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WO2024236153A1 - Combinaison de composition destinée à être utilisée dans le traitement et/ou la prévention de la chute des cheveux - Google Patents

Combinaison de composition destinée à être utilisée dans le traitement et/ou la prévention de la chute des cheveux Download PDF

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Publication number
WO2024236153A1
WO2024236153A1 PCT/EP2024/063618 EP2024063618W WO2024236153A1 WO 2024236153 A1 WO2024236153 A1 WO 2024236153A1 EP 2024063618 W EP2024063618 W EP 2024063618W WO 2024236153 A1 WO2024236153 A1 WO 2024236153A1
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Prior art keywords
pharmaceutical composition
composition
extract
weeks
species
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English (en)
Inventor
Saad Harti
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Legacy Healthcare Switzerland SA
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Legacy Healthcare Switzerland SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/577—Malvaceae (Mallow family)
    • A61K36/5777—Theobroma, e.g. cocao or cocoa
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/882—Mixing prior to application
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/884—Sequential application

Definitions

  • Composition combination for use in the treatment and/or prevention of hair loss
  • the invention relates to a composition combination for use in the treatment and/or prevention of hair loss in a subject. Also disclosed are kits and methods of treating and/or preventing hair loss using said composition combination.
  • JAK Japanese kinase
  • cytokines operate through the JAK/STAT (signal transducer and activator of transcription) pathway that plays critical roles in orchestrating immune system. Dysregulation of the JAK-STAT pathway may result in pathological processes of various immune and inflammatory disorders.
  • Oral and topical JAK inhibitors are approved for the treatment of various autoimmune and inflammatory mediated chronic conditions, including alopecia areata (AA), an immune mediated disease characterized by patchy or total loss of scalp and/or body hair.
  • AA alopecia areata
  • JAK inhibitors have been documented to trigger serious side effects (Hoisnard, 2022), including serious infections, major adverse cardiovascular event (MACE), thrombosis, malignancy and mortality, as mentioned in the prescribing information of several JAK inhibitors, including baricitinib (Olumiant ®), and ritlecitinib (Litfulo®), two JAK inhibitor approved for the treatment of AA (prescribing information).
  • composition combination for use in the treatment and/or prevention of hair loss, comprising, i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered in time to a subject in need thereof.
  • a composition combination for use in the treatment and/or prevention of hair loss, comprising, i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical composition
  • a further object of the present invention is to provide a method of treatment and/or prevention of hair loss in a subject comprising, administering i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered in time to a subject in need thereof.
  • a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered
  • a further object of the present invention is to provide the use of a composition of the invention in the manufacture of a medicament for the treatment and/or prevention of hair loss in a subject, comprising, administering i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered in time to a subject in need thereof.
  • a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical
  • a further object of the present invention is to provide a kit for the treatment and/or prevention of hair loss comprising a combination composition, or combination composition for use, of the invention.
  • the subject is a subject in need of treatment or a subject with a disease or disorder.
  • the subject can be a normal subject.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.
  • the subject is a human, most preferably a human suffering from hair loss or a human that might be at risk of suffering from hair loss.
  • the term “about,” particularly in reference to a given quantity, number or percentage, is meant to encompass deviations of plus or minus twenty percent ( ⁇ 20%), preferably plus or minus ten percent ( ⁇ 10%).
  • about 5 encompasses any value between 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.
  • At least one means “one or more”, “two or more”, “three or more”, etc.
  • at least 8 weeks means 8 weeks or more i.e., 9 weeks, 10 weeks, 11 weeks, etc.
  • the invention provides a composition combination for use in the treatment and/or prevention of hair loss, comprising, i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered in time to a subject in need thereof.
  • a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly, separately or staggered in time to a subject in need
  • the first and the second pharmaceutical compositions are administered concomitantly, i.e. co-administered, at the same time.
  • the first and the second pharmaceutical compositions are administered from the beginning and as long as necessary or only during a period of time.
  • administration of the first pharmaceutical composition is discontinued once one or more therapeutic effects are detected, usually after 24 to 36 weeks, whereas the second composition continues to be administered.
  • the first pharmaceutical composition is usually administered first, and the second pharmaceutical composition is administered thereafter, usually within weeks (e.g. about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, weeks).
  • administration of the first pharmaceutical composition is discontinued once one or more therapeutic effects are detected, e.g. usually after 24 to 36 weeks, whereas the second composition continues to be administered.
  • the first and the second pharmaceutical compositions are administered staggered in time, e.g. there is no overlap in the administration as the second pharmaceutical composition is administered after the last administration of the first pharmaceutical composition.
  • the second pharmaceutical composition is administered about one hour, about 1 day, about 4 days, about one week, about 2 weeks, about 3 weeks, about 5 weeks, about 10 weeks, about 15 weeks, about 20 weeks or more, after the last administration of the first pharmaceutical composition.
  • the first pharmaceutical composition is administered for a period of time necessary to detect one or more therapeutic effects consisting of slowing down the loss of hair, stimulating its growth and/or increasing the density of hair, as evidenced by measuring the severity of alopecia tool (SALT) score.
  • SALT alopecia tool
  • said period of time is comprised between about 16 to about 48 weeks, preferably between about 20 to about 40 weeks, more preferably between about 20 and about 36 weeks and even more preferably about 36 weeks.
  • Any method known in the art may be used to detect, monitor and/or evidence the one or more therapeutic effects consisting of slowing down the loss of hair, stimulating its growth and/or increasing the density of hair.
  • the one or more therapeutic effects are detected, monitored and/or evidenced by measuring the severity of alopecia tool (SALT) score.
  • SALT alopecia tool
  • the SALT score is determined or measured before of the starting the administration of the first pharmaceutical composition or of the combination composition.
  • the SALT score is determined or measured at the beginning of the starting the administration of the first pharmaceutical composition or of the combination composition.
  • SALT scoring is a calculation based on a scoring system. Scalp is divided into four areas: left side of scalp representing 18% of the scalp surface area, right side of scalp - 18% of scalp surface area; top - 40% of scalp surface area and back - 24% of scalp surface area.
  • the percentage of hair loss in each of the four scalp areas is determined independently, each multiplied by its coefficient (left and right side: 0.18 each; top: 0.40 and back 0.24). The coefficient of each area varies according to the location. Then the resulting hair loss percentages of all four areas are summed up for a final total % hair loss, designated as the SALT score.
  • the percentage of hair loss in each quadrant is determined independently, each multiplied by its coefficient (0.04, 0.05, 0.06 or 0.1).
  • the coefficient of each quadrant varies according to the location ( Figure 1). Then the resulting hair loss percentages of all four areas (16 quadrants) are summed up for a final total percentage of hair loss, designated as the SALT score.
  • the SALT scoring is thus computer implemented.
  • the SALT score assessment described by Olsen is used to detect, monitor and/ or evidence the one or more therapeutically effects.
  • a subject's baseline SALT score is determined before starting the administration of a composition the invention.
  • a decrease of at least about 2% or more, at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, or at least about 50% or more in SALT score is detected when compared to the subject's baseline SALT score determined before starting the administration of the first pharmaceutical composition.
  • the administration of the first composition is discontinued after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, even more preferably after 36 weeks.
  • the second composition continues to be administered.
  • the administration of the second composition is started.
  • the first and second compositions are co-administered (i.e. concomitantly) for at least 1 hour, at least 1 day, at least 4 days, at least one 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, at least 36 weeks or more.
  • treatment means any administration of one or more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc. . . of the disclosure to a subject for the purpose of:
  • prevention means any administration of one ore more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc. . . of the disclosure to a subject for the purpose of preventing the disease, that is, causing the clinical symptoms and signs of the disease not to develop.
  • the disease is hair loss.
  • the hair loss is an immune-mediated disease, preferably an autoimmune disease. More preferably, the autoimmune disease is Alopecia Aerata.
  • Alopecia Areata is an immune-mediated, auto-immune, inflammatory hair disease affecting both paediatric and adult patients.
  • the immunoinflammatory attack of scalp hair follicles aborts normal hair cycling leading to their early entry in catagen and telogen and hair loss.
  • the disease starts with the occurrence of a perifollicular inflammation and invasion of immunoinflammatory cells around the anagen hair bulbs causing HF immune privilege collapse, tissue dystrophy, HF cell death, and hair shaft shedding (Lintzeri-2022).
  • a central role is played by NKG2D + T cells and natural killer (NK) cells and autoreactive CD8+ T- lymphocytes that recognize autoantigens upon exposure of MHC I, II expression on follicular cells.
  • T-cell activation is accompanied by an elevated IFN- y secretion recruiting or activating more inflammatory cells including macrophages, mast cells, and dendritic cells leading to accelerated cell death and apoptosis of hair follicular cells (Bertolini, M., 2020).
  • AA early clinical manifestations appear as random, patchy hair loss - that may result sometimes in total scalp hair loss (alopecia totalis) or even become generalized to all body parts (alopecia universalis). AA affects patients from all ethnicities, but more women than men, with similar clinical manifestations. Most importantly, when AA starts early in infancy, its prognosis is usually more severe and associated with a higher frequency of unpredictable relapses during adulthood (Villasante Fricke, A.C., 2015).
  • the subject in need thereof is a subject suffering from Alopecia Totalis/Universalis (SALT score > 95) or severe AA (SALT core between 50-95), or moderate AA (SALT core between 25-50) or mild AA (SALT score ⁇ 25) (Solomon, 2015).
  • an effective amount means a therapeutically effective amount of one or more compositions, pharmaceutical compositions, therapeutic agents, active ingredients, compounds, etc of the disclosure, high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable risk/benefit ratio), within the scope of sound medical judgment.
  • the first pharmaceutical composition comprises a therapeutically effective amount of at least one inhibitor of a protein tyrosine kinase (PTK) involved in cytokine signalling.
  • the inhibitor of a protein tyrosine kinase (PTK) involved in cytokine signalling is a Janus kinase (JAK) inhibitor.
  • JAK inhibitors have been reported to have promising efficacy in various autoimmune disorders, including AA (Bose P. et al., 2017). Overexpression of JAK3 and, to a lesser extent, JAK1 and JAK2 was observed in skin biopsy specimens of patients with AA (Alves de Medeiros AK et al., 2016).
  • Janus kinase (JAK)-inhibitors is a new class of immunosuppressant drugs.
  • the first JAK inhibitor, ruxolitinib was approved in 2011 by the US Food and drug Administration (FDA) for the treatment of rheumatoid arthritis. Since then, several other JAK inhibitors have been developed and approved for the treatment of other autoimmune diseases.
  • FDA US Food and drug Administration
  • Severe AA defines as patients with Severity of Alopecia Tool (SALT) score > 50. Patients with SALT score ⁇ 50 are therefore not eligible to use JAK inhibitors. Patients who have a SALT ⁇ 50 at start of treatment should be prescribed a drug which is authorized for patients with SALT ⁇ 50. For patients with SALT > 50 at start of treatment and prescribed an oral JAK inhibitor, an issue arises when their alopecia extent reaches SALT ⁇ 50 since both drugs approved are allowed only for patients with severe AA (i.e., SALT > 50).
  • JAK inhibitors discontinuation leads to rapid and significant disease relapse (Yan, 2022). Since JAK inhibitors’ discontinuation leads to disease relapse, a continuation treatment which is allowed to be used in patients with SALT ⁇ 50 is needed.
  • the composition (herein "the second pharmaceutical composition", preferably a topical formulation of the composition as described herein) comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species was authorized to be evaluated not only in patients with severe AA, but also in patients with moderate AA (SALT 25-50).
  • the composition could therefore be used as a continuation treatment after JAK inhibitors discontinuation.
  • JAK inhibitors The therapeutic efficacy of JAK inhibitors is based on their broad, relatively non-specific antiinflammatory activities as a result of their ability to block or disrupt several signaling pathways used by type I and type II cytokines (Gilhar et al., 2019).
  • AA is a T-cell mediated autoimmune disorder
  • disruption of downstream signaling initiated by these pro-inflammatory cytokines, such as IFNy can hinder leucocyte recruitment to the hair follicle and block the release of cytotoxic granzymes which are responsible for hair loss (Stefanis et al., 2023)
  • some of the T cells which invade the hair follicle remain there during treatment, as ‘resident memory T cells’ (Passeron et al., 2023)
  • patients experience recurrence of alopecia.
  • the second pharmaceutical composition of the invention not only has anti-inflammatory function, but also exerts its beneficial effects on hair follicle/perifollicular areas by normalizing the apoptotic process via upregulating cell expression of the anti-apoptotic protein Bcl-2 in the scalp towards the level identified in healthy subjects, thus prolonging anagen phase and preventing the premature onset of catagen. Meanwhile, the observed improved expression of Ki-67 in hair follicle cells after use of the composition indicates enhanced cell survival capacity, signifying higher number of active cycling cells (Cuce et al., 2011).
  • the JAK inhibitor is selected from the group comprising a JAK 1 inhibitor, a JAK 2 inhibitor, a JAK 3 inhibitor, and a tyrosine kinase 2 (TYK2) inhibitor, or a combination of one or more thereof (such as e.g. combination of JAK1/JAK2 inhibitors, JAK1/JAK3 inhibitors, and/or JAK2/JAK3 inhibitors).
  • Non limiting examples of combined JAK1/JAK2 inhibitors are selected from the group comprising baricitinib, ruxolitinib and deuruxolitinib.
  • JAK1 inhibitors are selected from the group comprising abrocitinib and upadacitinib.
  • Non limiting examples of JAK3 inhibitors are selected from the group comprising ritlecitinib and tofacitinib.
  • the first pharmaceutical composition is administered in a route selected from the group comprising intra-muscular injection, intra-peritoneal injection, an infusion, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, nasal and rectal, or a combination thereof.
  • the first pharmaceutical composition is administered by oral or topical route.
  • Suitable topical administration formulations include liquid or semi-liquid preparations suitable for penetration through the skin 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.
  • the second pharmaceutical composition of the invention comprises, as active ingredients, effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species active Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species.
  • extract or aqueous-alcoholic extract, of Allium species refers particularly to aqueous-alcoholic extracts and native extracts (e.g. aqueous extracts) obtained from all species of the genus Allium (family Liliaceae) and especially Allium cepa.
  • extract, or aqueous-alcoholic extract, of Citrus species refers particularly to aqueous-alcoholic extracts and native extracts (e.g. aqueous extracts) obtained from all species of the genus Citrus (family Rutaceae) and especially Citrus lemon.
  • extract atomised or not
  • aqueous-alcoholic extract of Paullinia species refers particularly to aqueous-alcoholic extracts and native extracts (e.g. aqueous extracts) obtained from all species of the genus Paullinia (family Sapindaceae) and especially Paullinia cupana.
  • extract atomised or not
  • aqueous-alcoholic extract of Theobroma species refers particularly to aqueous-alcoholic extracts and native extracts (e.g. aqueous extracts) obtained from all species of the genus Theobroma (family Malvaceae) and especially Theobroma cacao.
  • the second pharmaceutical composition, or pharmaceutical composition for use, of the invention is administered topically, usually on external skin surface of the skull.
  • the second pharmaceutical composition is usually formulated for topical administration.
  • the second pharmaceutical composition is mixed with diluents and/or excipients to formulate a composition for topical administration containing about 20% or more by weigh, based on the total weight of the second pharmaceutical composition.
  • the second pharmaceutical composition of the invention is administered topically, preferably on external skin surface of the skull, at least once per day, at least twice per day, or more.
  • a volume comprised between about 0.5 ml and 2.5 ml of the second pharmaceutical composition formulated for topical administration is applied, at least once per day, at least twice per day, or more, in order to cover the whole scalp of the subject.
  • the second pharmaceutical composition, or second pharmaceutical composition for use, of the invention comprises from about 65% to about 93% by weight of an aqueous- alcoholic extract of Allium species; from about 5% to about 33% by weight of an aqueous- alcoholic extract of Citrus species; from about 0.25% to about 2.5% by weight of an aqueous extract of Paullinia species; and from about 0.25% to about 2.5% by weight of an aqueous- alcoholic extract of Theobroma species.
  • the second pharmaceutical composition, or second pharmaceutical composition for use, of the invention comprises from about 65% to about 93% by weight of an aqueous-alcoholic extract of Allium cepa; from about 5% to about 33% by weight of an aqueous-alcoholic extract of Citrus lemon; from about 0.25% to about 2.5% by weight of an aqueous extract of Paullinia cupana; and from about 0.25% to about 2.5% by weight of an aqueous-alcoholic extract of Theobroma cacao.
  • the second pharmaceutical composition, or second pharmaceutical composition for use, of the invention comprises about 87% by weight of an aqueous-alcoholic extract of Allium cepa; about 12% by weight of an aqueous-alcoholic extract of Citrus lemon; about 0.67% by weight of an aqueous extract of Paullinia cupana; and about 0.67% by weight of an aqueous-alcoholic extract of Theobroma cacao.
  • the second pharmaceutical composition of the invention further contains excipients and/or diluents.
  • excipients from about 0.05% to about 8.0% by weight of sodium chloride and from about 1% to about 40% by weight of glycerine are present, based on the total weight of the composition, preferably of the second pharmaceutical composition formulated for topical administration (i.e. topical pharmaceutical composition).
  • the second pharmaceutical composition of the invention comprises from about 0.05% to about 8.0%, preferably from about 0.1% to about 7.0%, more preferably from about 0.4% to about 6.0%, and even more preferably from about 0.9% to about 3% by weight of sodium chloride, based on the total weight of the composition, preferably of the second pharmaceutical composition formulated for topical administration (i.e. topical pharmaceutical composition).
  • the second pharmaceutical composition of the invention comprises from about 1% to about 20%, preferably from about 1.2% to about 15%, more preferably from about 1.8% to about 10%, and even more preferably from about 2% to about 5% by weight of glycerine, based on the total weight of the composition, preferably of the second pharmaceutical composition formulated for topical administration (i.e. topical pharmaceutical composition).
  • the second pharmaceutical composition of the invention suitable or formulated for topical administration includes liquid or semi-liquid preparations suitable for penetration through the skin 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.
  • the compositions of the invention suitable or formulated for topical administration are in the form of solutions or lotions.
  • the one or more therapeutic effects surprisingly persist and even improve.
  • the one or more therapeutically effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the second pharmaceutical composition, as evidenced by measuring the severity of alopecia tool (SALT) score.
  • SALT severity of alopecia tool
  • the first pharmaceutical composition is administered and, only once hair loss extent has reached SALT 95, the second pharmaceutical composition is administered.
  • the administration of the first pharmaceutical composition is then stopped after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, even more preferably after 36 weeks, and administration with the second pharmaceutical composition is maintained.
  • the first and second pharmaceutical compositions are co-administered.
  • the administration of the first pharmaceutical composition is then stopped after 24 to 36 weeks, preferably after 28 weeks, more preferably after 32 weeks, even more preferably after 36 weeks, and treatment with the second pharmaceutical composition is maintained.
  • the present invention also contemplates a pharmaceutical composition for use in the treatment and/or prevention of hair loss comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein said pharmaceutical composition is administered concomitantly with a pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor to a subject in need thereof as described herein.
  • a pharmaceutical composition for use in the treatment and/or prevention of hair loss comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein said pharmaceutical composition is administered concomitantly with a pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor to a subject in need thereof as described herein.
  • JK Janus kinase
  • the present invention also contemplates a pharmaceutical composition
  • a pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species as described herein for use in the treatment and/or prevention of hair loss in a subject in need thereof, wherein said pharmaceutical composition is administered once the administration of a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.
  • JK Janus kinase
  • the present invention further contemplates methods of treatment and/or prevention of hair loss in a subject.
  • the method of treatment and/or prevention of hair loss in a subject comprises, administering i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly or staggered in time to a subject in need thereof as described herein.
  • a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species
  • the method of treatment and/or prevention of hair loss in a subject comprises, administering a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, once the administration of a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species
  • the present invention further contemplates the use of the pharmaceutical compositions of the invention in the manufacture of a medicament for the treatment and/or prevention of hair loss in a subject, comprising, administering i) a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor and, ii) a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical compositions are administered concomitantly or staggered in time to a subject in need thereof as described herein.
  • a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor
  • a second pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, wherein the first and second pharmaceutical
  • the present invention also contemplates the use of a pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, of the invention, in the manufacture of a medicament for the treatment and/or prevention of hair loss in a subject, wherein said pharmaceutical composition is administered once the administration of a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.
  • a pharmaceutical composition comprising, as active ingredients, therapeutically effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species, of the invention, in the manufacture of a medicament for the treatment and/or prevention of hair loss in a subject, wherein said pharmaceutical composition is administered once the administration of a first pharmaceutical composition comprising a therapeutically effective amount of at least one Janus kinase (JAK) inhibitor is discontinued.
  • JK Janus kin
  • kits for the treatment and/or prevention of hair loss as described herein comprising the pharmaceutical compositions, or compositions for use, of the invention.
  • kits of the invention may also comprise a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, dispensers, a spray applicator, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the kit comprises at least two containers, one for each composition of the invention.
  • the label or package insert may comprise instructions for use thereof. Instructions included may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure.
  • the present disclosure is to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.
  • the composition comprises about 87% by weight of an aqueous-alcoholic extract of Allium cepa; about 12% by weight of an aqueous-alcoholic extract of Citrus limon; about 0.67% by weight of an aqueous extract of Paullinia cupana; and about 0.67% by weight of an aqueous- alcoholic extract of Theobroma cacao.
  • the final topical solution product contains at least 20% of the composition as described above.
  • the remainder of the finished product consists of water and regular excipients found in other cutaneous solutions, such as betaine, glycerin, sodium chloride, etc...
  • a finished cutaneous solution product (LH-8) containing 22.25% of the composition comprising, as active ingredients, effective amounts of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species has been evaluated in a clinical trial evaluating its safety and efficacy in subjects presenting AA (RAAINBOW study, ClinicalTrials.gov identifier NCT03240627). Approximately 1 mL of the composition was applied to whole scalp twice per day, at approximately 12-hour intervals (e.g. in the morning and in the evening)
  • the RAAINBOW study was a double-blind, randomized, multi-center study versus placebo. 107 subjects (males and females) were enrolled and serve for safety analysis. Among them 62 within inclusion criteria (i.e. moderate to severe AA) representing the Full Analysis Set population (FAS) were analyzed for efficacy.
  • composition is perfectly safe in the treatment of AA and warrants therefore no treatment discontinuation periods. Therefore, the composition can be used in chronic fashion with no risk to users’ health.
  • the invention consists in switching treatment, from JAK inhibitor to the composition, in order to maintain patient’s recovery from the disease, while ending his exposure to a drug which is documented to pose long term health risks.
  • This novel regimen is plausible since the composition seemed to offer a comparable chance of disease recovery, as presented below.
  • JAK Janus kinase
  • SALT severe of Alopecia Tool
  • SALT score was developed in 2004 by Olsen (Olsen, 2004) “to help facilitate well-controlled clinical trials for alopecia areata”. It consists of a standardized method to assess the extent of alopecia, a SALT score of 100% consisting of full-baldness. It is based on a 4 pictures-based scoring system, where each side of the head is split into 4 quadrants, and scored by the investigator accordingly.
  • the SALT score is the standard measurement endpoint, used by all trials evaluating new treatments efficacy in AA (see Figure 1)
  • the estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in a first trial, and 35.9%, 19.4%, and 3.3%, respectively, in a second trial (King 2021).
  • the proportion of patients achieving a SALT score of 20 or less was 38.3% in the 12 mg twice-daily dose group and 33.0% in the 8 mg twice-daily dose group, compared to 0.8% of patients in the placebo group, at the 24-week endpoint (press release).
  • 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 week 24, and 46,7% and 9,1% respectively at week 48. While patients in the JAK inhibitors trial had an AA extent above 50%, patients treated with the composition had an extent of hair loss of 25-95% (SALT 25-95).
  • JAK inhibitor discontinuation triggers disease relapse within 3 months (Yann, 2022)
  • the protocol for interrupting JAK inhibitor and switching treatment to the composition is defined as to minimize disease relapse.
  • treatment regimen consists in starting with the approved JAK inhibitor baricitinib at 4mg once a day, and the second pharmaceutical composition is administered once hair loss extent has reached SALT 95, at 1 ml, twice a day .
  • the JAK inhibitor treatment is then interrupted after 36 weeks, and treatment with the second pharmaceutical composition is maintained.
  • treatment regimen consists in administering, simultaneously or concomitantly at 1ml, twice a day.
  • the JAK inhibitor treatment is then interrupted after 36 weeks, and treatment with the second pharmaceutical composition is maintained.

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Abstract

L'invention concerne une combinaison de composition destinée à être utilisée dans le traitement et/ou la prévention de la chute des cheveux chez un sujet. L'invention concerne également des kits et des méthodes de traitement et/ou de prévention de la chute des cheveux à l'aide de ladite combinaison de compositions.
PCT/EP2024/063618 2023-05-17 2024-05-16 Combinaison de composition destinée à être utilisée dans le traitement et/ou la prévention de la chute des cheveux Pending WO2024236153A1 (fr)

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Citations (3)

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WO2013020719A2 (fr) * 2011-08-09 2013-02-14 Legacy Healthcare Holding Ltd Nouvelle utilisation de compositions pour retarder l'initiation de la phase catagène des cheveux

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US8361522B2 (en) * 2007-02-13 2013-01-29 Legacy Healthcare Holding Ltd Cosmetic and/or pharmaceutical compositions and their applications
US20120064174A1 (en) * 2010-08-05 2012-03-15 Legacy Healthcare Holding Ltd. Method for stimulating hair growth
WO2013020719A2 (fr) * 2011-08-09 2013-02-14 Legacy Healthcare Holding Ltd Nouvelle utilisation de compositions pour retarder l'initiation de la phase catagène des cheveux

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