Long-term treatment for alopecia

Abstract

The present invention relates to a topical composition used for the treatment and / or prevention of alopecia in a subject, wherein the therapeutic effect of the composition lasts for at least 24 weeks or longer after the final administration. Also disclosed are a kit and method for the treatment and / or prevention of alopecia using this composition.

Description

Technical Field

[0001] The present invention relates to a composition, preferably a topical agent, for use in the treatment and / or prevention of alopecia in a subject, the therapeutic effect of which persists for at least 24 weeks or more after the final administration of the composition. Also disclosed are kits and methods for the treatment and / or prevention of alopecia using the aforementioned composition.

Background Art

[0002] The hair follicle (HF) is a unique small organ that undergoes a repetitive regeneration cycle process throughout life. The lower part of the HF in the healthy anagen phase (the bulge and the bulb) has relative immune privilege (IP), which protects the hair follicle from the inflammatory process and promotes immune tolerance. These individual HF compartments are characterized by factors that act as IP-protective factors to maintain the IP of the HF (Lintzeri, 2022).

[0003] As hair follicles develop, blood vessels originating from the deep dermal vascular network surround them. These vessels supply nutrients to the hair follicles, supporting nutrient delivery, waste removal, and growth (Murphey 2022). The vascular system is responsible for guiding migrating immune cells, thereby supporting the body's protective immune function against pathogens and other threats. In inflammation or immune surveillance, cells lining the vascular lumen, known as endothelial cells (ECs), attract migrating immune cells, guide them to appropriate exit sites within the vessels, and allow them to enter the underlying tissues. Therefore, "immunomodulatory ECs (IMECs)" (Amersfoort, 2022) play a crucial supporting role in the guidance and directional migration of migrating immune cells. During inflammation, endothelial cells expose various adhesion molecules on their surface, which slow and halt the migration of immune cells in the bloodstream. These adhesion molecules are thought to provide immune cells with guiding cues that indicate their location for penetrating the blood vessel wall through a multi-step process known as trans-endothelial migration (TEM) or migration (Schimmel 2017).

[0004] In a normal hair growth cycle, scattered immune cells are found only around the hair bulb of rhizoid hair follicles, and their presence within the hair bulb is extremely rare (Lintzeri, 2022). However, in alopecia areata (AA), genetic or extrinsic factors induce significant undesirable transendothelial migration (TEM) of CD8+ T cells from the vascular system to the hair follicle.

[0005] Histologically, AA lesions exhibit a characteristic high-density perifollicular and intrafollicular inflammatory cell infiltration around the hair bulb, resembling a swarm of bees, pushing the hair follicle into early regression, dystrophy, and ultimately apoptosis. CD8+ T cells are typically the first cells to invade the interior of the hair follicle, severely impairing its integrity (Lintzeri, 2022).

[0006] During flare-ups of AA, the growth phase of the hair growth cycle is significantly shortened, and non-scarring alopecia develops acutely, ranging from small, localized patches on the scalp to complete hair loss of the scalp and body. While the exact etiology of AA is not yet fully understood, it is recognized that IP breakdown of the HF hair follicle plays a crucial role in the pathophysiology of this disease. The exact cause of this IP breakdown is still not fully understood.

[0007] Local inflammation in AA is primarily mediated by the JAK-STAT pathway. In AA, pro-inflammatory cytokines that signal receptors via the JAK / STAT pathway are overexpressed. This leads to JAK-mediated production of IFN-γ and IL-15, which promotes an inflammatory feedback loop and further advances local inflammation. Given the crucial role that the JAK-STAT pathway plays in mediating the CD8+ NKG2D+ T cell response, a major factor in AA pathogenesis, it is not surprising that a class of JAK inhibitors, which inhibit the JAK enzyme and disrupt the JAK-STAT signaling pathway, thereby blocking downstream signaling of various cytokines, protecting hair follicle damage, and safeguarding the initiation of new growth phases and hair regeneration (Dillon, 2021).

[0008] In 2022, the first JAK inhibitor was approved as a treatment for AA, marking the first approved treatment for the debilitating chronic autoimmune disease, with many more drugs under development (Dillon, 2021). Since the first JAK inhibitor was approved in 2011 for the treatment of rheumatoid arthritis (Shawky, 2022), real-world evidence of serious health-related risks has been collected (Hoisnard, 2022), leading to black-box warnings for the entire class of JAK inhibitors from the U.S. Food and Drug Administration and the European Medicines Agency (Kragstrup, 2022).

[0009] Due to the serious risks associated with immunosuppression from JAK inhibitors, regular drug-free periods are necessary.

[0010] However, because JAK inhibitors "simply" inhibit the JAK-STAT signaling pathway, discontinuation of treatment leads to a rapid and complete systemic relapse of the disease within three months (Askin, 2021). Tissue-resident memory T cells (TRMs) are long-lived lymphocytes that reside within tissues and colonize them after the initiation of a T cell-mediated immune response. In fact, endothelial cells are essential interaction partners for T cells migrating to inflammatory tissues, which may consequently promote TRM development. Wienke et al. demonstrated that interaction between T cells and activated ECs stimulates tissue residentization in a co-culture system of human cytokine-activated ECs and T cells sorted by FACS (Wienke, 2022). Reports of AA relapse, confirmation of upregulation of TRM cells, and clinical efficacy during JAK inhibitor administration support the important role of TRM cells in the disease pathogenesis (Ryan, 2021).

[0011] Prior to the initial drug approval for AA, standard treatment consisted mainly of off-label use of corticosteroids in addition to older immunosuppressants (Meah, 2020). Unfortunately, corticosteroids, particularly topical corticosteroids (TCS), have been reported to cause potential local side effects, including impaired epidermal barrier function and skin atrophy (Wollenberg 2018). Furthermore, transdermal absorption of TCS from damaged skin can lead to systemic exposure and subsequent growth retardation (Coureau 2008). As a result of both actual and perceived side effects and potential long-term toxicity, "corticosteroid phobia" often leads to poor adherence to TCS (Stalder 2017).

[0012] Similarly, serious risks associated with corticosteroids necessitate regular drug-free periods (drug holidays). However, as with JAK inhibitors, disease relapse is common upon discontinuation of treatment (Lintzeri, 2021).

[0013] Systemic disease relapses following treatment discontinuation transform the lives of AA patients into an exhausting state described as an "emotional rollercoaster" (McGettigan, 2013), characterized by alternating cycles of potential hair regrowth during treatment followed by hair loss after treatment discontinuation. [Overview of the Initiative] [Problems that the invention aims to solve]

[0014] There is a significant unmet medical need for treatments that are safe enough not to require a drug-free period and whose effects persist even after treatment discontinuation. [Means for solving the problem]

[0015] This objective is achieved by providing a composition for use in the treatment and / or prevention of alopecia in subjects, the composition comprising effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. This composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, one or more therapeutic effects are maintained for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose of the composition, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0016] A further object of the present invention is to provide a method for treating and / or preventing alopecia in a subject, the method comprising administering a composition comprising an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paullinia species, and an extract of a Theobroma species as an active ingredient, This composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, one or more therapeutic effects are maintained for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose of the composition, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0017] A further object of the present invention is to provide the use of the compositions of the present invention in the manufacture of pharmaceuticals for the treatment and / or prevention of alopecia in subjects.

[0018] A further object of the present invention is to provide a kit for the treatment and / or prevention of alopecia, comprising the composition of the present invention or a composition for use. [Brief explanation of the drawing]

[0019] [Figure 1] SALT scoring example (modified from Olsen, 2004) [Figure 2] SALT scores in patients administered the composition continuously improved, and the change in SALT scores was sustained throughout the follow-up period, demonstrating statistically significant superiority over placebo. [Modes for carrying out the invention]

[0020] In the practice or testing of the present invention, methods and materials similar or equivalent to those described herein can be used, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided only for the purpose of disclosure prior to the filing date of this application. Nothing in this specification should be construed as an admission that the present application does not have priority over such publications due to prior inventions. Further, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0021] In case of conflict, the specification, including definitions, will control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following definitions are provided to facilitate understanding of the present invention when used herein.

[0022] The terms "comprise" and "comprising" are generally used in the sense of "include" and "including", that is, they allow for the presence of one or more features or components. The terms "comprise" and "comprising" respectively subsume the more restrictive terms "consist", "consisting", and "consist essentially of".

[0023] [[ID=I2]]In the specification and claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include the plural.

[0024] As used herein, the terms "subject" / "subject in need of ~" or "patient" / "patient in need of ~" are widely recognized in the art and are used interchangeably herein to refer to companion animals including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some cases, the subject is a subject in need of treatment, or a subject having a disease or disorder. However, in other embodiments, the subject may be a normal subject. This term does not indicate a specific age or gender. Thus, adult and neonatal subjects, whether male or female, are intended to be included in the subject. Preferably, the subject is a human, and most preferably a human suffering from alopecia or a human at risk of suffering from alopecia.

[0025] The term "about" means, particularly with respect to a particular quantity, number, or percentage, to include a deviation of plus or minus 10 percent (±10). For example, about 5% includes any value between 4.5% and 5.5%, such as 4.5, 4.6, 4.7, 4.8, 5, 4.1, 5.2, 5.3, 5.4, or 5.5.

[0026] As used herein, "at least one" means "one or more", "two or more", "three or more", etc. For example, at least 8 weeks means 8 weeks or more, i.e., 9 weeks, 10 weeks, 11 weeks, etc.

[0027] Focusing on the treatment and prevention of alopecia, such as alopecia areata (AA), the inventors surprisingly discovered that the therapeutic effect of the compositions of the present invention persists for weeks to months after the final administration.

[0028] It is known that AA recurs after discontinuation of existing treatments (Lintzeri-2022).

[0029] The inventors have discovered that using the composition of the present invention, which contains an aqueous extract of a species of the genus Paulinia, yields a stronger anti-inflammatory effect, which is an unexpected synergistic effect with the other components of the composition. While not bound by theory, it is possible to obtain more caffeine by using an aqueous extract of a species of Paulinia than by using an aqueous alcohol extract. This strong anti-inflammatory effect was unexpectedly obtained as an unexpected synergistic effect with the other components of the composition, by allowing the composition to contain more caffeine compared to the aqueous alcohol extract.

[0030] The inventors believe that administering the composition of the present invention not only suppresses EC activation and improves endothelial permeability, but also unexpectedly yields a therapeutic effect that persists even after treatment discontinuation (i.e., a long-term effect after treatment cessation).

[0031] In one embodiment, the present invention provides a composition for the treatment and / or prevention of alopecia in a subject, the composition for use in the treatment and / or prevention of alopecia in a subject, comprising as an active ingredient an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paullinia species, and an extract of a Theobroma species. This composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, the persistence of one or more therapeutic effects after the final administration of the composition is verified by measuring the Saliva Severity Level (SALT) score.

[0032] In one embodiment, one or more therapeutic effects last for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer.

[0033] The compositions according to the present invention can be prepared according to any conventional method known in the art.

[0034] The terms “treatment” or “treating” mean administering the compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc., contained herein to a subject for the following purposes: (i) Suppression of disease, that is, prevention of the onset of clinical symptoms; (ii) Reversal of disease, and / or (iii) Relief of the disease, i.e., regression of clinical symptoms.

[0035] In this specification, “prevention” or “preventing” means administering the compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc., described herein to a subject for the purpose of preventing a disease, that is, for the purpose of preventing the clinical symptoms and signs of a disease from occurring.

[0036] In the context of this invention, "disease" refers to hair loss. In one embodiment, the hair loss is an immune-mediated disease, preferably an autoimmune disease. More preferably, the autoimmune disease is alopecia areata.

[0037] Alopecia areata (AA) is an immune-mediated, autoimmune, and inflammatory hair disorder affecting both pediatric and adult patients. Immune-inflammatory attacks on hair follicles in the scalp disrupt the normal hair cycle, leading to premature transition to the resting phase and hair loss. The disease begins with perifollicular inflammation and infiltration of immune-inflammatory cells around the hair bulb during the growth phase, leading to immune-privileged breakdown of the hair follicle, tissue dystrophy, follicular cell death, and shedding of the hair shaft (Lintzeri-2022). Key players include NKG2D-positive T cells, natural killer (NK) cells, and autoreactive CD8-positive T lymphocytes, which recognize autoantigens upon exposure to MHC I and II expression in hair follicle cells. T cell activation leads to increased IFN-γ secretion, which replenishes or activates inflammatory cells, including macrophages, mast cells, and dendritic cells, thereby promoting follicular cell death and apoptosis (Bertolini, M., 2020).

[0038] The initial clinical symptoms of alopecia areata (AA) present as random, patchy hair loss, which can sometimes progress to hair loss across the entire scalp (alopecia totalis) or even spread throughout the body (alopecia generalis). AA affects patients of all races, but it is more common in women than men, and the clinical symptoms are similar. Most importantly, if AA develops early in infancy, the prognosis is usually more severe, and the frequency of unpredictable relapses in adulthood is higher (Villasante Fricke, AC, 2015).

[0039] In this specification, “effective amount” means a therapeutically effective amount of the composition, pharmaceutical composition, formulation, therapeutic agent, active ingredient, compound, etc. of this disclosure, which is sufficient to significantly improve the symptoms and / or condition of the subject being treated, within reasonable medical judgment, while avoiding serious side effects (in a reasonable risk-benefit ratio).

[0040] In the context of the present invention, the composition of the present invention comprises, as an active ingredient, an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paullinia species, and an extract of a Theobroma species.

[0041] The term Allium species extract, or aqueous alcohol extract, specifically refers to aqueous alcohol extracts and natural extracts obtained from all species of the genus Allium (Liliaceae), particularly from onion (Allium cepa).

[0042] The term "citrus extract" or "aqueous alcohol extract" specifically refers to aqueous alcohol extracts and natural extracts obtained from all species of the genus Citrus (Rutaceae), particularly from Citrus limon.

[0043] The term Paullinia extract (whether in spray form or not) or aqueous extract refers specifically to aqueous and natural extracts obtained from all species of the genus Paullinia (Sapindaceae), particularly from guarana (Paullinia cupana).

[0044] The term Theobroma extract (whether sprayed or not) or aqueous alcohol extract refers specifically to aqueous alcohol extracts and natural extracts obtained from all species of the genus Theobroma (Malvaceae), especially from cacao (Theobroma cacao).

[0045] In one embodiment of the present invention, the composition of the present invention or the composition for use is typically administered topically to the external skin surface of the skull for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density.

[0046] The period required to detect one or more therapeutic effects is typically between approximately 16 and 48 weeks, preferably between approximately 20 and 40 weeks, more preferably between approximately 20 and 32 weeks, and even more preferably between approximately 24 weeks.

[0047] Any method well known to those skilled in the art can be used to detect, monitor, and / or demonstrate one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density.

[0048] In one embodiment, one or more therapeutic effects can be detected, monitored, and / or verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0049] SALT scoring is a calculation based on a scoring system. The scalp is divided into four regions: the left side of the scalp (18% of the scalp surface area), the right side (18%), the crown (40%), and the back of the head (24%). The percentage of hair loss in each of the four scalp regions is determined independently and multiplied by their respective coefficients (left and right sides: 0.18 each, crown: 0.40, back of the head: 0.24). The coefficients for each region differ depending on their location. Then, the percentages of hair loss from all four regions are summed up to calculate the final total hair loss percentage, called the SALT score.

[0050] Olsen et al. also propose a SALT score assessment method more suitable for clinical trials. As shown in Figure 1, each area is further subdivided into four quadrants (5%+4%+4%+5%; 10%+10%+10%+10% or 6%+6%+6%+6%) depending on the scalp area.

[0051] The hair loss rate in each quadrant is determined independently and multiplied by a coefficient (0.04, 0.05, 0.06, or 0.1). The coefficient for each quadrant differs depending on its location (Figure 1). Then, the hair loss rates for all four regions (16 quadrants) are summed up to calculate a final total hair loss rate called the SALT score.

[0052] Calculating the final SALT score requires numerous calculations, and since the coefficients differ for each domain, manual SALT scoring carries a risk of error. Therefore, in one embodiment, SALT scoring is performed by computer. In a preferred embodiment, the SALT score assessment described by Olsen is used to detect, monitor, and / or verify one or more treatment effects.

[0053] Typically, the baseline SALT score of a subject is measured before the initiation of administration of the composition of the present invention.

[0054] In one embodiment, if a decrease of at least approximately 2%, at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% is detected in the detected SALT score compared to the baseline SALT score of the subject, it indicates that one or more therapeutic effects have been detected and that administration of the composition of the invention is effective.

[0055] If, compared to the subject's SALT score measured after the final dose of this composition, a decrease of at least approximately 2%, at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 30%, at least approximately 40%, or at least approximately 50% in the detected SALT score, it indicates that one or more therapeutic effects have been detected and persisted even after discontinuation of topical administration. In some embodiments, one or more therapeutic effects may persist and even improve.

[0056] Typically, the composition of the present invention is administered topically to the external skin surface of the skull at least once a day, at least twice a day, or more frequently.

[0057] In a related embodiment, the composition of the present invention is prepared for topical administration. Preferably, the composition is mixed with a diluent and / or excipient for preparing a composition for topical administration, and is present in an amount of about 20% by weight or more based on the total weight of the composition.

[0058] Typically, to cover the entire scalp of the subject, the composition of the present invention, prepared for topical administration, is applied in a volume between approximately 0.5 ml and 2.5 ml at a frequency of once or twice or more per day.

[0059] In one embodiment, the composition of the present invention or the composition for use contains about 65% to about 93% by weight of an aqueous alcohol extract of an Allium species; about 5% to about 33% by weight of an aqueous alcohol extract of a Citrus species; about 0.25% to about 2.5% by weight of an aqueous extract of a Paulinia species; and further contains about 0.25% to about 2.5% by weight of an aqueous alcohol extract of a Theobroma species.

[0060] In a preferred embodiment, the composition of the present invention or composition for use contains about 65% to about 93% by weight of an aqueous alcohol extract of onion (Allium cepa); about 5% to about 33% by weight of an aqueous alcohol extract of citrus lemon (Citrus limon); about 0.25% to about 2.5% by weight of an aqueous extract of guarana (Paullinia cupana); and further contains about 0.25% to about 2.5% by weight of an aqueous alcohol extract of cocoa (Theobroma cacao).

[0061] In a more preferred embodiment, the composition of the present invention or composition for use contains about 87% by weight of an aqueous alcohol extract of onion; about 12% by weight of an aqueous alcohol extract of citrus lemon; about 0.67% by weight of an aqueous extract of guarana; and further about 0.67% by weight of an aqueous alcohol extract of cocoa.

[0062] In one embodiment, the composition of the present invention or the composition for use further contains an excipient. Examples of excipients include, based on the total weight of the composition, about 0.05% to about 8.0% by weight of sodium chloride and about 1% to about 40% by weight of glycerin.

[0063] In one aspect, the composition of the present invention or the composition for use contains, based on the total weight of the composition, about 0.05% to about 8.0% by weight, preferably about 0.1% to about 7.0% by weight, more preferably about 0.4% to about 6.0% by weight, and even more preferably about 0.9% to about 3% by weight of sodium chloride.

[0064] In one aspect, the composition of the present invention or the composition for use contains, based on the total weight of the composition, about 1% to about 20% by weight, preferably about 1.2% to about 15% by weight, more preferably about 1.8% to about 10% by weight, and even more preferably about 2% to about 5% by weight of glycerin.

[0065] The compositions of the present invention suitable for topical administration include liquid or semi-liquid formulations suitable for skin penetration, such as solutions, lotions, shake lotions, creams, ointments, gels, foams, transdermal patches, powders, solids, sponges, tapes, vapors, pastes, tinctures, microparticles, microcapsules, nanoparticles, liposomes, or emulsions. Preferably, the compositions of the present invention suitable for topical administration are in the form of solutions or lotions.

[0066] The present invention also envisions a method for treating and / or preventing alopecia in subjects.

[0067] In one embodiment, a method for treating and / or preventing alopecia in a subject comprises administering a composition comprising, as an active ingredient, an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paullinia species, and an extract of a Theobroma species. This composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, one or more therapeutic effects are maintained for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose of the composition, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0068] The present invention also envisions the use of the composition of the present invention in the manufacture of a pharmaceutical for the treatment and / or prevention of alopecia in subjects, which involves administering a composition comprising, as an active ingredient, an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paullinia species, and an extract of a Theobroma species. This composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, one or more therapeutic effects are maintained for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose of the composition, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0069] The present invention also envisions a kit for the treatment and / or prevention of alopecia as described herein. In one embodiment of the present invention, the kit comprises a composition of the present invention, or a composition for use.

[0070] The kit of the present invention may also include a container and a label or accompanying documentation attached to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, dispensers, spray applicators, etc. Containers can be formed from a variety of materials, such as glass or plastic.

[0071] Labels or accompanying documents may include instructions on how to use them. These instructions may be affixed to the packaging material or included as accompanying documents. Instructions are typically, but not limited to, written or printed materials. This disclosure assumes any medium capable of holding and communicating such instructions to the end user.

[0072] This disclosure should be considered as illustrative and not restrictive in all embodiments, the scope of the invention is indicated by the appended claims, and all modifications that fall within the meaning and equivalents thereof are intended to be incorporated herein.

[0073] [Examples] [material and method] composition This composition contains approximately 87% by weight of an aqueous alcohol extract of onion (Allium cepa), approximately 12% by weight of an aqueous alcohol extract of citrus lemon (Citrus limon), approximately 0.67% by weight of an aqueous extract of guarana (Paullinia cupana), and approximately 0.67% by weight of an aqueous alcohol extract of cocoa (Theobroma cacao).

[0074] External preparation The final topical solution product contains at least 20% of the above composition. The remainder of the finished product consists of water and common excipients found in other skin solutions, such as betaine, glycerin, and sodium chloride.

[0075] A finished skin solution product (LH-8) containing 22.25% of this composition was evaluated in a clinical trial (RAAINBOW trial, ClinicalTrials.gov identifier NCT03240627) to assess the safety and efficacy of this composition in subjects exhibiting AA. Approximately 1 mL of the composition was applied to the entire scalp twice daily, with an interval of approximately 12 hours (e.g., morning and evening).

[0076] The RAAINBOW trial was a placebo-controlled, double-blind, randomized, multicenter trial. 107 participants (male and female) were enrolled and included in the safety analysis. Of these, 62 participants who met the eligibility criteria for the full analysis set population (FAS) (i.e., moderate to severe AA) were analyzed for efficacy.

[0077] result The safety analysis is summarized below.

[0078] [Table 1]

[0079] No subjects in the composition group experienced serious adverse events (AEs). Only 5.6% of subjects in the composition treatment group experienced drug-related adverse events (compared to 11.1% in the placebo group). One adverse event was serious, involving severe scalp and facial eczema. However, eczema is the most common comorbidity of AA, and AA patients are more likely to have atopic dermatitis or eczema (17.4% vs. 2.2% control) (Conic, 2020). All other adverse events were mild, moderate, localized, and transient.

[0080] No side effects observed with JAK inhibitors or corticosteroids were reported in this study.

[0081] Furthermore, the RAAINBOW trial was specifically designed not only to evaluate the efficacy of this composition for AA after 6 months of treatment, but also to assess the potential for disease recurrence after treatment discontinuation, as measured at 6 months after treatment discontinuation.

[0082] Alopecia areata (AA) was assessed using a scalp alopecia severity score known as the SALT (Alopecia Severity Assessment Tool) score, which is based on globally standardized scalp photographs. The SALT score was developed in 2004 by Olsen (Olsen, 2004) "to facilitate well-controlled clinical trials of alopecia areata." It is a standardized method for assessing the degree of alopecia, with a 100% SALT score indicating complete baldness. It is a scoring system based on four photographs, dividing each side of the head into four quadrants, which researchers score accordingly (see Figure 1). The SALT score is a standard measurement endpoint used in all trials evaluating the effectiveness of novel treatments in AA. An example is shown below.

[0083] In the RAAINBOW trial, SALT scores (Figure 2) were measured at baseline (V1), and at 3 months (V2) and 6 months (V3) of the treatment period. Treatment was then discontinued, and AA was reassessed in patients at 3 months (V4) and 6 months (V5) of the treatment-free follow-up period.

[0084] After testing the normality assumption of the data (using both QQ plots and the Shapiro-Wilk test), a generalized linear model (SAS's GLIMMIX procedure) was preferred over MMRM. The GLIMMIX model had the rank of relative change from baseline in SALT score as the dependent variable, treatment, visits, and the interaction between treatment and visits as fixed effects, and baseline severity based on SALT score as a covariate.

[0085] There were statistically significant differences between the LH-8 group and the placebo group in both relative and absolute changes in SALT scores from baseline to week 24, with the LH-8 group showing a larger change. Therefore, the planned primary endpoint was met (p-value: <0.0001).

[0086] In subjects treated with the composition and showing improvement during the 6-month treatment period (between V1 and V3), the disease recurrence rate after discontinuation of treatment was only 4%, as measured 6 months after the treatment-free period (V5). 96% of subjects who responded to treatment did not recur after discontinuation. Furthermore, as shown in Figure 2, SALT scores in patients treated with this composition continuously improved, and the change in SALT scores was sustained throughout the entire follow-up period, demonstrating statistically significant superiority compared to placebo.

[0087] In chronic diseases, a 6-month period is considered representative of disease progression (Ostbye, 2005). Therefore, a 6-month treatment-free follow-up period is considered representative of long-term disease progression (Figure 2).

[0088] In this case, it can be concluded that discontinuation of treatment with the composition did not lead to disease relapse in 4% of cases. Therefore, unlike JAK inhibitors and corticosteroids, treatment with this composition does not require discontinuation for safety reasons, but can be discontinued without the risk of disease relapse. Although AA is a chronic disease and has traditionally required chronic treatment, this composition allows for treatment only until the disease is controlled, rather than a chronic approach, after which treatment can be safely discontinued.

[0089] References

[0090] [Table 2]

Claims

1. A composition for use in the treatment and / or prevention of alopecia due to immune-mediated diseases in subjects, comprising, as active ingredients, about 65% to about 93% by weight of aqueous alcohol extracts of Allium species, about 5% to about 33% by weight of aqueous alcohol extracts of Citrus species, about 0.25% to about 2.5% by weight of aqueous extracts of Paulinia species, and about 0.25% to about 2.5% by weight of aqueous alcohol extracts of Theobroma species. The composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, the one or more therapeutic effects of the composition last for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose of the composition, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

2. The composition for use according to claim 1, wherein the immune-mediated disease is an autoimmune disease.

3. The composition for use according to claim 2, wherein the autoimmune disease is alopecia areata.

4. The composition for use according to any one of claims 1 to 3, wherein the period required to detect one or more therapeutic effects is between approximately 16 weeks and approximately 48 weeks, preferably between approximately 20 weeks and approximately 40 weeks, more preferably between approximately 20 weeks and approximately 32 weeks, and even more preferably between approximately 24 weeks.

5. The composition for use according to any one of claims 1 to 3, wherein the one or more therapeutic effects are detected or verified by measuring the Salvia Alopecia Severity Assessment Tool (SALT) score.

6. A composition for use according to any one of claims 1 to 3, which detects a reduction in the SALT score of at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% compared to the baseline SALT score of the subject measured before administration of the composition was initiated.

7. A composition for use according to any one of claims 1 to 3, wherein a decrease of at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% in the SALT score of a subject measured after the final administration of the composition is detected.

8. A composition for use according to any one of claims 1 to 3, comprising: about 65% to about 93% by weight of an aqueous alcohol extract of onion (Allium cepa); about 5% to about 33% by weight of an aqueous alcohol extract of citrus lemon (Citrus limon); about 0.25% to about 2.5% by weight of an aqueous extract of guarana (Paullinia cupana); and about 0.25% to about 2.5% by weight of an aqueous alcohol extract of cocoa (Theobroma cacao).

9. The composition for use according to claim 8, comprising: about 87% by weight of an aqueous alcohol extract of onion; about 12% by weight of an aqueous alcohol extract of citrus lemon; about 0.67% by weight of an aqueous alcohol extract of guarana; and about 0.67% by weight of an aqueous extract of cocoa.

10. The composition for use according to any one of claims 1 to 3, wherein the composition is mixed with a diluent and / or excipient for preparing a composition suitable for topical administration, and contains about 20% by weight or more based on the total weight of the composition.

11. The composition for use according to any one of claims 1 to 3, further comprising, based on the total weight of the composition, about 0.05% to about 8.0% by weight of sodium chloride and about 1% to about 40% by weight of glycerin as excipients.

12. The composition for use according to claim 11, which contains, based on the total weight of the composition, about 0.05% to about 8.0% by weight, preferably about 0.1% to about 7.0% by weight, more preferably about 0.4% to about 6.0% by weight, and even more preferably about 0.9% to about 3% by weight of sodium chloride.

13. The composition for use according to claim 11, comprising, based on the total weight of the composition, about 1% to about 20% by weight, preferably about 1.2% to about 15% by weight, more preferably about 1.8% to about 10% by weight, and even more preferably about 2% to about 5% by weight of glycerin.

14. A composition comprising an effective amount of an extract of an Allium species, an extract of a Citrus species, an aqueous extract of a Paulinia species, an extract of a Theobroma species, as an active ingredient, and at least one excipient.

15. The composition according to claim 14, wherein the composition is mixed with a diluent and / or excipient for preparing a composition suitable for topical administration, and contains about 20% by weight or more based on the total weight of the composition.

16. A method for treating and / or preventing alopecia in a subject, comprising administering the composition according to claim 1 or claim 14, The composition is administered topically for a period of time necessary to detect one or more therapeutic effects, including delaying hair loss, promoting hair growth, and / or increasing hair density. Furthermore, the method is characterized in that the one or more therapeutic effects described above last for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or longer after the final dose, and this is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

17. Use of the composition according to claim 1 or claim 14 in the manufacture of a pharmaceutical product for the treatment and / or prevention of alopecia in a subject.

18. A kit for the treatment and / or prevention of alopecia, comprising the composition according to claim 14, or the composition for use according to claim 1.

19. The kit according to claim 18, further comprising one or more containers, and labels or accompanying documents attached to or associated with the one or more containers.

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