of the present invention without departing from the scope of the appended claims.

[0360] The compounds described herein may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, for example, double bond isomers (i.e., geometric isomers such as E and Z), enantiomers, or diastereomers. The disclosure includes each of the isolated stereoisomers (e.g., enantiomerically pure isomers, E and Z isomers, and other substitutes for stereoisomers), as well as mixtures of stereoisomers at varying degrees of chiral purity or percentages of E and ZE (e.g., racemic mixtures, mixtures of diastereomers, and mixtures of E and Z isomers).

[0361] Accordingly, the compounds described herein encompass all possible enantiomers and stereoisomers, including, for example, sterically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomer mixtures and stereoisomer mixtures. Enantiomer mixtures and stereoisomer mixtures can be separated into enantiomers or stereoisomers of their components using separation techniques or chiral synthesis techniques known to those skilled in the art. This disclosure includes each of the isolated stereoisomer forms, and mixtures of stereoisomers at varying degrees of chiral purity (e.g., racemic mixtures). This disclosure also encompasses various diastereomers.

[0362] If a chemical name does not specify an isomer of the compound, the chemical name indicates either a possible isomer of the compound or a mixture of these isomers. The compound may also exist in several tautomers. Therefore, the compounds described herein encompass all of their possible tautomers.

[0363] The term "tautomer" is generally understood to refer to isomers that readily transform into each other so that they can coexist together in equilibrium, and this equilibrium may strongly favor one of the tautomers, depending on stability considerations. For example, ketones and enols are two tautomers of the same compound.

[0364] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" also include plural references unless otherwise explicitly indicated by the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the invention pertains.

[0365] When used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, that is, elements that exist in some cases conjugately and in other cases separately. Multiple elements enumerated by "and / or" should be interpreted similarly, that is, "one or more" of the elements so combined. Other elements may optionally exist in addition to those specifically identified by the "and / or" clause, whether or not they are related to the specifically identified elements. As a non-restrictive example, when used in combination with open-ended language such as "includes," for example, in one embodiment, it may refer to A only (optionally including elements other than B); in another embodiment, it may refer to B only (optionally including elements other than A); and in yet another embodiment, it may refer to both A and B (optionally including other elements).

[0366] As used herein and in the claims, “or” should be understood to encompass the same meaning as “and / or” as defined above. For example, if items in a list are separated, “or” or “and / or” should be interpreted as inclusive, that is, encompassing at least one (but more than one) of the elements of a list and any additional, optional, unlisted items.

[0367] Where used herein, the transitional terms “comprising,” “including,” “having,” “containing,” “involving,” and similar terms should be understood to be either comprehensive or open-ended (i.e., including but not limited) and they do not exclude any elements, materials, or processes of methods not enumerated. Only the transitional phrases “consisting of” and “essentially consisting of” are closed or semi-closed transitional phrases with respect to the claims and the paragraphs describing exemplary embodiments herein. The transitional phrase “consisting of” excludes any elements, processes, or components not specifically enumerated. The transitional phrase “essentially consisting of” limits its scope to specific elements, materials, or processes that do not substantially affect the fundamental characteristics of the invention disclosed and / or claimed herein.

Claims

1. (a) One or more cannabinoids in a concentration of 0.1 mg / ml to 40 mg / ml; (b) One or more terpenes selected from beta-caryophyllene, linalool, and alpha-bisabolol, in a concentration of 25 mg / ml to 1000 mg / ml; and (c) One or more flavonoids selected from quercetin, diosmin, kaempferol, apigenin, hesperidin, cannaflavin, chrysin, luteolin, and rutin, in a concentration of 10 mg / ml to 500 mg / ml; A topical formulation for direct application to external wounds, including, A topical preparation comprising one or more of the aforementioned cannabinoids, each containing at least 0.1 mg / ml of tetrahydrocannabinolic acid.

2. The topical formulation according to claim 1, wherein the one or more cannabinoids further comprises cannabidiol or cannabidiolic acid.

3. The topical formulation according to claim 1 or 2, wherein the one or more terpenes include beta-caryophyllene, and the concentration of beta-caryophyllene is 50 mg / ml to 500 mg / ml.

4. The topical formulation according to any one of claims 1 to 3, wherein the one or more terpenes further comprises linalool, and the concentration of linalool is 25 mg / ml to 500 mg / ml.

5. The topical formulation according to any one of claims 1 to 4, wherein the one or more flavonoids comprises at least one of diosmin, quercetin, and hesperidin.

6. The topical formulation according to any one of claims 1 to 5, wherein the one or more flavonoids comprises diosmin, quercetin, and hesperidin.

7. The topical formulation according to any one of claims 1 to 6, further comprising a liquid carrier selected for dropping the topical formulation onto an external wound.

8. A first topical formulation for the treatment of a target external wound, wherein the first topical formulation comprises one or more cannabinoids; one or more terpenes selected from beta-caryophyllene, linalool, and alpha-bisabolol; and one or more flavonoids selected from quercetin, diosmin, kaempferol, apigenin, hesperidin, cannaflavin, chrysin, luteolin, and rutin, and is for application to the external wound, wherein the one or more cannabinoids comprises at least 0.1 mg / ml of tetrahydrocannabinolic acid.

9. The first topical formulation according to claim 8, used in combination with a second topical formulation comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids, wherein the second topical formulation is for application to a peri-wound area surrounding the exocutaneous wound.

10. The first topical formulation according to claim 9, wherein the first topical formulation comprises aloe vera gel and hyaluronic acid gel, and the second topical formulation comprises pluronic lecithin organogel or a transdermal base containing a liposome component.

11. The first topical preparation according to any one of claims 8 to 10, wherein the first topical preparation is the topical preparation according to any one of claims 1 to 7.

12. The first topical formulation according to claim 11, wherein the second topical formulation is the topical formulation according to any one of claims 1 to 7.

13. A first topical formulation according to any one of claims 8 to 12, to be used in combination with an oral formulation comprising one or more cannabinoids; one or more terpenes; and one or more flavonoids.

14. The first topical formulation according to any one of claims 8 to 13, wherein the cutaneous wound is caused by a skin disease or condition, the skin disease or condition being skin cancer, vascular ulcers and erosions, microbial cutaneous ulcers and erosions, ulcers and erosions caused by diabetes, vesicular skin conditions, ulcers and erosions caused by autoimmune diseases, vasculitic ulcers and erosions, or ulcers and erosions caused by other complex diseases selected from hidradenitis suppurativa, chronic lichen simplex, lichen sclerosing, lichen planus, Wegener's granulomatosis, cryoglobulinemia, Behçet's disease, cryofibrinogenemia, antiphospholipid antibody syndrome, allergic dermatitis, psoriasis, or porokeratosis.

15. The skin cancer is selected from primary tumors, metastatic tumors, or Bowen's disease; the vascular ulcers and erosions are selected from sickle cell disease, Maltrell's ulcer, uremic calciphylaxis, non-uremic calciphylaxis, venous lower extremity ulcers, or arterial ulcers; the microorganisms are selected from bacteria, fungi, viruses, or Mycobacterium; the ulcers and erosions caused by diabetes are diabetic foot ulcers, diabetic lipoids, etc. The first topical formulation according to claim 14, wherein the vesicular skin condition is selected from necrotosis or diabetic skin disorder; the vesicular skin condition is selected from epidermolysis bullosa, pemphigus, or bullous pemphigoid; the autoimmune disease is selected from pyoderma gangrenosum, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or morphea; and the vasculitic ulcers and erosions are selected from cutaneous vasculitis, leukocytosis vasculitis, cutaneous polyarteritis nodosa, or microscopic polyangiitis.

16. The first topical formulation according to any one of claims 8 to 15, in the form of an aerosolized spray for nasal or oral application to mucosal wounds.

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