TOPICAL FORMULATIONS AND METHODS FOR BIOACTIVE & BIOAVAILABLE NARINGENIN FOR TREATING SKIN CONDITIONS

TECHNICAL FIELD

The disclosure relates to shelf-stable formulations of naringenin—with and without its glucosidic form naringin—and methods for the treatment of human skin, for example, for the prevention, treatment, or maintenance of inflammatory skin conditions, irritated skin, skin redness, uncomfortable skin and/or for improvement in skin barrier function.

BACKGROUND

The endeavor to improve skin barrier function and relieve or “calm” chronic or acute symptoms of irritation, inflammation, “hot” and “angry” skin—which are characteristic of a compromised skin barrier—remains a central focus for both the cosmetic and pharmaceutical industries. In addition, therapeutic experts, including dermatologists and estheticians, have not adopted a single, accepted treatment for these conditions outside of topical corticosteroids and, to a much lesser degree, topical hypochlorous acid solutions.

The demand and consumer need for products that address skin redness, inflammation and symptoms of sensitive and/or sensitized skin has grown rapidly in recent years. Analysis of volume of related search engine terms using Google Trends demonstrates this growth, as shown in FIGS. 9A and 9B.

Many skin conditions related to these symptoms result in chronic inflammation stemming from a number of causes, e.g., UV radiation. Chronic inflammation can cause a number of skin conditions such as rosacea, psoriasis, eczema, etc. Resolution of these conditions has become a focus of current marketing and consumer attention and a large demand exists for products that may treat or alleviate such conditions.

Some research has found efficacy for treatment of ultraviolet B (UVB) irradiation-induced skin inflammation in mice. See, e.g., Martinez et al, Topical Formulation Containing Naringenin: Efficacy against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice, Published Jan. 7, 2016. However, even that research acknowledges that naringenin is highly unstable and quickly experiences oxidative degradation with exposure to light, oxygen, or heat, inhibiting widespread use of naringenin formulations for treatment. Specifically, the study observes that naringenin's instability in the presence of oxygen and water simultaneously—which, the study notes, is problematic for delivering naringenin as a treatment outside of a clinical research setting. Further, the study proposes a formulation in which naringenin is suspended in the non-aqueous, polymer-based excipient, Carbopol 940, as a solution to this stability problem. However, the study fails to demonstrate via an in vivo measurement of naringenin skin levels before and after topical application of this formulation, whether or not naringenin could be absorbed percutaneously (through the outer layer of the skin) from this vehicle to be made bioavailable to the skin cells beneath. The study has not been expanded upon since its publishing in 2016 and no naringenin-based topical solutions have been brought to market for any purpose, despite a clear market demand for treatment of skin conditions.

A need exists for an effective treatment of a wide variety of skin conditions in humans that is shelf-stable and viable for widespread distribution and treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

Non-limiting and non-exhaustive embodiments are described in reference to the following drawings. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the disclosure. In the drawings, like reference numerals refer to like parts through all the various figures unless otherwise specified.

For a better understanding of the present disclosure, a reference will be made to the following detailed description, which is to be read in association with the accompanying drawings, wherein:

FIG. 1 shows a structure of a naringenin molecule in accordance with the disclosure;

FIG. 2 shows a structure of a naringin molecule in accordance with the disclosure;

FIG. 3 shows a demonstration of inflammation improvement on human skin in accordance with the disclosure;

FIG. 4 shows a demonstration of a visible anti-inflammatory effect in accordance with the disclosure;

FIG. 5A shows a human test subject's skin prior to treatment;

FIG. 5B shows the human test subject skin of FIG. 5A one hour post-treatment in accordance with the disclosure;

FIG. 5C shows human test subject skin of FIG. 5A twenty-four hours post-treatment in accordance with the disclosure;

FIG. 6A shows the human test subject's skin of FIG. 5A including a visual overlay of visual results of a Gaussian redness calculation;

FIG. 6B shows the human test subject's skin of FIG. 5A one hour post-treatment in accordance with the disclosure along with visual results of a Gaussian redness calculation;

FIG. 6C shows the human test subject's skin of FIG. 5A twenty-four hours post-treatment in accordance with the disclosure along with visual results of a Gaussian redness calculation;

FIG. 7A shows another human test subject's skin with an untreated portion of skin and a portion of skin one hour post-treatment accordance with the disclosure;

FIG. 7B shows the human test subject's skin of FIG. 7A twenty-four hours post-treatment of the treated portion in accordance with the disclosure;

FIG. 8A shows the human test subject's skin of FIG. 7A including a visual overlay of visual results of a Gaussian redness calculation;

FIG. 8B shows the human test subject's skin of FIG. 7A twenty-four hours post-treatment of the treated portion in accordance with the disclosure 7A including a visual overlay of visual results of a Gaussian redness calculation;

FIG. 9A shows a graph demonstrating trends of volume of related search engine terms for anti-inflammatory beauty products; and

FIG. 9B shows a graph demonstrating trends of volume of related search engine terms related to sensitive skin.

Persons of ordinary skill in the art will appreciate that elements in the figures are illustrated for simplicity and clarity so not all connections and options have been shown to avoid obscuring the inventive aspects. For example, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are not often depicted in order to facilitate a less obstructed view of these various embodiments of the present disclosure. It will be further appreciated that certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not required. It will also be understood that the terms and expressions used herein are to be defined with respect to their corresponding respective areas of inquiry and study except where specific meanings have otherwise been set forth herein.

SUMMARY

The following presents a simplified summary of the present disclosure in order to provide a basic understanding of some aspects of the disclosure. This summary is not an extensive overview of the disclosure. It is not intended to identify key or critical elements of the disclosure or to delineate the scope of the disclosure. The following summary merely presents some concepts of the disclosure in a simplified form as a prelude to the more detailed description provided below.

In an embodiment, the disclosure describes a method for treating skin disease. The method may include applying to the affected areas of the skin a naringenin formulation with and without naringin having an amount of naringenin with and without naringin effective to reduce or inhibit inflammatory and/or immune processes. In some embodiments, the method may include applying the formulation as an alternative or adjunct therapy to topical or oral corticosteroid. In some embodiments, the formulation may be applied as an alternative or adjunct therapy to topical or oral corticosteroid and/or topical or oral antibiotic. In some embodiments, the naringenin and/or naringin formulation may be applied to affected areas from 1 to about 10 times daily. In some embodiments, the naringenin and/or naringin may be applied to affected areas from 1 to about 5 times daily.

In another embodiment, the disclosure describes a method for treating a skin condition in a human patient. The method may include applying, to one or more affected areas of the human patient's skin, a naringenin formulation having an amount of naringenin effective to reduce or inhibit inflammatory processes.

In another embodiment, the disclosure describes a method of packaging a skin treatment product for widespread consumer treatment. The method may include providing an oxygen-free packaging environment and providing one or more product packages within the oxygen-free packing environment. The one or more product packages may be substantially non-gas permeable. The method may include, within the oxygen-free packing environment, substantially filling the one or more product packages with a naringenin formulation. The method may include sealing the one or more product packages so as to be substantially non-gas permeable.

In another embodiment, the disclosure describes a packaged treatment for treating a skin condition in a human patient. The packaged treatment may include a product package that is substantially non-gas permeable and a naringenin formulation disposed within the product package, wherein the naringenin formula may have been disposed within the product package within an oxygen-free environment.

DETAILED DESCRIPTION

In some embodiments, the disclosure describes methods of treating inflammatory conditions of the skin. Such diseases include but are not limited to hereditary defects in the skin, and conditions associated with aging or damaged skin, among others. For example, as described more fully below, the disclosure in various embodiments provides for methods of treating or managing conditions such as Rosacea, Ichthyosis, Actinic Keratosis, pruritus, and skin cancers. In other embodiments, the conditions include those with an underlying hypersensitivity, such as dermatitis (e.g., atopic dermatitis or contact dermatitis), psoriasis, and dermatitis herpetiformis, among others.

In some embodiments, the disclosed methods address both chronic and acute inflammation, creating a versatile treatment with a plethora of benefits ranging from improving the skin's appearance to the improvement of daily life. Treatment benefits of such skin agents include, but are not limited to: smoothing of skin damaged from acne scars, wound scars, markings left from diseases such as smallpox, skin blemishes, reduction or removal of age spots, skin spots, discoloration of stretch marks, discoloration due to exposure of the sun, lightening of dark skin areas to brighten skin tone for better facial glow, skin soothing and anti-inflammation, infusion of essential nutrients to promote healthy skin growth, reduction of redness in skin tone as a result from inflammation, reduction in rashes, relief from redness due to genetic and environmental abnormalities, and relief of other skin abnormalities. An overactive immune system, genetic factors, or environmental factors can cause chronic skin conditions that may lead to discomfort and self-consciousness. Improving skin function and modulating the underlying immunology may be important in the prevention, treatment, and management of skin conditions, including inflammatory conditions resulting from acute or chronic chemical, environmental, and/or biological insult; hereditary defects in skin barrier function; conditions associated with aging or damaged skin; and proliferative disorders involving the skin, among other conditions. In some embodiments, the disclosure may help treat or otherwise help moderate these and/or other skin conditions.

Those skilled in the art understand that naringenin is inherently unstable due to its molecular composition. In some embodiments, in order to be an effective, feasible widespread topical application on human skin, the disclosure describes protecting the naringenin/naringin from oxygen and ultraviolet light during manufacturing, packaging and transport up until the time of application. Exposure to such environments rapidly destabilizes the molecules and may render them ineffective for their intended purpose due to degradation and/or oxidization. Exemplary systems and method for packaging and conserving naringenin with or without naringin is described in U.S. Pat. No. 12,030,680, issued on Jul. 9, 2024 and titled SYSTEMS AND METHODS FOR OXYGEN FREE PACKAGING, the disclosure of which is incorporated by reference herein in its entirety.

Additionally, in some embodiments, the disclosure recognizes that treatment methods using naringenin with or without naringin may benefit from a tailored delivery mechanism that facilitates percutaneous absorption. This may be done via an excipient vehicle in a variety of possible formulations. Excipient vehicles may vary based on the formulation goal, such as stability of the product, extended shelf life, integrity of the naringenin and naringin molecules, or a combination of these goals. Excipient formulations may also vary based on the use of naringenin, naringin, or both-as naringin, the glycosidic form of naringenin, is itself more stable and metabolized more slowly by the skin, thus allowing for a controlled release of the flavanone over time.

These properties of naringenin contribute to the reality that, despite a long-felt need and large demand for such skin treatments, there still exists no widespread, consumer-available use for naringenin as a topical. Even studies purporting to identify potential efficacy of naringenin in treating UVB irradiated skin in mice have acknowledged these characteristics as impediments to widespread production and use of naringenin treatment in humans, providing no viable solutions or suggestions as to how treatment of human skin conditions with naringenin could be accomplished. Further, traditional methods to prevent such oxygen degradation, such as suspension in silicone or mixing with Carbopol, may inhibit adequate absorption. Due to these known challenges, development of naringenin formulations as a treatment to many widespread symptoms and conditions has not occurred. Accordingly, naringenin has not traditionally been available in topical therapeutic preparations in either the cosmetic or pharmaceutical industries.

By addressing the degradation risks and correctly facilitating bioavailability and percutaneous absorption process, this disclosure may provide use cases of naringenin/naringin for wide availability in new ways, such as through topical application in a consumable, consumer product. Overcoming these previous barriers, the disclosure demonstrates, in some embodiments, the benefit of naringenin for daily or other use on humans and provides a method of making naringenin widely available to a large consumer market in its bioavailable formulation for the first time. In some embodiments, the disclosure describes a novel, water-based naringenin solution that may provide bioavailability and percutaneous absorption of naringenin in a stable, consumer-packaged product usable to treat a wide variety of common inflammatory skin conditions and symptoms in addition to oxidative stress and prevention of cancer cell formation.

In some embodiments, the disclosed methods and formulations may remove or neutralize these significant barriers to access, providing the ability to measurably treat at least the above conditions and to address this massive, long-felt, and growing unmet consumer need.

In some embodiments, the disclosure provides the formulation and methods of treating conditions of the skin and/or conditions involving compromised skin barrier function. Such diseases may include hereditary defects in skin barrier function, proliferative conditions involving the skin, conditions associated with aging or damaged skin, immunological disorders involving the skin, among others. In some embodiments, the disclosure may include applying naringenin formulations to the affected areas to thereby ameliorate symptoms as both a non-steroidal anti-inflammatory and antioxidant ingredient. In some embodiments, the formulation and method may promote healthy apoptosis, inhibit migration, inhibit the cell cycle, inhibit tube formation of endothelial cells, inhibit or modulate immune responses, thereby allowing skin to reach a more healthy immune state. The formulation and methods may provide for balancing of systemic immune mediators and acting as an antioxidant free radical scavenger that may reduce oxidative stress due various causes, such as UV light exposure. As shown herein, in some embodiments, naringenin may inhibit inflammatory processes according to a classic dose response.

In accordance with some embodiments of the invention, the inflammatory condition may be present in a human or animal patient. In some embodiments, the patient may be a pediatric or geriatric patient, or may be immunocompromised. In some embodiments, the patient may be refractory to corticosteroid treatment or treatment with other conventional agents, such as antihistamines, immunosuppressants and immunomodulators, retinoids, antibiotics (e.g., cyclosporine), among others.

In some embodiments, the condition for treatment may be a proliferative condition involving the skin, such as squamous cell carcinoma, basal cell carcinoma, or cutaneous T-cell Lymphoma. Tumor development in the skin may be accompanied by an immune response that may lead to tumor infiltration by inflammatory cells, and consequently, local and systemic production of cytokines, chemokines and other mediators. These inflammatory mediators may be associated with cancer development.

In some embodiments, the condition for treatment may be a result of, or may be associated with, aging or damaged skin, such as Actinic keratosis, UV damage, or other physical damage to the skin barrier that results in a hypersensitivity reaction.

In various embodiments, the naringenin may be applied as an alternative or adjunct therapy to conventional treatments with corticosteroids, vitamin D ointment (or vitamin D analog), retinoid, analgesic, immunosuppressant, phototherapy, antihistamine, and anti-infective agent (e.g., antibiotic or antifungal), for example.

In other aspects, the disclosure provides naringenin formulations that may be used for treating inflammatory disorders involving the skin. The disclosed methods and formulations may dictate and satisfy some or all necessary conditions for the therapeutic utility, bioactivity and bioavailability of topical naringenin. Inflammatory disorders include, but are not limited to, rosacea, dermatitis, rashes, psoriasis, red patches, blisters, etc.

The disclosed formulation and methods may further comprise, in some embodiments, components and accompanying anaerobic manufacturing and packaging to render the naringenin formulation shelf-stable and to provide the desired physical characteristics for topical treatment of skin. For example, U.S. Pat. No. 12,030,680,issued Jul. 9, 2024 and titled SYSTEMS AND METHODS FOR OXYGEN FREE PACKAGING, the disclosure of which is incorporated by reference herein, may provide examples of such manufacturing and packaging systems and methods that may be used to render a shelf-stable formulation of naringenin. Accordingly, in some embodiments, the disclosure describes providing a naringenin formulation that has been packaged in an oxygen-free environment so as to prevent or reduce oxidative degradation and thereby increase stability. Such packaging may itself be sealed so as to prevent or substantially limit exposure to oxygen, light, and/or heat while packaged and thereby provide increased shelf stability. Increased shelf-stability provided by oxygen-free packaging and storage may alleviate traditional and long-felt concerns relating to naringenin's instability that has prevented its widespread use for effective skin treatment.

The disclosure describes, in various embodiments, applying a formula of naringenin with and without naringin, as described more fully herein, to the affected areas to thereby ameliorate or otherwise treat disease symptoms and/or dampen or alter inflammatory responses. An embodiment of the structure of a naringenin molecule is shown in FIG. 1, and an embodiment of the structure of a naringin molecule is shown in FIG. 2.

In accordance with the disclosure, naringenin, with and without naringin, may be formulated for application to the skin for the treatment of acute and chronic inflammatory conditions and diseases. While topical and systemic steroids are the most commonly prescribed medications for the treatment of inflammatory skin diseases, there is increasing awareness of the side effects and damage that can result from long-term steroid use, which include increased appetite, weight gain, sudden mood swings, muscle weakness, blurred vision, increased growth of body hair, easy bruising, lower resistance to infection, swollen, puffy face, acne, osteoporosis, worsening of diabetes, high blood pressure, stomach irritation, nervousness, restlessness, difficulty sleeping, cataracts or glaucoma and water retention or swelling, among others. Topical retinoid, topical vitamin D (and analogues thereof), antihistamine, and immunosuppressants are used for some dermatological conditions, but these agents can be associated with substantial toxicity. Further, some patients and conditions are refractory to such treatments. The naringenin formulation described herein may be used as an alternative or adjunct therapy to these agents. The naringenin formulation in various embodiments of the disclosure may comprise an amount of naringenin and naringin that is effective in reducing or inhibiting inflammation.

In accordance with the disclosure, the naringenin formulation may be administered to a patient for treating a variety of inflammatory conditions. As used herein, the term “treating” may refer to providing therapy to a patient to prevent (by means of prophylactic treatment), reduce, inhibit, ameliorate, or manage symptoms (e.g., inflammatory symptoms) of a disease, or to slow or stop the progression of the disease, as well as, in some embodiments, to prevent or reduce onset or re-occurrence of a condition or symptom. For example, in various embodiments the disclosure provides methods of treating skin to inhibit, reduce, prevent, or alter inflammatory processes including acute, chronic, and delayed reactions, thereby allowing regeneration and/or healing of tissues, and/or preventing tissue damage or loss of tissue integrity. In some embodiments, the disclosure describes methods for treating chronic inflammation. Chronic inflammation may last for weeks to months, and possibly years, in which tissue destruction and biological processes that may be intended to repair injury are simultaneously ongoing. Chronic inflammation may involve lymphocytes, macrophages, and keratinocytes, and may also include a proliferation of blood vessels, fibrosis, and/or necrosis. Chronic inflammation may result from a number of factors including persistent infections, prolonged exposure to toxic agents, genetic malady, and autoimmune reactions. Chronic inflammation is often maintained by the production of cytokines at the site of the persistent insult.

Treatment as it relates to certain inflammatory skin conditions:

Dermatitis herpetiformis (DH) may be characterized by intensely itchy, chronic papulovesicular eruptions, usually distributed symmetrically on extensor surfaces, such as buttocks, back of neck, scalp, elbows, knees, back, hairline, groin, or face. The condition may be extremely itchy. Although the first signs and symptoms of dermatitis herpetiformis may be intense itching and burning, the first visible signs are the small papules or vesicles. Dermatitis herpetiformis symptoms may be chronic, and tend to come and go. Symptoms may be accompanied by symptoms of celiac disease, commonly including abdominal pain, bloating or loose stool, and fatigue. In terms of pathology, the first signs of the condition may be observed within the dermis. The main autoantigen of dermatitis herpetiformis is epidermal transglutaminase (eTG), a cytosolic enzyme involved in cell envelope formation during keratinocyte differentiation. While immunosuppressive therapies may sometimes be administered to help control the condition (and may not terribly effective), DH may ultimately controlled by strict adherence to a gluten-free diet (GFD). Strict adherence to a GFD is difficult, and some patients remain refractory to GFD with underlying immune activation. Accordingly, patients suffering from DH may benefit from treatment using the methods and formulations of naringenin disclosed herein.

In some embodiments, the condition is a hereditary defect in skin barrier function, including (in addition to those described above), Netherton Syndrome, Ichthyosis, and palmoplantar hyperkeratosis. These conditions can result in persistent activation of inflammatory and immune processes in the skin resulting in considerable suffering and morbidity.

Netherton Syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the SPINK5 gene. Netherton syndrome is characterized by chronic skin inflammation, universal pruritus (itch), severe dehydration, and stunted growth. Patients with this disorder tend to have a hair shaft defect (trichorrhexis invaginata), also known as “bamboo hair”. The disrupted skin barrier function in affected individuals also presents a high susceptibility to infection and allergy, leading to the development of scaly, reddish skin similar to atopic dermatitis. In severe cases, these atopic manifestations persist throughout the individual's life, post-natal mortality rates are high. In less severe cases, this develops into the milder ichthyosis linearis circumflexa. Patients may be more prone than healthy people to infections of all types, especially recurrent skin infections with staphylococcus. Steroid and retinoid products are generally ineffective against Netherton Syndrome, and may even exacerbate the condition. Accordingly, patients suffering from Netherton Syndrome may benefit from treatment using the methods and formulations of naringenin disclosed herein.

Ichthyosis is a family of mostly genetic skin disorders. All types of ichthyosis have dry, thickened, scaly or flaky skin. In many types there is cracked skin, which is said to resemble the scales on a fish. The severity of symptoms can vary enormously, from the mildest, most common, type such as ichthyosis vulgaris (which may be mistaken for normal dry skin) up to life-threatening conditions such as harlequin type ichthyosis. Ichthyosis vulgaris accounts for more than 95% of cases. Types of ichthyoses are classified by their appearance and their genetic cause. Ichthyosis caused by the same gene can vary considerably in severity and symptoms, and different genes can produce ichthyoses with similar symptoms. Accordingly, patients suffering from ichthyosis may benefit from treatment using the methods and formulations of naringenin disclosed herein Palmoplantar keratodermas (e.g., Palmoplantar hyperkeratosis) are a heterogeneous group of disorders characterized by abnormal thickening of the palms and soles. Clinically, three distinct patterns of palmoplantar keratoderma are diffuse, focal, and punctate. Diffuse palmoplantar keratoderma is characterized by an even, thick, symmetric hyperkeratosis over the whole of the palm and sole, usually evident at birth or in the first few months of life. Focal palmoplantar keratoderma, a type of palmoplantar keratoderma in which large, compact masses of keratin develop at sites of recurrent friction, principally on the feet, although also on the palms and other sites, a pattern of calluses that may be discoid or linear. Punctate palmoplantar keratoderma is a form of palmoplantar keratoderma in which many tiny keratoses involve the palmoplantar surface, skin lesions which may involve the whole of the palmoplantar surface, or may be more restricted in their distribution. Accordingly, patients suffering from Palmoplantar keratodermas may benefit from treatment using the methods and formulations of naringenin disclosed herein.

In some embodiments, the condition is a hyperproliferative condition involving the skin, such as squamous cell carcinoma, basal cell carcinoma, or cutaneous T-cell Lymphoma. Tumor development in the skin is accompanied by an immune response that leads to tumor infiltration by inflammatory cells, and consequently, local and systemic production of cytokines, chemokines and other mediators. These inflammatory mediators are associated with cancer development.

Squamous-cell carcinoma (SCC) is a cancer of the squamous cell, which is a main part of the epidermis of the skin. SCC is one of the major forms of skin cancer. However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, mouth, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others. The SCCs of different body sites can show tremendous differences in their presenting symptoms, natural history, prognosis, and response to treatment. SCC is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous-cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, structures involved in cell-to-cell adhesion. SCC of the skin begins as a small nodule and as it enlarges the center becomes necrotic and sloughs and the nodule turns into an ulcer. The lesion caused by SCC is often asymptomatic. The clinical appearance is highly variable. The tumor can lie below the level of the surrounding skin, and eventually ulcerates and invades the underlying tissue. The tumor commonly presents on sun-exposed areas. On the lip, the tumor forms a small ulcer, which fails to heal and bleeds intermittently. Unlike basal-cell carcinoma (BCC), SCC has a substantial risk of metastasis. Risk of metastasis is higher in SCC arising in scars, on the lower lips or mucosa, and occurring in immunosuppressed patients. SCC is generally treated by surgical excision, Mohs surgery or electrodessication and curettage. Nonsurgical options for the treatment of cutaneous SCC include topical chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy, and systemic chemotherapy. The use of topical therapy, such as Imiquimod cream and PDT is generally limited to premalignant and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC. Systemic chemotherapy is used exclusively for patients with metastatic disease. The methods and formulations of naringenin disclosed herein may provide patients suffering from these disorders with another or more effective treatment option.

Basal-cell carcinoma (BCC) is another form of skin cancer. It rarely metastasizes or kills. However, BCC can cause significant destruction and disfigurement by invading surrounding tissues. Treatments include surgery, radiation, photodynamic therapy (PDT), as well as topical chemotherapy.

Cutaneous-T-Cell Lymphoma (CTLC) is a non-Hodgkin's lymphoma that may present with an intractable itch, and red and scaly skin. The stabilized hypochlorous acid formulation can provide a relief from the discomfort of skin irritation associated with CTCL.

In some embodiments, the condition is a result of, or is associated with, aging or damaged skin, such as Actinic keratosis, or UV damage, or other physical damage to the skin barrier that results in hypersensitivity reactions. Actinic keratosis (AK) is a precancerous patch of thick, scaly, or crusty skin.

These growths are more common in fair-skinned people and those who are frequently in the sun. They usually form when skin gets damaged by ultraviolet (UV) radiation from the sun or indoor tanning beds. AKs are considered potentially precancerous; left untreated, they may turn into a type of cancer (e.g., squamous cell carcinoma). Development of these growths occurs when skin is constantly exposed to the sun over time. They usually appear as thick, scaly, or crusty areas that often feel dry or rough. They may be dark, light, tan, pink, red, a combination of all these, or have the same color as the surrounding skin. An actinic keratosis lesion commonly ranges between 2 and 6 millimeters in size but can grow to be a few centimeters in diameter. They often appear on sun-exposed areas of the skin. Because they are related to sun damage on the skin, most people who have an AK have more than one. Conventional treatments include 5-fluorouracil cream. In accordance with some embodiments, the naringenin with or without naringin formulation may be effective against AK as a topical anti-inflammatory agent.

UV damage, e.g., resulting from too much sun exposure, can range from dry skin (as skin loses moisture and essential oils) and sunburn. Mild sunburn causes only painful reddening of the skin, but more severe cases can produce tiny fluid-filled bumps or larger blisters. Long term sun exposure can result in actinic keratosis. Treatments for UV damaged skin, when conventional moisturizers are insufficient, can include anti-inflammatory medications, such as ibuprofen or aspirin. In accordance with some embodiments, the naringenin with or without naringin formulation may be effective against UV damage.

Atopic dermatitis (AD), also known as atopic eczema, results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thicken over time. It typically starts in childhood with changing severity over the years. In children under one year of age much of the body may be affected. As they get older the back of the knees and front of the elbows are the most common area for the rash. In adults the hands and feet are most affected. Scratching worsens symptoms and affected people have an increased risk of skin infections. Many people with atopic dermatitis develop hay fever or asthma. The cause is unknown but believed to involve genetics, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin. The diagnosis is typically based on the signs and symptoms. Conventional treatment involves avoiding things that make it worse, daily bathing with the application of a moisturizing cream afterward, applying steroid creams when flares occur, and medications to help with itchiness. Phototherapy may be useful for some people. Oral steroids may occasionally be used if other measures are not effective. Antibiotics (either by mouth or topically) may be administered if a bacterial infection develops. Psoriasis is a long-lasting autoimmune disease characterized by patches of abnormal skin. These skin patches are typically red, itchy, and scaly. They may vary in severity from small and localized to complete body coverage. Injury to the skin can trigger psoriatic skin changes at that spot. There are five main types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic. Plaque psoriasis, also known as psoriasis vulgaris, makes up about 90% of cases. Topical agents are typically used for mild disease, phototherapy for moderate disease, and systemic agents for severe disease. In accordance with some embodiments, the naringenin with or without naringin formulation may be effective against AD as a topical anti-inflammatory agent.

Many psoriasis patients experience a recurrence of psoriasis after systemic treatment is discontinued. Non-biologic systemic treatments frequently used for psoriasis include methotrexate, cyclosporine, hydroxycarbamide, fumarates such as dimethyl fumarate, and retinoids. Methotrexate and cyclosporine are drugs that suppress the immune system; retinoids are synthetic forms of vitamin A. These agents are also regarded as first-line treatments for psoriatic erythroderma. Several monoclonal antibodies targeting TNF-a have been developed for treatment of psoriasis (e.g., infliximab, adalimumab, golimumab, and certolizumab pegol) and one recombinant TNF-a decoy receptor, etanercept. Additional monoclonal antibodies have been developed against pro-inflammatory cytokines interleukin-12, interleukin-23 and interleukin-17, which inhibit the inflammatory pathway at a different point than the anti-TNF-a agents. Two drugs have been developed that target T cells (efalizumab and alefacept). Individuals with psoriasis may develop neutralizing antibodies against these biologic agents. Further, treatment with these agents is expensive. Accordingly, in accordance with some embodiments, the naringenin with or without naringin formulation may be effective against psoriasis as a topical anti-inflammatory agent.

In some embodiments, the patient has pruritus, which in some embodiments is associated with an underlying skin or immunological condition, including those mentioned above. Embodiments of the naringenin with or without naringin formulation can be administered to combat itch, including where there is no discernible (e.g., objective) inflammatory reaction or irritant. For example, such condition may result from sensitive skin in combination with physical factors (such as ultraviolet radiation, heat, cold, wind), general chemical stress (e.g., cosmetics, soap, water, pollution), physiological stress or disorder, substance abuse, hormonal conditions (e.g., menstrual cycle), or other systemic maladies. Even in the absence of an objective perception of skin inflammation, the naringenin and naringin are useful for reducing the subjective stinging, burning, warmth, and tightness associated with itch (e.g., pruritus). For example, in some embodiments, the subject has or is determined to have a psychogenic itch, which can be associated with for example substance abuse or withdrawal, psychosis, mania, depression, stress, anxiety, or obsessive-compulsive disorder. In other embodiments, the itch is a neurogenic itch that is, for example, secondary to disease occurring in places other than the skin such as hematologic disorder (polycythemia vera), lymphoproliferative diseases (e.g., leukemia, Hodgkin Lymphoma, Sezary syndrome), cholestasis, hepatic disease, endocrine disease, or chronic kidney disease. In some embodiments, the patient has prurigo nodularis, which is a skin disease characterized by pruritic (itchy) nodules. Patients often present with multiple excoriated lesions caused by scratching. In other embodiments, the naringenin with or without naringin formulation may be administered to combat the itch associated with ichthyosis.

In some embodiments, the naringenin with or without naringin formulation may be useful for treating inflammation that results from, for example, one or a combination of contact with noxious substances, genetic malady affecting the skin, injury (e.g., impaired or damaged skin, including that resulting from persistent scratching), infection, autoimmune reaction, systemic autoimmune reaction manifesting in itching and/or hives, hypersensitivity (of Type I, II, III, or IV), allergic reaction, including allergic reactions associated with cellular histamine and pro-inflammatory cytokines. Additional conditions in which embodiments of the naringenin with or without naringin formulation may be beneficial, include sarcoidosis involving the skin, pemphigus (e.g., vulgaris or foliaceus), erythema multiforme, urticaria (including chronic urticaria), Selective Immunoglobulin M Deficiency, Hidrotic Ectodermal Dysplasia (HED), Sjogren's Syndrome, contact dermatitis, rosacea (including of treatment of inflammatory lesions associated with rosacea), acne (including inflammatory acne), and skin allergy. In some embodiments, embodiments of the naringenin with or without naringin formulation may relieve itch and discomfort from the disorder and may provide general relief from symptoms and reduce the severity of the disease.

In various embodiments, embodiments of naringenin with or without naringin may be applied as an alternative or adjunct therapy to conventional treatments with corticosteroids, vitamin D ointment (or vitamin D analog), retinoid, analgesics, immunosuppressant, phototherapy, antihistamine, anti-infectives (e.g., antibiotic or antifungal), or biologic in the case of psoriasis, for example. Without limitation, various conventional treatments for indications are disclosed herein. In some embodiments, embodiments of the naringenin with or without naringin formulation may be used in place of a corticosteroid. The inflammatory condition may be present in a human or animal patient of any age (including pediatric and geriatric patients) and/or in an immunocompromised patient. Exemplary animal patients include mammals such as dogs, cats, horses, lamb, cattle, goats, pigs, and guinea pigs. In various embodiments, the patient is a human patient. The disclosure further contemplates preventive care (including prophylactic use) for such inflammatory conditions or prevention of such conditions where the patient may be genetically or environmentally predisposed to such conditions, as well as conditions that don't completely resolve with antimicrobial or steroidal treatment, or treatment with retinoid, vitamin D ointment, immunosuppressant, or biologic anti-inflammatory agent. Pediatric patients include infants, children, and adolescents, and the age limit usually ranges from birth up to 18 years of age (age 21 in the United States). In some embodiments, the patient is under 12 years of age, or is an infant. Geriatric patients in accordance with this disclosure include individuals over the age of 60. Immunocompromised patients include those having an immune response attenuated by administration of immunosuppressive drugs, chemotherapy, by irradiation, by malnutrition, genetic malady, or by certain disease processes such as acquired immunodeficiency syndrome (AIDS).

In some embodiments, the naringenin with or without naringin formulation may be applied to affected areas as needed to combat and/or control disease symptoms (including itch), or may be applied using a more precise regimen, such as about daily, or from 1 to about 10 times daily, or from 1 to about 5 times daily, or from 1 to about 3 times daily (e.g., about twice daily). In some embodiments, the naringenin with or without naringin formulation may be applied periodically to control symptoms or flare-ups, such as a regimen of the formulation that lasts for 1 to about 12 weeks, or for 1 to about 10weeks, or for 1 to about 8 weeks, or for 1 to about 6 weeks, or for 1 to about 4 weeks. In some embodiments, the regimen may last for about 1 or 2 weeks. In some embodiments, the naringenin with or without naringin formulation may be used between flare-ups to prevent or reduce the severity and/or frequency of symptom flare-ups (e.g., formation of blisters, bumps, lesions, or itch). In these or other embodiments, the naringenin with or without naringin formulation may be used between conventional treatments such as corticosteroid, immunosuppressant, topical vitamin D, retinoid, and/or antibiotic. In some embodiments, the naringenin with or without naringin formulation may be used alongside topical or oral corticosteroid, and in some embodiments, allows for lower dose or frequency of steroid use. In some embodiments, naringenin with or without naringin may be used in place of a corticosteroid, thereby allowing for prolonged use without side effects associated with corticosteroid use. In some embodiments, the naringenin with or without naringin formulation may be applied for a prolonged period of time, particularly but not exclusively in the case of treatment of a chronic condition. Generally, a chronic condition is a condition that will not be eliminated even with therapy, and thus the therapy may be intended to reduce, inhibit, or prevent (by means of prophylactic treatment) inflammatory symptoms, thereby managing the condition. Prolonged use generally includes treatment for at least about six months, at least about one year, at least about two years, or more. The naringenin with or without naringin formulation may be used continuously in some embodiments.

In certain embodiments of the disclosure, naringenin and neringin may be formulated or administered in combination with another therapeutic agent, including one or more of a corticosteroid, vitamin D ointment (or vitamin D analogue), retinoid, analgesic, immunosuppressant, topical chemotherapy, and anti-infectives (e.g., antibiotic or antifungal). Non-limiting examples of therapeutic agents may include antimicrobial agents such as antibiotics, antivirals, anti-fungal and anti-parasitics, immune-modulators/suppressants anti-inflammatory agents, anti-histamines, analgesics, local anesthetics, anti-oxidants such as vitamins, and moisturizing agents. For example, naringenin and naringin may be formulated or administered with antibiotics such as bacitracin, neomycin, neosporin, framycetin, fusidic acid, chloramphenicol, gentamicin, tobramycin, ceftriaxone, sulfacetamide, erythromycin, gentamicin, ciprofloxacin, ofloxacin, cefoxitin, cefotaxime, spectinomycin, tetracycline, doxycycline, and azithromycin; antivirals such as acyclovir, valacyclovir, famciclovir, and oseltamivir; antifungals such a as ketoconazole, fluconazole, itraconazole, voriconazole, terbinafine, and nystatin; anti-parasitics such as metronidazole, ivermectin, pyrantel pamoate, albendazole, and atovaquone-proguanil; immune-modulators/suppressants such as thalidomide, lenalidomide, apremilast, cyclosporine, prednisone, prednisolone, and tacrolimus; corticosteroids, and NSAIDs such as aspirin, ibuprofen, naproxen sodium, celecoxib; anti-histamines such as diphenhydramine, loratadine, fexofenadine, cimetidine, ranitidine, olopatadine, ciproxifan, and cromoglycate; analgesics such as acetaminophen/paracetamol, buprenorphine, codeine, meperidine, and tramadol; local anesthetics such as epinephrine, lidocaine, bupivacaine, and benzocaine; antioxidants such as vitamin A & E; topical vitamin D ointment, moisturizing agents such as silicones, emollients, lanolin, mineral oil, urea, alpha-hydroxy acids, glycerine, fatty acids, ceramides, collagen or keratin.

Formulation and composition considerations for optimal bioavailability and stability:

The following does not limit the scope or use of the invention. Factors such as a proper solvent such as deionized water and propylene glycol; anaerobic bottling; adding a preservative such as phenonip; adding an excipient, i.e. Carbopol, to emulsify; and maintaining proper naringenin concentration, i.e. 0.5%; may have profound effects on naringenin's stability and bioavailability. These formulations do not limit the scope or use of the invention. In some embodiments, proper pH, i.e. pH of the skin ˜5.5, can have profound effects on naringenin's stability and bioavailability. In some embodiments, the disclosure describes a method of treatment that includes topical application of the naringenin formulation to the skin on a routine basis as needed in both treatment and prevention of skin conditions.

The disclosed composition may comprise a pharmaceutically acceptable carrier. Non-limiting examples of suitable carriers include hectorite, silicates, fluorosilicates, bentonite, oil emulsions, cyclomethicone, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water. The disclosed composition may also include various other ingredients, such as tonicity agents, buffers, surfactants, co-solvents, viscosity-building agents, preservatives, and other therapeutic agents. Examples of viscosity-enhancing agents include, but are not limited to: pharmaceutically acceptable silicates for topical application, polysaccharides, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers, etc. For example, the composition may exhibit a viscosity of 1 to 400,000 centipoises (“cps”). In some embodiments, the composition may be a hydrogel comprising a silicate-based carrier (e.g., fluorosilicate carrier). For example, the silicate may comprise a fluorosilicate salt such as sodium magnesium fluorosilicate or sodium lithium magnesium fluorosilicate. In some embodiments, the naringenin with or without naringin solution can be used as a dispersing media with the silicate carrier to prepare the hydrogel.

Regarding tonicity agents, in some embodiments of the composition, such agents may be employed to adjust the tonicity of a composition. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent may vary, depending on the particular agent to be added and the type of composition. In some embodiments, the naringenin with or without naringin formulation may be hypertonic, hypotonic, or isotonic with respect to physiological fluids, but in some embodiments may be hypotonic. The formulation may contain varying levels of salinity, such as from 0.01 to about 2.0%. In some embodiments, the formulation may contain from about 0.02% to about 0.9%) w/v NaCl. In some embodiments, the formulation may contain from about 0.01 to 2.0%) w/v one or more salts, such as a halide salt, e.g. NaCl, KC1, or a mixture of salts or halide salts. The salt, or halide salt may be a salt of an alkali metal or alkaline earth metal, such as sodium, potassium, calcium, or magnesium.

Regarding buffers and pH adjusting agents, sodium phosphates, potassium phosphates, potassium carbonate, sodium bicarbonate, sodium borate or boric acid, phosphoric acid, or other suitable acid may be added to some embodiments of the compositions to achieve a target pH and/or prevent pH drift under storage conditions. The particular concentration may vary, depending on the agent employed. In some embodiments, the buffer of pH adjusting agents may be chosen to maintain a target pH within the range of about pH 4-7.

In some embodiments, the formulation may be packaged for sale, using any suitable container, such as any suitable plastic or glass bottles, or bags (e.g., plastic bags), tubes, or cans (e.g., spray or aerosol). Certain container materials may provide advantages in shelf-life. In certain embodiments, the packaging material may have minimal gas permeability (e.g., are non-permeable), including by species such as C02and 02. Thus, these containers may maintain the stabilizing amount of dissolved inorganic carbon, without losing the stabilizer in the form of C02. The containers may be transparent, or opaque so that they are impenetrable by light. In some embodiments, the containers may be specially configured for use in an oxygen-free packaging environment so as to transfer the naringenin formula into consumer-sized packaging without exposing the formulation to oxygen or other degrading effects.

EXAMPLES

Our studies include in vitro, in vivo and ex vivo studies with statistically significant sample sizes to show demonstrated and quantifiable improvements to the inflammatory skin conditions described herein when using the novel naringenin formulation of this disclosure. The studies also demonstrate effectiveness of the disclosed formulation as a preventative therapy for reducing the frequency of inflammatory flare ups when applied daily, for example.

Our human efficacy studies address a long-felt need for producing a consumable consumer product for widespread availability outside of a small laboratory setting.

Our studies demonstrate, for the first time, a rapid and statistically significant improvement of inflammation and its various related symptoms on human skin using the naringenin formulation and methods described herein, using industry standard instruments such as the Canfield VISIA-CR as in FIG. 3.

An example of the measurable and visible impact of the anti-inflammatory effect is presented in FIG. 4 as a before image 50 and an after image 52. The study indicates that, when “patch testing,” there may be a localized inflammatory response that creates a defined line between where the novel naringenin formulation was applied and where it was not. Prior to these studies, this effect had not been successfully demonstrated on humans in this manner to date.

FIGS. 5 and 6 show an example of treating acute inflammation with noticeable telangiectasia and symptoms of puffiness and redness using a naringenin formulation that had been packaged and stored in an oxygen-free environment as disclosed herein. FIGS. 5A and 6A show the subject's skin prior to treatment, with FIG. 6A including an overlay of the visual results of a Gaussian redness calculation. FIG. 5B shows the subject's skin one hour post-treatment with a naringenin formulation that had been packaged and stored in an oxygen-free environment as disclosed herein. FIG. 5B indicates visible post-treatment reduced telangiectasia and redness. FIG. 6B shows the same image as FIG. 5B, but with a visual overlay showing 43% reduced telangiectasia and general redness based on a Gaussian redness calculation. FIG. 5C shows the subject's skin twenty-four hours post-treatment with a naringenin formulation that had been packaged and stored in an oxygen-free environment as disclosed herein. FIG. 5C indicates almost fully diminished telangiectasia and redness. FIG. 6C shows the same image as FIG. 5C, but with a visual overlay showing 88% reduced telangiectasia and general redness based on a Gaussian redness calculation.

FIGS. 7 and 8 show an example of treating rosacea with significant telangiectasia and redness using a naringenin formulation that had been packaged and stored in an oxygen-free environment as disclosed herein. FIG. 7A shows a subject's skin with a treated portion 60 and an untreated portion 62 one hour post-treatment of the treatment portion, showing significant redness reduction as compared to the untreated portion. FIG. 8A shows the same image as FIG. 7A, but with a visual overlay showing an application line 64 separating the treated portion 60 from the untreated portion 62 and reduced telangiectasia and redness based on a Gaussian redness calculation. FIG. 7B shows the same subject's skin twenty-four hours post-treatment of the treatment portion 60, showing significant redness reduction as compared to the untreated portion 62. FIG. 8B shows the same image as FIG. 7B, but with a visual overlay showing a 67% reduction in redness in the treated portion 60 based on a Gaussian redness calculation.

In view of the disclosure, several advantages may be achieved and other advantageous results may be attained. As various changes could be made in the above products and methods without departing from the scope of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

While various embodiments have been described above, it should be understood that such disclosures have been presented by way of example only and are not limiting. Thus, the breadth and scope of the subject methods, products, and systems should not be limited by any of the above-described exemplary embodiments but should be defined only in accordance with the following claims and their equivalents.

Having now fully described the subject methods, products, and systems, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting their scope or any embodiment thereof. All cited patents, patent applications, and publications are fully incorporated by reference in their entireties.

	Number	Date	Country
	63544850	Oct 2023	US
	63028722	May 2020	US

	Number	Date	Country
Parent	17328439	May 2021	US
Child	18765975		US

	Number	Date	Country
Parent	18765975	Jul 2024	US
Child	18922183		US

TOPICAL FORMULATIONS AND METHODS FOR BIOACTIVE & BIOAVAILABLE NARINGENIN FOR TREATING SKIN CONDITIONS

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