Combinations of compositions for use in the treatment and / or prevention of alopecia

Abstract

This invention relates to a combination of compositions used for the treatment and / or prevention of alopecia in a subject. Furthermore, a kit and method for the treatment and / or prevention of alopecia using this combination of compositions are disclosed.

Description

Technical Field

[0001] The present invention relates to a combination of compositions for use in the treatment and / or prevention of alopecia in a subject. Also disclosed are kits and methods for the treatment and / or prevention of alopecia using this combination of compositions.

Background Art

[0002] JAK (Janus kinase) inhibitors are a group of drugs having a mechanism of action that suppresses intracellular signal transduction via multiple cytokines. These cytokines act via the JAK / STAT (signal transducer and activator of transcription) pathway, which plays an important role in the regulation of the immune system. Dysregulation of the JAK-STAT pathway can cause the pathological processes of various immune and inflammatory diseases. Oral and topical JAK inhibitors are approved for the treatment of various autoimmune and inflammatory chronic diseases, including alopecia areata (AA), an immune-mediated disease characterized by patchy or complete loss of scalp and / or body hair.

[0003] Chronic use of JAK inhibitors has been reported to cause serious side effects (Hoisnard, 2022), including serious infections, major adverse cardiovascular events (MACE), thrombosis, malignancies, and death, which are noted in the prescribing information of multiple JAK inhibitors such as baricitinib (Olumiant(R)) and ritlecitinib (Litfulo(R)), which are two JAK inhibitors approved for the treatment of AA.

[0004] In response to the confirmation of the long-term health risks associated with chronic use of JAK inhibitors, the United States Food and Drug Administration issued a warning in 2021 and imposed a black box warning on all drugs belonging to the JAK inhibitor class (FDA warning). The European Medicines Agency also followed in 2022 (EMA warning).

[0005] Because long-term exposure to JAK inhibitors is associated with serious health risks, a rational medical approach is to discontinue high-risk treatments once the patient's symptoms have subsided. In individual cases of AA, JAK inhibitor treatment is discontinued when the patient's hair regrowth occurs. However, data have shown that hair loss recurs within three months of discontinuing JAK inhibitor treatment (Yan 2022). [Overview of the project] [Problems that the invention aims to solve]

[0006] There is a significant unmet medical need for a treatment that allows AA patients who respond to JAK inhibitors to discontinue treatment upon symptom resolution, without experiencing hair loss recurrence, and with reduced long-term health risks. [Means for solving the problem]

[0007] This objective is achieved by providing a combination of compositions for use in the treatment and / or prevention of alopecia, which is, i) A first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount, and ii) A second pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. It includes, The first pharmaceutical composition and the second pharmaceutical composition are administered to subjects requiring them, either in combination or with a time difference.

[0008] A further object of the present invention is to provide a method for treating and / or preventing alopecia in subjects, comprising: i) administering a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor; and ii) administering a second pharmaceutical composition containing a therapeutically effective amount of an extract of an Allium species, a Citrus species, a Paulinia species, and a Theobroma species as active ingredients, wherein the first and second pharmaceutical compositions are administered to subjects in need, either in combination, separately, or with a time difference.

[0009] A further object of the present invention is to provide the use of the compositions of the present invention in the manufacture of a pharmaceutical for the treatment and / or prevention of alopecia in subjects, which comprises i) administering a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor, and ii) administering a second pharmaceutical composition containing a therapeutically effective amount of an extract of an Allium species, a Citrus species, a Paulinia species, and a Theobroma species as an active ingredient, wherein the first and second pharmaceutical compositions are administered to subjects in need, either in combination, separately, or with a time difference.

[0010] A further object of the present invention is to provide a kit for the treatment and / or prevention of alopecia, comprising a combination of the compositions of the present invention, or a combination of compositions for use. [Brief explanation of the drawing]

[0011] [Figure 1] SALT scoring example (modified from Olsen, 2004) [Figure 2] SALT scores in patients treated with the composition continuously improved during and after treatment, 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]

[0012] In carrying out or testing the present invention, methods and materials similar to or equivalent to those described herein may be used, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for disclosure prior to the filing date of this application. Nothing in this specification should be construed as acknowledging that this application does not have priority over such publications due to prior inventions. Furthermore, the materials, methods and examples are illustrative and not intended to be limiting.

[0013] In the event of any conflict, this specification, including its definitions, shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to the extent of the subject matter herein. Where used herein, the following definitions are provided to facilitate understanding of the invention.

[0014] The terms "comprise / comprising" are generally used to mean "include / including," that is, to allow the presence of one or more features or components. The terms "comprise(s)" and "comprising" encompass the more restrictive terms "consist(s)," "consisting," and "consist / consisting essentially of," respectively.

[0015] In the specification and claims, unless otherwise clearly indicated by the context, the singular forms "a," "an," and "the" include the plural forms.

[0016] Where used herein, the terms “Subject” / “Subject requiring” or “Patient” / “Patient requiring” are widely recognized in the art and are used interchangeably herein, and refer to mammals including dogs, cats, rats, mice, monkeys, cattle, horses, goats, sheep, pigs, camels, and most preferably humans. In some cases, a Subject is a subject requiring treatment or a subject with a disease or disability. However, in other embodiments, a Subject may be a healthy subject. The term does not indicate a specific age or sex. Therefore, adult and neonatal subjects, whether male or female, are intended to be included in the Subject. Preferably, a Subject is a human, most preferably a human with alopecia or at risk of developing alopecia.

[0017] The term "approximately" is intended to include a deviation of plus or minus 20 percent (±20%), preferably plus or minus 10 percent (±10%), particularly with respect to a particular quantity, number, or percentage. For example, approximately 5 includes any value from 4.5 to 5.5, such as 4.5, 4.6, 4.7, 4.8, 4.9, 5, 4.1, 5.2, 5.3, 5.4, or 5.5.

[0018] As used herein, "at least one" means "one or more," "two or more," "three or more," etc. For example, "at least eight weeks" means eight weeks or more, i.e., nine weeks, ten weeks, eleven weeks, etc.

[0019] In one embodiment, the present invention provides a combination of compositions for use in the treatment and / or prevention of alopecia, which i) A first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount, and ii) A second pharmaceutical composition containing, as an active ingredient, a therapeutically effective amount of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species, and an extract of Theobroma species. comprising The first pharmaceutical composition and the second pharmaceutical composition are administered to the subject in need thereof, either in combination, separately, or with a time lag.

[0020] In one embodiment, the first pharmaceutical composition and the second pharmaceutical composition are administered in combination, i.e., co-administered simultaneously. For example, the first pharmaceutical composition and the second pharmaceutical composition are administered for as long as needed from the start or only for a specific period. In this case, when one or more therapeutic effects are detected usually after 24 to 36 weeks, the administration of the first pharmaceutical composition is discontinued, while the administration of the second composition is continued.

[0021] In another example, usually, the first pharmaceutical composition is administered first, and then the second pharmaceutical composition is administered usually within a few weeks (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 10 weeks, about 20 weeks, about 30 weeks). In this case, for example, when one or more therapeutic effects are detected usually after 24 to 36 weeks, the administration of the first pharmaceutical composition is discontinued, while the second composition is continuously administered.

[0022] In another embodiment, the first pharmaceutical composition and the second pharmaceutical composition are administered with a time shift. For example, the second pharmaceutical composition is administered after the last administration of the first pharmaceutical composition so that the administration periods do not overlap. Usually, the second pharmaceutical composition is administered after about 1 hour, about 1 day, about 4 days, about 1 week, about 2 weeks, about 3 weeks, about 5 weeks, about 10 weeks, about 15 weeks, about 20 weeks or more have passed after the last administration of the first pharmaceutical composition.

[0023] In one aspect, the first pharmaceutical composition is administered for a period necessary to detect one or more therapeutic effects including delay of hair loss, promotion of hair growth, and / or increase in hair density, which is verified by measurement of the Scalp Alopecia Severity Tool (SALT) score.

[0024] Typically, this period is between about 16 weeks and about 48 weeks, preferably between about 20 weeks and about 40 weeks, more preferably between about 20 weeks and about 36 weeks, and even more preferably about 36 weeks.

[0025] Any method known in the art can be used to detect, monitor, and / or verify one or more therapeutic effects including delay of hair loss, promotion of hair growth, and / or increase in hair density.

[0026] In one aspect, one or more therapeutic effects are detected, monitored, and / or verified by measuring the Scalp Alopecia Severity Tool (SALT) score.

[0027] In one aspect, the SALT score is determined or measured before the start of administration of the first pharmaceutical composition or combination of compositions.

[0028] In one aspect, the SALT score is determined or measured before the start of administration of the first pharmaceutical composition or combination of compositions. SALT scoring is a calculation based on a scoring system. The scalp is divided into four regions: the left side of the scalp, which occupies 18% of the scalp surface area; the right side of the scalp, which occupies 18%; the vertex, which occupies 40%; and the occipital region, which occupies 24%. The percentage of hair loss in each of the four scalp regions is determined independently, and each coefficient (left side and right side: 0.18 each, vertex: 0.40, occipital region: 0.24) is multiplied. The coefficients for each region vary according to the position. Then, the percentages of hair loss in all four regions are totaled to calculate the final total percentage of hair loss, called the SALT score.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] Typically, the baseline SALT score of a subject is measured before the initiation of administration of the composition of the present invention.

[0033] In one embodiment, a reduction in the SALT score 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 compared to the baseline SALT score of the subject measured before the initiation of administration of the first pharmaceutical composition.

[0034] Typically, administration of the first composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks. In one embodiment, the second composition is administered continuously. In another embodiment, administration of the second composition is initiated.

[0035] In one embodiment, the first composition and the second composition are administered together (i.e., in combination) for at least 1 hour, at least 1 day, at least 4 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 5 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, and at least 36 weeks or more.

[0036] The terms “treatment” or “treating” mean administering one or more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc., provided 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.

[0037] In this specification, “prevention” or “preventing” means administering one or more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc., described herein to a subject for the purpose of preventing a disease, that is, to prevent the clinical symptoms and signs of a disease from occurring.

[0038] In the context of this invention, "disease" refers to hair loss. In some embodiments, the hair loss is an immune-mediated disease, preferably an autoimmune disease. More preferably, the autoimmune disease is alopecia areata.

[0039] 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).

[0040] 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).

[0041] In one embodiment, the subjects requiring the present invention are those suffering from alopecia totalis / alopecia generalis (SALT score > 95), severe AA (SALT core between 50 and 95), moderate AA (SALT core between 25 and 50), or mild AA (SALT score < 25) (Solomon, 2015).

[0042] As used herein, “effective amount” means a therapeutically effective amount of one or more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc. of this disclosure, within reasonable medical judgment, that is sufficient to significantly improve the symptoms and / or condition being treated, while avoiding serious side effects (in a reasonable risk-benefit ratio).

[0043] In the context of the present invention, the first pharmaceutical composition contains a therapeutically effective amount of at least one type of inhibitor of protein tyrosine kinase (PTK) involved in cytokine signaling. Preferably, the inhibitor of protein tyrosine kinase (PTK) involved in cytokine signaling is a Janus kinase (JAK) inhibitor.

[0044] Over the past few years, various JAK inhibitors have been reported to show promising efficacy in various autoimmune diseases, including AA (Bose P. et al., 2017). Overexpression of JAK3 was observed in skin biopsy specimens from AA patients, and to a lesser extent, overexpression of JAK1 and JAK2 was also observed (Alves de Medeiros AK et al., 2016).

[0045] Janus kinase (JAK) inhibitors are a novel class of immunosuppressants. The first JAK inhibitor, ruxolitinib, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of rheumatoid arthritis. Since then, several other JAK inhibitors have been developed and approved for the treatment of other autoimmune diseases.

[0046] In recent years, two JAK inhibitors have been approved for the treatment of AA, an autoimmune disease. Baricitinib is approved for the treatment of severe AA in adults, and ritrecitinib is approved for the treatment of severe AA in adults and adolescents aged 12 years and older.

[0047] Severe AA is defined as patients with a Saliva Severity Rating Tool (SALT) score > 50. Therefore, patients with a SALT score < 50 are ineligible for JAK inhibitors. Patients with a SALT < 50 at the start of treatment should be prescribed medications approved for patients with a SALT < 50. Since both approved medications are only permitted for patients with severe AA (i.e., SALT ≥ 50), patients who are prescribed oral JAK inhibitors with a SALT ≥ 50 at the start of treatment will face problems if their hair loss progresses to a SALT < 50 level.

[0048] However, discontinuation of JAK inhibitors has been observed to lead to rapid and significant disease relapse (Yan, 2022). Since discontinuation of JAK inhibitors leads to disease relapse, continued treatment is necessary, even for patients with SALT < 50.

[0049] In a Phase 2 / 3 clinical trial conducted by the inventors (RAAINBOW trial), a composition containing therapeutically effective amounts of extracts from Allium species, Citrus species, Paulinia species, and Cacao species (hereinafter referred to as "the second pharmaceutical composition," preferably a topical formulation of the composition described herein) was evaluated positively not only in patients with severe AA but also in patients with moderate AA (SALT 25-50). Therefore, this composition can be used as a continuing treatment after discontinuation of JAK inhibitors.

[0050] Based on strong evidence, the inventors also cite the fact that the mechanisms of action of the two drugs are complementary as a reason to believe that using this composition after discontinuation of JAK inhibitors is effective.

[0051] The therapeutic effect of JAK inhibitors is based on broad, relatively nonspecific anti-inflammatory effects stemming from their ability to inhibit or disrupt multiple signaling pathways utilized by type I and type II cytokines (Gilhar et al., 2019). Since AA is a T-cell-mediated autoimmune disease, inhibiting downstream signaling initiated by pro-inflammatory cytokines such as IFNγ can prevent the recruitment of leukocytes to hair follicles and block the release of cytotoxic granzymes that cause hair loss (Stefanis et al., 2023). However, some T cells that invade hair follicles remain as "resident memory T cells" during treatment (Passeron et al., 2023). As a result, patients experience a relapse of alopecia when JAK inhibitor treatment is discontinued. This relapse is primarily caused by excessive cellular apoptosis resulting from the "de-suppression" of pro-inflammatory cytokines and other signaling molecules following the discontinuation of JAK inhibitor treatment, forcing the premature termination of the growth phase (anagen) and shifting hair follicles (HF) into the regression phase (catagen). This is a major underlying event in AA and a key indicator of immune privilege breakdown in AA development (Paus et al., 2018).

[0052] The second pharmaceutical composition of the present invention not only has anti-inflammatory function, but also normalizes the apoptotic process by upregulating the cell expression of the anti-apoptotic protein Bcl-2 in the scalp to a level equivalent to that of healthy individuals, thereby exerting beneficial effects on the hair follicle / perifollicle region, extending the growth phase and preventing the premature onset of the regression phase. On the other hand, the improvement in Ki-67 expression observed in hair follicle cells after use of this composition indicates enhanced cell viability, which means an increase in the number of cells in the active cell cycle (Cuce et al., 2011).

[0053] In one embodiment, the JAK inhibitor is selected from the group including JAK1 inhibitors, JAK2 inhibitors, JAK3 inhibitors, tyrosine kinase 2 (TYK2) inhibitors, or one or more combinations thereof (e.g., JAK1 inhibitor / JAK2 inhibitor, JAK1 inhibitor / JAK3 inhibitor, and / or JAK2 inhibitor / JAK3 inhibitor combinations).

[0054] Non-exclusive examples of JAK1 inhibitor / JAK2 inhibitor combinations include the group containing baricitinib, ruxolitinib, and deuruxolitinib.

[0055] Non-restrictive examples of JAK1 inhibitors are selected from the group including abrocitinib and upadacitinib.

[0056] Non-restrictive examples of JAK3 inhibitors are selected from the group including ritrecitinib and tofacitinib.

[0057] The first pharmaceutical composition is administered by a route selected from intramuscular injection, intraperitoneal injection, intravenous infusion, intradermal administration, subcutaneous administration, oral administration, inhalation, transdermal administration, topical administration, transmucosal administration, nasal administration, rectal administration, or a combination thereof. In one embodiment, the first pharmaceutical composition is administered by an oral or topical administration route.

[0058] Appropriate topical formulations 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.

[0059] In the context of the present invention, the second pharmaceutical composition of the present invention comprises effective amounts of extracts of Allium species, Citrus species, Paullinia species, and Theobroma species as active ingredients.

[0060] The term Allium species extract, or aqueous alcohol extract, more specifically refers to aqueous alcohol extracts and natural extracts (e.g., aqueous extracts) obtained from all species of the genus Allium (Liliaceae), especially from onion (Allium cepa).

[0061] The term "citrus extract" or "aqueous alcohol extract" more specifically refers to aqueous alcohol extracts and natural extracts (e.g., aqueous extracts) obtained from all species of the genus Citrus (Rutaceae), particularly from Citrus limon.

[0062] The term Paullinia extract (whether in spray form or not) or aqueous alcohol extract refers more specifically to aqueous alcohol extracts and natural extracts (e.g., aqueous extracts) obtained from all species of the genus Paullinia (Sapindaceae), especially from guarana (Paullinia cupana).

[0063] The term Theobroma extract (whether in spray form or not) or aqueous alcohol extract refers more specifically to aqueous alcohol extracts and natural extracts (e.g., aqueous extracts) obtained from all species of the genus Theobroma (Malvaceae), especially from cacao (Theobroma cacao).

[0064] In one embodiment of the present invention, the second pharmaceutical composition of the present invention, or the pharmaceutical composition for use, is typically administered topically to the external skin surface of the skull.

[0065] In a related embodiment, the second pharmaceutical composition of the present invention is prepared for topical administration. Preferably, the second pharmaceutical composition is mixed with a diluent and / or excipient for preparing a composition for topical administration, and the mixture contains about 20% by weight or more based on the total weight of the second pharmaceutical composition.

[0066] Typically, the second pharmaceutical 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.

[0067] Preferably, to cover the entire scalp of the subject, a second pharmaceutical composition prepared for topical administration is applied in a volume between approximately 0.5 ml and 2.5 ml at a frequency of at least once a day, at least twice a day, or more frequently.

[0068] In one embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical 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.

[0069] In a preferred embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical 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).

[0070] In a more preferred embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical 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 contains about 0.67% by weight of an aqueous alcohol extract of cocoa.

[0071] In one embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical composition (mode of use), further comprises excipients and / or diluents. Typically, based on the total weight of the composition, preferably the total weight of the second pharmaceutical composition prepared for topical administration (i.e., the topical pharmaceutical composition), the excipients include sodium chloride in an amount of about 0.05% to about 8.0% by weight and glycerin in an amount of about 1% to about 40% by weight.

[0072] In one embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical composition for use, contains sodium chloride in an amount of 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, based on the total weight of the composition, preferably the total weight of the second pharmaceutical composition prepared for topical administration (i.e., the topical pharmaceutical composition).

[0073] In one embodiment, the second pharmaceutical composition of the present invention, or the second pharmaceutical composition for use, contains glycerin in an amount of 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 more preferably about 2% to about 5% by weight, based on the total weight of the composition, preferably the total weight of the second pharmaceutical composition prepared for topical administration (i.e., the topical pharmaceutical composition).

[0074] A second pharmaceutical composition suitable for or prepared for topical administration according to the present invention includes 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 composition of the present invention suitable for or prepared for topical administration is in the form of a solution or lotion.

[0075] In some embodiments, one or more therapeutic effects are remarkably persistent and even improve. As noted by the inventors, one or more therapeutic effects last for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, and at least 24 weeks or more after the final dose of the second pharmaceutical composition, which is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0076] [SALT > 95] In a preferred embodiment, the first pharmaceutical composition is administered to patients whose degree of hair loss is determined to be SALT95 or higher, and the second pharmaceutical composition is administered only when the degree of hair loss reaches SALT95. Thereafter, administration of the first pharmaceutical composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks, while administration of the second pharmaceutical composition is maintained.

[0077] [SALT < 95] In a preferred embodiment, the first and second pharmaceutical compositions are administered jointly to patients whose degree of hair loss is determined to be less than SALT95. Subsequently, the administration of the first pharmaceutical composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks, and treatment with the second pharmaceutical composition is continued.

[0078] The present invention also covers pharmaceutical compositions used for the treatment and / or prevention of alopecia, the compositions containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients, the pharmaceutical compositions being administered to subjects in need, as described herein, in combination with a pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor.

[0079] The present invention also envisions a pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients, for use in the treatment and / or prevention of alopecia in subjects requiring such treatment, as described herein. This pharmaceutical composition is administered when administration of a first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically significant amount is discontinued.

[0080] The present invention also envisions a method for treating and / or preventing alopecia in subjects. In one embodiment, a method for treating and / or preventing alopecia in subjects comprises: i) administering a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor; and ii) administering a second pharmaceutical composition containing a therapeutically effective amount of an extract of an Allium species, a Citrus species, a Paulinia species, and a Theobroma species as active ingredients. The first pharmaceutical composition and the second pharmaceutical composition are administered to subjects requiring them, either in combination or with a time difference, as described herein.

[0081] In one embodiment, a method for treating and / or preventing alopecia in a subject comprises administering a second pharmaceutical composition containing, as an active ingredient, an extract of an Allium species, an extract of a Citrus species, an extract of a Paulinia species, and an extract of a Theobroma species, upon discontinuation of administration of a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor.

[0082] The present invention further envisions the use of the pharmaceutical compositions of the present invention in the manufacture of pharmaceuticals for the treatment and / or prevention of alopecia in subjects, which comprises i) administering a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor, and ii) administering a second pharmaceutical composition containing a therapeutically effective amount of an extract of an Allium species, a Citrus species, a Paulinia species, and a Theobroma species as an active ingredient, wherein the first and second pharmaceutical compositions are administered in combination or with a time difference to subjects requiring such treatment, as described herein.

[0083] The present invention also envisions the use of a pharmaceutical composition of the present invention, containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients, in the manufacture of a pharmacopoeia for the treatment and / or prevention of alopecia in a subject, which is administered when administration of a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.

[0084] 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 pharmaceutical composition of the present invention, or a composition for use.

[0085] The kit of the present invention may 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, and spray applicators. Containers can be formed from a variety of materials, such as glass or plastic.

[0086] In one embodiment, the kit comprises at least two containers, each corresponding to one of the compositions of the present invention.

[0087] Labels or accompanying documents may include instructions on how to use the product. These instructions may be affixed to the packaging material or included as accompanying documents. The instructions are typically, but not limited to, written or printed materials. This disclosure assumes any medium capable of holding such instructions and communicating support to the end user.

[0088] 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.

[0089] [Examples] Materials and methods 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).

[0090] 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.

[0091] A finished skin solution product (LH-8) containing 22.25% of this composition, which includes effective amounts of extracts from Allium, Citrus, Paulinia, and Theobroma species as active ingredients, was evaluated in a clinical trial (RAAINBOW trial, ClinicalTrials.gov identifier NCT03240627) to assess its safety and efficacy 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).

[0092] 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.

[0093] [Example 1 Results] The safety analysis is summarized below.

[0094] [Table 1]

[0095] No serious adverse events (AEs) were reported in the composition group. Only 5.6% of participants 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 in 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, local, and transient. No side effects observed with JAK inhibitors were reported.

[0096] No serious adverse events (AEs) were reported in the composition group. Only 5.6% of participants 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 in 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, local, and transient. No side effects observed with JAK inhibitors were reported.

[0097] This composition is completely safe in the treatment of AA and therefore does not require any interruption of treatment. Thus, this composition can be used chronically without any health risk to the user.

[0098] This composition has demonstrated clinical efficacy in treating AA patients with less than 95% hair loss (SALT<95) and carries no health risks. Therefore, the present invention includes switching treatment from JAK inhibitors to this composition, thereby maintaining the patient's recovery from the disease while discontinuing exposure to drugs that have been reported to cause long-term health risks. This novel treatment method is justified because, as described below, this composition has been shown to potentially provide an equivalent disease recovery rate.

[0099] Presentation of Janus kinase (JAK) inhibitors JAK inhibitors have been evaluated in the treatment of AA patients with hair loss of 50% or more (SALT>50). In clinical trials, multiple JAK inhibitors have been evaluated after 24 to 36 weeks of treatment, and their clinical efficacy has been confirmed in placebo-controlled settings.

[0100] Alopecia areata (AA) was assessed using the SALT (Alopecia Areata Severity Assessment Tool) score, a globally standardized scalp photograph-based alopecia areata severity score. 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. The SALT score is a standard measurement endpoint used in all trials evaluating the effectiveness of novel treatments in AA (see Figure 1).

[0101] To date, three JAK inhibitors (baricitinib, ritrecitinib, and deulxolitinib) have been evaluated in late-stage clinical trials targeting AA patients with SALT > 50. For these three JAK inhibitors, the primary endpoint was the proportion of patients who achieved SALT < 20 or less than 20% hair loss.

[0102] Regarding baricitinib, in the first trial, the estimated proportion of patients with a SALT score of 20 or less at 36 weeks was 38.8% in the 4 mg baricitinib group, 22.8% in the 2 mg baricitinib group, and 6.2% in the placebo group. In the second trial, these figures were 35.9%, 19.4%, and 3.3%, respectively. (King 2021)

[0103] Regarding ritrecitinib, at 24 weeks, 31% of patients in the ritrecitinib 200 mg + 50 mg group, 22% in the 200 mg + 30 mg group, 23% in the 50 mg group, 14% in the 30 mg group, and 2% in the placebo group achieved a SALT score of 20 or less (King, 2023).

[0104] Regarding deulxolitinib, at the 24-week endpoint, 38.3% of patients in the 12 mg twice daily dose group and 33.0% in the 8 mg twice daily dose group achieved a SALT score of 20 or less, compared to only 0.8% in the placebo group (press release).

[0105] For this composition, the proportion of patients with a SALT score of 20 or less was 21.2% in the composition group and 5.3% in the placebo group at 24 weeks, and 46.7% and 9.1%, respectively, at 48 weeks. While the degree of alopecia (AA) exceeded 50% in patients in the JAK inhibitor trial, the degree of alopecia was 25-95% in patients treated with this composition (SALT 25-95).

[0106] Since discontinuation of JAK inhibitors causes disease relapse within three months (Yann, 2022), protocols for discontinuing JAK inhibitors and switching to other treatment compositions are designed to minimize disease relapse.

[0107] [Example 2] [Combination therapy - when the degree of hair loss exceeds SALT 95] For AA patients with alopecia exceeding SALT95, the treatment plan involves initiating treatment with the approved JAK inhibitor baricitinib at 4 mg once daily, followed by administration of the second pharmaceutical composition at 1 ml twice daily once alopecia reaches SALT95. After 36 weeks, JAK inhibitor treatment is discontinued, and treatment with the second pharmaceutical composition is continued.

[0108] [Example 3] [Combination therapy - when the degree of hair loss is less than SALT 95] For AA patients with hair loss severity less than SALT95, the treatment plan includes administering 1 ml twice daily, either concurrently or in combination. After 36 weeks, JAK inhibitor therapy is discontinued, and treatment with the second pharmaceutical composition is continued.

[0109] [result] In both cases, hair regeneration continued over time, and no long-term health risks were observed from the long-term use of the composition of the present invention.

[0110] References https: / / pi.lilly.com / us / olumiant-uspi.pdf

[0111] [Table 2]

[0112] https: / / www.fda.gov / drugs / drug-safety-and-availability / fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death https: / / www.ema.europa.eu / en / news / ema-confirms-measures-minimise-risk-serious-side-effects-janus-kinase-inhibitors-chronic https: / / ir.concertpharma.com / news-releases / news-release-details / late-breaking-phase-3-data-aad-2023-show-oral-investigational

Claims

1. A combination of compositions for use in the treatment and / or prevention of alopecia, i) A first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount, and ii) A second pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. It includes, The first pharmaceutical composition and the second pharmaceutical composition are a combination of compositions that are administered to subjects requiring them, either in combination or with a time difference.

2. The combination of compositions for use according to claim 1, wherein the first pharmaceutical composition is administered 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, which is verified by measuring the Alopecia Severity Assessment Tool (SALT) score.

3. The combination of compositions for use according to claim 2, 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 36 weeks, and even more preferably between approximately 36 weeks.

4. The combination of compositions for use according to claim 1, claim 2, or claim 3, wherein administration of the first composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks.

5. A combination of compositions for use according to any one of claims 1 to 3, wherein the first composition and the second composition are administered in combination for at least 1 hour, at least 1 day, at least 4 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 5 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, and at least 36 weeks or more.

6. A combination of compositions for use according to any one of claims 1 to 3, wherein the first composition and the second composition are administered with a time difference, and the second pharmaceutical composition is administered after the final administration of the first pharmaceutical composition.

7. The combination of compositions for use according to claim 6, wherein the second pharmaceutical composition is administered approximately 1 hour, approximately 1 day, approximately 4 days, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 5 weeks, approximately 10 weeks, approximately 15 weeks, or approximately 20 weeks or more after the final administration of the first pharmaceutical composition.

8. A combination of compositions for use according to any one of claims 1 to 3, wherein the alopecia is an immune-mediated disease.

9. The combination of compositions for use according to claim 8, wherein the immune-mediated disease is an autoimmune disease.

10. The combination of compositions for use according to claim 9, wherein the autoimmune disease is alopecia areata.

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

12. A combination of compositions 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 first pharmaceutical composition was initiated.

13. The combination of compositions for use according to any one of claims 1 to 3, wherein the JAK inhibitor is selected from the group comprising a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, or a combination of one or more thereof.

14. The combination of compositions for use according to claim 13, wherein the JAK1 inhibitor is selected from the group comprising abrocitinib and upadacitinib, or a combination thereof.

15. The combination of compositions for use according to claim 13, wherein the JAK3 inhibitor is selected from the group comprising ritrecitinib and tofacitinib, or a combination thereof.

16. The combination of a JAK1 inhibitor / JAK2 inhibitor is selected from the group comprising baricitinib, ruxolitinib, and deuruxolitinib, or a combination of two or more thereof, as described in claim 13.

17. A combination of compositions for use according to any one of claims 1 to 3, wherein the second pharmaceutical composition 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 about 0.25% to about 2.5% by weight of an aqueous alcohol extract of a Theobroma species.

18. A combination of compositions for use according to any one of claims 1 to 3, wherein the first pharmaceutical composition is administered by a route selected from the group including intramuscular injection, intraperitoneal injection, intravenous drip, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, nasal, rectal, or a combination thereof.

19. A combination of compositions for use according to any one of claims 1 to 3, wherein the second pharmaceutical composition is administered topically.

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

21. A combination of compositions for use according to any one of claims 1 to 3, wherein the second pharmaceutical composition contains sodium chloride in an amount of 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, based on the total weight of the topical pharmaceutical composition.

22. A combination of compositions for use according to any one of claims 1 to 3, wherein the second pharmaceutical composition contains glycerin in an amount of 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, based on the total weight of the topical pharmaceutical composition.

23. If the degree of hair loss is determined to be higher than SALT95, i) The first pharmaceutical composition is administered, ii) A combination of compositions for use according to any one of claims 1 to 3, wherein the second pharmaceutical composition is administered when the degree of hair loss reaches SALT 95.

24. The combination of compositions for use according to claim 23, wherein the administration of the first pharmaceutical composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks, and the administration of the second pharmaceutical composition is maintained.

25. A combination of compositions for use according to any one of claims 1 to 3, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered together if the degree of hair loss is determined to be less than SALT 95.

26. The combination of compositions for use according to claim 25, wherein the administration of the first pharmaceutical composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, and even more preferably after 36 weeks, and the administration of the second pharmaceutical composition is maintained.

27. A method for treating and / or preventing alopecia in the subject, i) Administering a first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount, and ii) Administer a second pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. Includes, The first pharmaceutical composition and the second pharmaceutical composition are administered to the person in need, either in combination or with a time difference.

28. The method for treatment and / or prevention according to claim 27, wherein the first pharmaceutical composition is administered by a route selected from the group including intramuscular injection, intraperitoneal injection, intravenous drip, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, nasal, rectal, or a combination thereof.

29. The method for treatment and / or prevention according to claim 27 or 28, wherein the second pharmaceutical composition is administered topically.

30. The method for treatment and / or prevention according to claim 29, wherein the second pharmaceutical composition is mixed with a diluent and / or excipient for preparing a composition for topical administration, and comprises about 20% by weight or more based on the total weight of the second pharmaceutical composition.

31. The use of a combination of compositions according to any one of claims 1 to 3 in the manufacture of a pharmaceutical product for the treatment and / or prevention of alopecia in a subject, i) Administering a first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount, and ii) Administer a second pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. Includes, The use of a combination of compositions, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered in combination or with a time difference to a person who requires them.

32. A kit for the treatment and / or prevention of alopecia, comprising a composition for use according to any one of claims 1 to 3.

33. The kit according to claim 32, further comprising one or more containers, and labels or accompanying documents attached to or associated with the one or more containers.

34. A pharmaceutical composition for use in the treatment and / or prevention of alopecia, comprising an effective therapeutic amount of an extract of an Allium species, an extract of a Citrus species, an extract of a Paulinia species, and an extract of a Theobroma species. A pharmaceutical composition which is administered to a person in need of such a treatment in combination with a pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor in a therapeutically effective amount.

35. A pharmaceutical composition for use in the treatment and / or prevention of alopecia in subjects requiring it, containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients. The pharmaceutical composition is administered when administration of a first pharmaceutical composition containing at least one Janus kinase (JAK) inhibitor is discontinued.

36. A method for treating and / or preventing alopecia in a subject, comprising administering a second pharmaceutical composition containing therapeutically effective amounts of extracts of Allium species, Citrus species, Paulinia species, and Theobroma species as active ingredients when administration of a first pharmaceutical composition containing a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.

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