EP4373496A1 - Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids - Google Patents

Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids

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Publication number
EP4373496A1
EP4373496A1 EP22713729.6A EP22713729A EP4373496A1 EP 4373496 A1 EP4373496 A1 EP 4373496A1 EP 22713729 A EP22713729 A EP 22713729A EP 4373496 A1 EP4373496 A1 EP 4373496A1
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EP
European Patent Office
Prior art keywords
cas number
acid
composition
acid cas
derivative
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EP22713729.6A
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German (de)
French (fr)
Inventor
Carlo Clerici
Graziano CLERICI
Gabriele Cruciani
Bernard Fioretti
Lucio Leonardi
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G&c Biotech Srl
S&R Farmaceutici SpA
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G&c Biotech Srl
S&R Farmaceutici SpA
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Publication of EP4373496A1 publication Critical patent/EP4373496A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • 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

Definitions

  • the purpose of the invention is to provide a topical composition for the treatment of androgen-dependent dermatoses characterized by the association of one or more bile acids and one or more inhibitors of the 5 alpha reductase enzyme.
  • Androgen-dependent dermatoses constitute a disparate series of skin abnormalities associated with a local overproduction of DHT from Testosterone catalyzed by the 5 ⁇ reductase enzyme.
  • the use of anti-androgen drugs that block the activity of the 5 ⁇ reductase enzyme is considered a treatment for these disorders.
  • Orfanos CE The 5 alpha-reductase system and its inhibitors. Recent development and its perspective in treating androgen-dependent skin disorders. Dermatology.
  • baldness refers to the most common form of baldness, which affects genetically predisposed individuals starting from the period of puberty, affecting 40% of males between 30-40 years of age and 70% of those in older age.
  • Hair follicles are believed to be genetically predisposed to miniaturization after androgenic stimulation resulting in a gradual replacement of normal pigmented hair with depigmented hair in the frontoparietal and vertex areas, with retraction of the hair insertion line and opening of the frontoparietal angles (receding hairline) (Frieden IJ,
  • the cells of the dermal papilla play a key role in hair growth inside the hair follicle. Specifically, the cells of the dermal papilla determine the phases of the hair cycle with particular reference to the transition from the anagenic to the telogenic phase
  • the follicular cycle is divided into three phases: anagenic, catagenic and telogenic: Anagenic phase or growth phase: the follicular cells are in full proliferative activity and the hair grows on average by 0.3 -0.4 mm per day.
  • the duration of this phase is generally between 2-7 years; Catagenic phase or involution phase: during this period the follicle block its proliferative activity and the hair no longer stretches.
  • the duration of this phase is very short, on average around to 2-3 weeks; Telogenene phase or resting phase: during this period the follicle is completely inactivated. At the end of this phase, in fact, the follicle resumes its activity entering the anagenic phase and generating a new hair.
  • the average duration of this period is three months (Hoover et al., 2020 see above).
  • the pilosebaceous unit consists of the hair stem, the hair follicle, the sebaceous gland and the erector hair muscle (Mercury MG, Gogstetter DS. Androgen physiology and the cutaneous pilosebaceous unit. J Gend Specif Med. 2000 May-Jun; 3 (4): 59-64.
  • the hair follicle is a sac-shaped introflexion of the epidermis that has a deep dilation, called the bulb, which continues with the collar narrowing up to the outlet on the epidermis.
  • the hair bulb is the deepest part of the follicle and generates all the components of the hair and hair follicle.
  • the hair bulb encloses the dermal papilla, an area of spindle-shaped cells immersed in an environment rich in mucopolysaccharides.
  • the dermal papilla forms the part of the bulb that gives life to the hair.
  • the dermal papilla is of mesodermal origin and produces a whole series of factors that regulate the proliferation and differentiation of the cells that make up the hair follicle in the various phases of the hair cycle (Hoover et al., 2020 see above).
  • the fibroblastic cells that make up the dermal papilla produce factors that stimulate the proliferation and differentiation of the overlying keratinocytes, such as insulin-like growth factor 1 (IGF-1), hepatic growth factor
  • HGF vascular and endothelial growth factor
  • VEGF vascular and endothelial growth factor
  • the dermal papilla regulates the transition from the anagenic to the telogenic phase through the production of factors such as transforming growth factor type bl and
  • TGF-b1 and TGF-b2 TGF-b1 and TGF-b2
  • DKK-1 Kwack MH, Kim MK, Kim JC , Sung YK.
  • Polygonum multiflorum extract support hair growth by elongating anagen phase and abrogating the effect of androgen in cultured human dermal papilla cells.
  • Apoptosis is a process of programmed cell death that can occur through an intrinsic or extrinsic pathway (Wanner E, Thoppil H, Riabowol K. Senescence and
  • Apoptosis Architects of Mammalian Development. Front Cell Dev Biol. 2021 Jan 18;
  • the intrinsic pathway of apoptosis sees as the first events the depolarization of the mitochondrion, which triggers the transition of permeability in the outer mitochondrial membrane, releasing in the cytosol factors that promote apoptosis, such as cytochrome c, which ultimately activates the caspase pathway (Pedley R, Gilmore
  • the cells that make up the dermal papilla express the enzymes necessary for the de novo synthesis of dehydrotestosterone (DHT) or for the recovery of the circulating DHEAS, by means of the enzymes 5 alpha reductase and steroid sulfatase respectively.
  • DHT dehydrotestosterone
  • the cells of the dermal papilla express the enzymes that convert cholesterol along the androgen pathway such as StAR (steroidogenesis acute regulatory protein), P450scc, P450cl7 and 3b hydroxy-steroid dehydrogenase (3b-HSD).
  • StAR steroidogenesis acute regulatory protein
  • P450scc steroidogenesis acute regulatory protein
  • P450cl7 steroid dehydrogenase
  • 3b-HSD 3b hydroxy-steroid dehydrogenase
  • the cells also express enzymes capable of decreasing DHT levels such as aromatase and 3 alpha hydroxy steroid dehydrogenase.
  • This set of enzymes indicates the important glandular function of the dermal papilla
  • DHT acts on the dermal papilla itself, causing its miniaturization and stimulating the production of TGF b1 which regulates the transition from the anagenic to the telogenic phase.
  • Partial or limited hair loss can also affect pets such as cats and dogs for various reasons.
  • Androgenetic alopecia for example, defined as non-inflammatory alopecia, mainly due to hormonal imbalances (androgens GH, thyroid hormones, estrogens, etc.), is very different from the absolutely normal loss of hair during moulting, in which tufts of hair fall out but they are replaced by other hairs which, instead remain attached.
  • Non- inflammatory alopecias represent a large group of skin diseases, united by thinning or lack of hair, by the absence of itching (which differentiates them from scratching alopecias due to allergic causes), and by negative results of fungal tests and skin scrapings.
  • Androgens play an important role in their modulatory action on the activity of the hair follicle, especially in the hairs located in the neck, perineum and hips of dogs and cats. Also in this case, as in humans, the 5 alpha reductase enzyme plays a fundamental role, which converts testosterone into a much more powerful androgen called dehydrotestosterone. Alongside this form of alopecia in pets there are other forms of dermatosis such as atopic dermatitis etc. (Chen and Chuong, 2012; Chenet al., 2016 see above).
  • SEBORRHEIC DERMATITIS This refers to a skin alteration characterized by reddened and inflamed areas that lead to oily yellowish scaling of the skin, the production of dandruff and seborrhea.
  • the scalp, the areas of the face, shoulder blades and sternum are more easily affected as they are rich in sebaceous glands.
  • the enzyme 5 ⁇ -reductase type 1 plays an important role, that is, in addition to being involved in the transformation of testosterone into dihydrotestosterone (DHT), it is able to act on the sebaceous glands, causing an increase and modification of secretion of sebum responsible for hair loss.
  • DHT dihydrotestosterone
  • the infection of bacteria and yeasts aggravates the pathological state already in place, all this causes damage to the normal life cycle of the hair (William D. James, Timothy G.
  • ALOPECIA AREATA Condition characterized by patches of hair loss on the scalp, which can worsen even in more severe forms such as alopecia totalis (total hair loss) or alopecia universalis (complete loss of hair in the head and hair of the body).
  • the etiology still remains uncertain and hormonal involvement is hypothesized as an excess of androgens (total, free testosterone and androstenodione).
  • alopecia totalis total hair loss
  • alopecia universalis complete loss of hair in the head and hair of the body.
  • TELOGEN EFFLUVIUM it is a copious hair loss without the formation of hairless patches. In acute Telogen effluvium, the fall is sudden and violent, its duration is around three months, subsequently there is a regrowth that can be partial but also total.
  • the causes can be multiple associated with an arrest of mitosis pilari, including hormonal imbalances such as pregnancy (estrogen reduction and presence of androgens), trauma, chemotherapy, operations undergone and stress, deficiency or excess of thyroid hormones (hypothyroidism or hyperthyroidism), vitamin A hypovitaminosis, nutritional protein deficiencies, iron deficiency anemia (due to iron deficiency) and deficiency of trace elements (selenium, zinc, etc.).
  • hormonal imbalances such as pregnancy (estrogen reduction and presence of androgens), trauma, chemotherapy, operations undergone and stress, deficiency or excess of thyroid hormones (hypothyroidism or hyperthyroidism), vitamin A hypovitaminosis, nutritional protein deficiencies, iron deficiency anemia (due to iron deficiency) and deficiency of trace elements (selenium, zinc, etc.).
  • MENOPAUSE 50% of postmenopausal women, in fact, complain of conspicuous hair loss over time and its severity increases with age (Birch et al., 2001). Similar to male androgenetic alopecia, it is characterized by the progressive miniaturization of the hair follicles and by a reduction in the percentage of hair in the anagenic phase while the telogenic phase lengthens (Courtois et al., 1995).
  • postmenopausal alopecia There are mainly three forms of postmenopausal alopecia: the first, where there is a reduction of hair in the frontoparietal area, the second similar to that of the male type with retreat of the frontoparietal hairline and involvement of the vertex of the head, the third with greater hair loss on the midline of the scalp, which gradually extends towards the frontal area.
  • This third form is the most common and appears in 70% of women (Olsen, 1999).
  • the pathophysiological mechanism of postmenopausal alopecia is similar to that of androgenetic alopecia in men, (Frieden and Price, 1986 see supra) where the enzyme 5 ⁇ reductase (5 ⁇ R) plays a key role in the peripheral conversion of testosterone to dihydrotestosterone (DHT).
  • 5 ⁇ R-I which is widely distributed throughout the body
  • 5 ⁇ R-II which is expressed in androgen-dependent tissues such as the prostate and hair follicles.
  • ACNE commonly refers to acne vulgaris; a chronic disease (Zouboulis,
  • CAIS CAIS
  • Laron syndrome insensitivity to GH resulting in extremely low levels by IGF-1
  • HERSUTISM defined as excessive hair growth in anatomical sites where such growth is considered a secondary male characteristic. It is generally believed to occur as a result of a slight overproduction of androgens locally in the skin (Bienenfeld A,
  • ATOPIC DERMATITIS Multifactorial syndrome with autosomal recessive transmission strongly influenced by environmental factors. Atopic dermatitis is widespread and is the most common inflammatory skin disease, with a prevalence of
  • Atopic dermatitis is manifested by areas of dry and red skin, very itchy, prone to flaking and cracking. Skin lesions range from mild erythema to severe lichenification (skin thickening with accentuation of the normal skin texture; lichen results from repeated rubbing). Sex hormones (androgens and estrogens) appear to play an important role in the pathogenesis of atopic dermatitis (N. Kanda, T.
  • Androgen receptors are present in keratinocytes (Gilliver SC, Wu F, Ashcroft
  • HAIR TRANSPLANT The hair transplant is a surgical operation with which the surgeon removes a part of the hair (including the root) from areas called donors to another where the density of the hair is very low, or zero, called recipient.
  • the hair with the relative bulbs is taken, choosing them carefully, from the posterior and lateral regions of the patient's head, thus avoiding any risk of rejection and ensuring continuous regrowth in the areas where they are implanted.
  • the FUT and FUE techniques have established themselves on the market, which differ in the ways in which the hair is taken from the scalp, each with its own advantages and disadvantages. With the FUE
  • FUT (or STRIP) is the most common technique for removing hair from the donor area.
  • the surgeon takes a strip of scalp from the back of the head, where there is regular hair growth and is transplanted into the no hair area (Mohamed Mohamed EE, Younes
  • ROSACEA Chronic dermatosis, that is a pathological alteration of the skin, which usually affects the central area of the face and manifests itself with erythema, with telangiectasias and with inflammatory lesions of the acneiform type (i.e. with papules and pustules similar to those of acne ) (Standard classification of rosacea:
  • the “topical” application is an administration that can be in the form of solutions, lotions, ointments, creams, liposomes, sprays, gels, roller sticks, shampoos, foams, solid soaps, lip sticks or any other method that utilizes pharmaceutically acceptable micelles and penetration stimulators such as medical devices.
  • these applications are applied to the scalp at bedtime and again after a shower in the morning for a total of two applications per day.
  • 5-DHT is generated from testosterone through the activity of 5 ⁇ -reductase (5 ⁇ -R).
  • 5 ⁇ -R 5 ⁇ -reductase
  • Two isoforms of 5 ⁇ were characterized, which differ both in the distribution at the tissue site, and in the optimal pH for enzymatic activity. While the type II isoform is considered the major isoenzyme in genital tissues, the type 1 isoform is most expressed in the skin and pilosebaceous unit (Russell DW, Wilson ID. Steroid 5 alpha-reductase: two genes
  • Dutasteride is a drug with 5 -alpha-reductase inhibiting action in the two isoforms I and II. It has been approved as a drug against benign prostatic hyperplasia.
  • Finasteride has shown very interesting results as anti-baldness, acting on the formation of dehydrotestosterone is indicated in case of androgenic baldness.
  • PMID
  • Progesterone is a weak 5 alpha reductase inhibitor, and was one of the first drugs with scientifically proven results. In the form of a lotion, it is used as an antiseborrheich drug and often associated with other substances in topical anti-baldness preparations (Krieg M, Schlenker A, Voigt KD. Inhibition of androgen metabolism in stroma and epithelium of the human benign prostatic hyperplasia by progesterone, estrone, and estradiol. Prostate. 1985; 6 (3): 233-40. doi: 10.1002 / pros. 2990060303).
  • Serenoa Repens also known as Florida Palmetto, this plant has berries from which a phyto-derivative with antiandrogenic activity is obtained as it is capable of reducing the production of dehydrotestosterone. It acts generally and its effect is similar to that of finasteride; now known throughout the world, studies on its anti-baldness and antiseborrheic effect are very recent, while drugs and supplements based on serenoa repens have been on the market for some time for the treatment and prevention of prostatic hypertrophy. It also does not cause major side effects like other 5 alpha reductase inhibitors such as erectile dysfunction. (Buonocore D, Verri M, Cattaneo L,
  • Berberine and mono caffeil tartaric acid are compounds present in nature, effective and well tolerated by the body, able to inhibit particularly type 25 -a reductase
  • Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro. Front Pharmacol. 2018
  • Resveratrol is a polyphenol with a stilbenic structure contained in micromolar concentration in red wine and grape skin as well as in some plant species such as poliginum cuspidatum. Resveratrol inhibits 5 alpha reductase at microM concentrations
  • resveratrol can be modified by formulations used in the field of cosmetics and dermatology such as the one in which the polyphenol is co-precipitated with at least one hydrocalcite or hydroxide as described in patent application EP
  • Azelaic acid is an antiacne par excellence, locally inhibits the transformation of testosterone into dehydrotestosterone. It has only recently been considered as an anti- baldness principle. (Stamatiadis D, Bulteau-Portois MC, Mowszowicz I. Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid. Br J Dermatol. 1988
  • Camellia Sinensis phyto-derivative also known as Green Tea extract has a proven antioxidant effect, effective against free radicals, co-responsible for the anti- aging of the skin and skin appendages including hair follicles.
  • the recent hypothesis on its antiandrogenic effect (in particular it would inhibit the formation of dehydrotestosterone), has not yet been scientifically proven. (Dhariwala MY,
  • Zinc and vitamin B6 topically applied zinc inhibits the production of dehydrotestosterone and tiie association with vitamin B6 enhances this anti-DHT effect
  • vitamin B6 also has antiandrogenic effects on its own. It can also be used generally, associated with vitamin B6 in order to reduce the circulation of DHT.
  • Arginine and cysteine are used for the treatment of androgenetic alopecia; not because they have anti-DHT effects, but by acting: arginine as a stimulator of growth activity while cysteine as a nutrient necessary for hair formation and development.
  • the phytocomplex of Poligonum multiflurum has been used as a component of hair loss treatments while in animal experiments it increases the number and size of hair follicles.
  • the PM phytocomplex contains many active ingredients and among these emodin has been found to be a powerful inhibitor of 5 alpha reductase
  • PM extracts stimulate mitochondrial activity, proliferation and expression of bcl2. Furthermore, by altering the growth factors, it prolongs the anagenesis. It also reduces androgen receptors (Shin et al., 2020).
  • Bile acids show mitochondrial protective activity and are cytoprotective and anti- apoptotic by increasing the levels of bcl-2. Bile acids show an anti-apoptotic effect by stabilizing mitochondrial activity even when applied individually.
  • the invention refers to a composition or formulation comprising one or more inhibitors of the 5 alpha reductase and one or more bile acids in the neutral or salified form in a weight ratio between these components comprised between 0.01 and
  • At least one inhibitor of the 5 alpha reductase and/or at least one bile acid is in the form of a salt of a bivalent
  • (metal) cation such as an alkaline earth metal salt, preferably a calcium or magnesium salt.
  • the salt of the divalent metal is a direct salt between at least one 5 alpha reductase inhibitor and / or at least one bile acid with an alkaline earth metal, preferably a salt of calcium, or magnesium or zinc.
  • composition of the invention is shown useful for use in the treatment of androgen-dependent dermatoses, in particular in the treatment of acne, alopecia, and seboroic dermatitis, and in the treatment of hair loss in dogs and cats. Furthermore, the composition of the invention can be used for topical use in the form of a medical device.
  • the invention also refers to a composition or formulation comprising one or more inhibitors of 5 alpha reductase and one or more bile acids in the neutral or salified form in a weight ratio between these components comprised between 0.01 and 100, preferably between 0.1 and 10. even more preferably 1, for use in association with a precursor compound of a divalent metal (cation), such as an alkaline earth metal salt, for the treatment of one or more of the aforementioned pathologies.
  • a divalent metal (cation) such as an alkaline earth metal salt
  • Bile acids are amphipathic molecules with steroid scaffolds produced in the liver from cholesterol from which the primary bile acids directly derive which in humans are represented by cholic acid (CA) and chenodeoxycholic acid (CDCA) and are represented by the following general formula (I) indicated below.
  • the de novo biosynthesis of BA uses about 90% of the cholesterol actively metabolized in the body, while the remaining 10% is part of the biosynthesis processes of steroid hormones.
  • BA varies widely between different vertebrate species and the observed chemical diversity of the pool is further expanded by the actions of anaerobic gut bacteria which convert primary bile acids into dozens of secondary and tertiary bile acids.
  • UDCA ursodeoxycholic acid
  • Chenodexosycholic acid reduces mitochondrial damage of 5 alpha reductase inhibitors only in the presence of divalent cations in the extracellular solution:
  • FIG 2 Change in mitochondrial potential over time monitored by the nerstian probe tetramethylrodamine methyl ester (TMRM).
  • TMRM nerstian probe tetramethylrodamine methyl ester
  • alpha reductase inhibitors can be chosen: Emodin, Dutasteride,
  • Bile acids can be chosen from the compounds deriving from the formula (I)
  • glycine derivatives glycine derivatives
  • taurine Tauro derivatives
  • glucuronic acid glucuronate derivatives
  • sulfuric acid sulfates derivatives
  • CA cholic acid CAS Number: 81-25-4
  • CDCA Chenodeoxycholic acid CAS Number: 474-25-9
  • UDCA ursodeoxycholic acid CAS Number: 128-13-2
  • Glucoronide of the disodium salt of ursodeoxycholic acid CAS Number 75672-30-9 MCA muricolic acid CAS Number: 2393-58-0
  • DCA deoxycholic acid CAS Number 83-44-3
  • HDCA iodesoxycholic acid CAS Number: 83-49-8
  • bile salts specifically but not limited to, alkali metal salts selected from sodium, lithium or potassium salt or alkaline earth metal salts selected from calcium or magnesium.
  • Base addition salts further include inorganic and organic amine salts including, but are not limited to, ammonium, methylammonium, ethylammonium, diethylammonium, triethylammonium, lysine, arginine, N-methylglucamine and choline.
  • composition or formulation of the invention includes one or more inhibitors of 5 alpha reductase here inafter referred to as "inhibitory component of the enzyme 5 alpha reductase” and one or more of bile salts hereinafter referred to as “component of bile salts”.
  • the weight ratio (referred below to as the RATIO) between the “inhibitory component of the 5 alpha reductase enzyme” and the “bile salts component” is between
  • the amount of the inhibitory component of the 5 alpha reductase enzyme and of the "bile salts component”, expressed as% by weight of the total formulation is between 0.01% and 20%, preferably between 0.01 and 10% even more preferably 5%.
  • the amount of the divalent metal, expressed as% by weight of the total formulation is between 0.01% and
  • composition or formulation may further comprise pharmaceutically acceptable excipients.
  • excipients that can be used, the following can be used by way of example: lecithin, maltodextrin, isopropyl palmitate, lecithin organogel,
  • Example 1 of the formulation of the mixture of association with a ratio of 1
  • Example 2 of the formulation of the mixture of association with a ratio of 1
  • Example 13 AL., 35 years old, male, characterized by thinning alopecia of the vertex and the fronto-pariatal area: The trichogram shows the following formula: anagen 50%, catagen 5%, telogen 45%.
  • the lotion as described in example 9 was applied every evening, lightly rubbed into dry hair. After six weeks the area showed initial hair regrowth and at the end of treatment (twelfth week) small light-colored hairs were present on 2/3 of the alopecic area, especially in the anterior area with reappearance of hair with normal trichogram (anagen 85 %, catagen 2%, telogen 13%). This aspect is surprising given that
  • AL had previously applied a lotion similar to the example, but without bile acids and had not observed beneficial effects on alopecia, on the contrary, erythema had appeared.

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Abstract

The purpose of the invention is to provide a topical composition for the treatment of androgen-dependent dermatoses characterized by the association of one or more bile acids and one or more inhibitors of the 5 alpha reductase enzyme. A composition or formulation comprising one or more inhibitors of 5 alpha reductase and one or more bile acids is useful for the treatment of pathologies linked to androgenic imbalance (androgenic dermatoses) with the ability to limit the side effects of the inhibitors, of 5 alpha reductase and enhance the cytoprotective effects of bile acids.

Description

COMPOSITION OR FORMULATION COMPRISING ONE OR MORE 5-ALPHA-REDUCTASE INHIBITORS AND ONE OR MORE BILE ACIDS
DESCRIPTION
Field of application
The purpose of the invention is to provide a topical composition for the treatment of androgen-dependent dermatoses characterized by the association of one or more bile acids and one or more inhibitors of the 5 alpha reductase enzyme.
Known art
Androgen-dependent dermatoses constitute a disparate series of skin abnormalities associated with a local overproduction of DHT from Testosterone catalyzed by the 5α reductase enzyme. The use of anti-androgen drugs that block the activity of the 5α reductase enzyme is considered a treatment for these disorders.
However, since anti-androgens are indiscriminate in their action, their use is associated with side effects that limit their use. The most frequent androgen-dependent dermatitis are androgenic alopecia, acne, seborrhea and female hirsutism (Chen W, Zouboulis CC,
Orfanos CE. The 5 alpha-reductase system and its inhibitors. Recent development and its perspective in treating androgen-dependent skin disorders. Dermatology.
1996;193(3):177-84. doi: 10.1159/000246242. PMID: 8944337).
The term "androgenetic alopecia" refers to the most common form of baldness, which affects genetically predisposed individuals starting from the period of puberty, affecting 40% of males between 30-40 years of age and 70% of those in older age.
Women can also be affected but at a later age, i.e. around 30-20 40% after 70 years.
Hair follicles are believed to be genetically predisposed to miniaturization after androgenic stimulation resulting in a gradual replacement of normal pigmented hair with depigmented hair in the frontoparietal and vertex areas, with retraction of the hair insertion line and opening of the frontoparietal angles (receding hairline) (Frieden IJ,
Price VH Androgeneticalopecia. In:ThiersBH, Dobson RL, editors. Pathogenesis of skin disease. New York: Churchill Livingstone; 1986. p. 41-55 e Kaufman KD.
Androgens and alopecia. Mol Cell Endocrinol. 2002 Dec 30;198(1-2):89-95. doi:
10.1016/s0303-7207(02)00372-6. PMID: 12573818.
The cells of the dermal papilla play a key role in hair growth inside the hair follicle. Specifically, the cells of the dermal papilla determine the phases of the hair cycle with particular reference to the transition from the anagenic to the telogenic phase
(Hoover E, Alhajj M, Flores JL. Physiology, Hair. 2020 Jul 27. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2020 Jan- PMID: 29763123).
The follicular cycle is divided into three phases: anagenic, catagenic and telogenic: Anagenic phase or growth phase: the follicular cells are in full proliferative activity and the hair grows on average by 0.3 -0.4 mm per day. The duration of this phase is generally between 2-7 years; Catagenic phase or involution phase: during this period the follicle block its proliferative activity and the hair no longer stretches. The duration of this phase is very short, on average around to 2-3 weeks; Telogenene phase or resting phase: during this period the follicle is completely inactivated. At the end of this phase, in fact, the follicle resumes its activity entering the anagenic phase and generating a new hair. The average duration of this period is three months (Hoover et al., 2020 see above).
The pilosebaceous unit consists of the hair stem, the hair follicle, the sebaceous gland and the erector hair muscle (Mercury MG, Gogstetter DS. Androgen physiology and the cutaneous pilosebaceous unit. J Gend Specif Med. 2000 May-Jun; 3 (4): 59-64.
PMID: 11253232).
The hair follicle is a sac-shaped introflexion of the epidermis that has a deep dilation, called the bulb, which continues with the collar narrowing up to the outlet on the epidermis. The hair bulb is the deepest part of the follicle and generates all the components of the hair and hair follicle.
The hair bulb encloses the dermal papilla, an area of spindle-shaped cells immersed in an environment rich in mucopolysaccharides. Around the dermal papilla forms the part of the bulb that gives life to the hair.
The dermal papilla is of mesodermal origin and produces a whole series of factors that regulate the proliferation and differentiation of the cells that make up the hair follicle in the various phases of the hair cycle (Hoover et al., 2020 see above).
During the anagenic phase, the fibroblastic cells that make up the dermal papilla produce factors that stimulate the proliferation and differentiation of the overlying keratinocytes, such as insulin-like growth factor 1 (IGF-1), hepatic growth factor
(HGF), vascular and endothelial growth factor (VEGF) and keratinocyte growth factor
(KGF) (Madaan A, Verma R, Singh AT, Jaggi M. Review of Hair Follicle Dermal
Papilla cells as in vitro screening model for hair growth, hit J Cosmet Sci. 2018 Oct; 40
(5): 429-450. Doi: 10.1111 / ics.12489. Epub 2018 Oct 4. PMID: 30144361.
The dermal papilla regulates the transition from the anagenic to the telogenic phase through the production of factors such as transforming growth factor type bl and
2 (TGF-b1 and TGF-b2) and DKK-1 (Kwack MH, Kim MK, Kim JC , Sung YK.
Dickkopf 1 promotes regression of hair follicles. J Invest Dermatol. 2012 Jun; 132 (6):
1554-60. Doi: 10.1038 / jid.2012.24. Epub 2012 Feb 23. PMID: 22358062 and Shin JY,
Choi YH, Kim J, Park SY, Nam YJ, Lee SY, Jeon JH, Jin MH, Lee S.
Polygonum multiflorum extract support hair growth by elongating anagen phase and abrogating the effect of androgen in cultured human dermal papilla cells. BMC
Complement Med Ther. 2020 May 12; 20 (1): 144. doi: 10.1186 / s 12906-020-02940-
5. PMID: 32398000; PMCID: PMC7218528). During the catagenic phase, many of the cell types of the follicle undergo apoptosis, caused by the activation of apoptotic ligands or by mitochondrial dysfunctions that lead to the disappearance of the follicle, while the dermal papilla remains intact in physiological conditions. The resistance to apoptosis of the dermal papillae cells is conferred by the expression of antiapoptotic proteins such as bcl2
(Muller-Rover S, Rossiter H, Lindner G, Peters EM, Kupper TS, Paus R. Hair follicle apoptosis and Bcl-2. J Investig Dermatol Symp Proc. 1999 Dec; 4 (3): 272-7. Doi:
10.1038 / sj.jidsp.5640228. PMID: 10674380).
Apoptosis is a process of programmed cell death that can occur through an intrinsic or extrinsic pathway (Wanner E, Thoppil H, Riabowol K. Senescence and
Apoptosis: Architects of Mammalian Development. Front Cell Dev Biol. 2021 Jan 18;
8: 620089. doi: 10.3389 / fcell.2020.620089. PMID: 33537310; PMCID:
PMC7848110).
The intrinsic pathway of apoptosis sees as the first events the depolarization of the mitochondrion, which triggers the transition of permeability in the outer mitochondrial membrane, releasing in the cytosol factors that promote apoptosis, such as cytochrome c, which ultimately activates the caspase pathway (Pedley R, Gilmore
AP. Mitosis and mitochondrial priming for apoptosis. Biol Chem. 2016 Jul 1; 397 (7):
595-605. Doi: 20 10.1515 / hsz-2016-0134. PMID: 27016149).
The behavior of dermal papillae cells is controlled by many factors (for a comprehensive review see Chen WC, Zouboulis CC. Hormones and the pilosebaceous unit. Dermatoendocrinol. 2009 Mar; 1 (2): 81-6. Doi: 10.4161 / derm .1.2.8354. PMID:
20224689; PMCID: PMC2835896). Among these factors the best known are androgenic hormones. Among the androgenic hormones, testosterone and its metabolites are particularly powerful in determining their cellular behavior. The cells that make up the dermal papilla express the enzymes necessary for the de novo synthesis of dehydrotestosterone (DHT) or for the recovery of the circulating DHEAS, by means of the enzymes 5 alpha reductase and steroid sulfatase respectively. In fact, the cells of the dermal papilla express the enzymes that convert cholesterol along the androgen pathway such as StAR (steroidogenesis acute regulatory protein), P450scc, P450cl7 and 3b hydroxy-steroid dehydrogenase (3b-HSD). The cells also express enzymes capable of decreasing DHT levels such as aromatase and 3 alpha hydroxy steroid dehydrogenase.
This set of enzymes indicates the important glandular function of the dermal papilla
(Wen-che and Zouboulis, 2009 see above).
DHT acts on the dermal papilla itself, causing its miniaturization and stimulating the production of TGF b1 which regulates the transition from the anagenic to the telogenic phase.
Partial or limited hair loss can also affect pets such as cats and dogs for various reasons. Androgenetic alopecia, for example, defined as non-inflammatory alopecia, mainly due to hormonal imbalances (androgens GH, thyroid hormones, estrogens, etc.), is very different from the absolutely normal loss of hair during moulting, in which tufts of hair fall out but they are replaced by other hairs which, instead remain attached. Non- inflammatory alopecias represent a large group of skin diseases, united by thinning or lack of hair, by the absence of itching (which differentiates them from scratching alopecias due to allergic causes), and by negative results of fungal tests and skin scrapings.
Androgens play an important role in their modulatory action on the activity of the hair follicle, especially in the hairs located in the neck, perineum and hips of dogs and cats. Also in this case, as in humans, the 5 alpha reductase enzyme plays a fundamental role, which converts testosterone into a much more powerful androgen called dehydrotestosterone. Alongside this form of alopecia in pets there are other forms of dermatosis such as atopic dermatitis etc. (Chen and Chuong, 2012; Chenet al., 2016 see above).
Among the androgen-dependent dermatoses are included:
SEBORRHEIC DERMATITIS: This refers to a skin alteration characterized by reddened and inflamed areas that lead to oily yellowish scaling of the skin, the production of dandruff and seborrhea. The scalp, the areas of the face, shoulder blades and sternum are more easily affected as they are rich in sebaceous glands. In the pathogenesis of this dermatosis the enzyme 5α-reductase type 1 plays an important role, that is, in addition to being involved in the transformation of testosterone into dihydrotestosterone (DHT), it is able to act on the sebaceous glands, causing an increase and modification of secretion of sebum responsible for hair loss. Furthermore, the infection of bacteria and yeasts aggravates the pathological state already in place, all this causes damage to the normal life cycle of the hair (William D. James, Timothy G.
Berger, Dirk M. Elston; Richard B. Odom, Andrews' diseases of the skin: clinical dermatol, Philadelphia (Pennsylvania), Saunders Elsevier, 2006).
ALOPECIA AREATA: Condition characterized by patches of hair loss on the scalp, which can worsen even in more severe forms such as alopecia totalis (total hair loss) or alopecia universalis (complete loss of hair in the head and hair of the body). The etiology still remains uncertain and hormonal involvement is hypothesized as an excess of androgens (total, free testosterone and androstenodione). Among the other etiopathogenetic causes considered are encounter genetic predisposition, traumatic psychological stress (eg accidents, bereavement, etc.), serious bacterial and viral infections. (Islam, N., Leung, PSC, Huntley, AC, & Eric Gershwin, M. (2015). The autoimmune basis of alopecia areata: A comprehensive review. Autoimmunity
Reviews, 14 (2), 81-89. Doi: 10.1016 /j.autrev. 2014.10.014).
TELOGEN EFFLUVIUM: it is a copious hair loss without the formation of hairless patches. In acute Telogen effluvium, the fall is sudden and violent, its duration is around three months, subsequently there is a regrowth that can be partial but also total.
In chronic Telogen effluvium, the duration is much longer and does not heal over time, forming areas of thinning (Aron BR, Binet O., Dompmartin PD: "Diagnostic des alopecies diffuses. Une approche objective: the trichogramma" Rev. Medicine 1977; 18:
1263).
The causes can be multiple associated with an arrest of mitosis pilari, including hormonal imbalances such as pregnancy (estrogen reduction and presence of androgens), trauma, chemotherapy, operations undergone and stress, deficiency or excess of thyroid hormones (hypothyroidism or hyperthyroidism), vitamin A hypovitaminosis, nutritional protein deficiencies, iron deficiency anemia (due to iron deficiency) and deficiency of trace elements (selenium, zinc, etc.).
ALOPECIA OF THE MENOPAUSE: 50% of postmenopausal women, in fact, complain of conspicuous hair loss over time and its severity increases with age (Birch et al., 2001). Similar to male androgenetic alopecia, it is characterized by the progressive miniaturization of the hair follicles and by a reduction in the percentage of hair in the anagenic phase while the telogenic phase lengthens (Courtois et al., 1995).
There are mainly three forms of postmenopausal alopecia: the first, where there is a reduction of hair in the frontoparietal area, the second similar to that of the male type with retreat of the frontoparietal hairline and involvement of the vertex of the head, the third with greater hair loss on the midline of the scalp, which gradually extends towards the frontal area. This third form is the most common and appears in 70% of women (Olsen, 1999).
The pathophysiological mechanism of postmenopausal alopecia is similar to that of androgenetic alopecia in men, (Frieden and Price, 1986 see supra) where the enzyme 5α reductase (5αR) plays a key role in the peripheral conversion of testosterone to dihydrotestosterone (DHT). Two isoenzymes encoded by 2 different genes have been described: 5αR-I, which is widely distributed throughout the body, and 5αR-II, which is expressed in androgen-dependent tissues such as the prostate and hair follicles. The diversity of interest of the areas affected by alopecia depends on the different distribution of 5αR, aromatase and androgenic receptors in the hair follicles between men and women (Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter and the prevalence of female pattern hair loss. Br J Dermatol. 2001; 144: 297-304;
Courtois M, LoussouarnG, HourseauC, GrollierJF.Ageing and hair cycles. Br J
Dermatol. 1995; 15 132: 86-93 and Olsen EA. The midline part: an important physical clue to the clinical diagnosis of androgenetic alopecia in women. J Am Acad Dermatol.
1999; 40: 106-9.
ACNE: commonly refers to acne vulgaris; a chronic disease (Zouboulis,
Katsambas, Kligman. (2014), Christos C. Zouboulis, Harald PM Gollnick:
Understanding Acne as a Chronic Disease, pp. 209-212; Zouboulis, Katsambas,
Kligman. (2014), Bodo C. Melnik: Acne and Genetics, pp. 110-130) of the skin with benign evolution called in common language "pimple" or "zit". The maximum onset of these manifestations in adolescence is usually explained by the increased secretion of androgens (Darren D Lynn, Tamara Umari, Cory A Dunnick, Robert P Dellavalle, The epidemiology of acne vulgaris in late adolescence, in Adolesc Health Med Ther., N. 7,
2016, pp. 13-25; Yahya, 1973). The most affected parts are: face, shoulders, back and pectoral region of the chest. The manifestations of acne are extremely polymorphic and range from comedones, papules, pustules, up to more destructive manifestations
(nodules, cysts, abscesses, phlegmonous infiltrates). More severe acne lesions also lead to scarring. There is also a neonatal acne that usually manifests itself by the fourth month of age, a post-adolescent, adult, premenstrual, summer form. It has been estimated that around 650 million people were affected by acne worldwide in 2010, equal 9.4% of the population. Acne is extremely common (~ 85%) in people aged 12 to 25 and is distributed globally (Institute for Health Metrics and Evaluation: Global Burden of disease Bhate K., Williams 10 HC, Epidemiology of acne vulgaris, in The British
Journal of Dermatology, vol. 168, n. 3, March 2013, pp. 474-85). Acne is not hereditary, but there are genetic predisposing factors that lead to a 78% heritability among first degree relatives. Early onset and severity may be associated with family history (Bhate and Williams, 2013 see above; DM Evans, KM Kirk, DR Nyholt, C. Novac, NG Martin,
Teenage acne is influenced by genetic factors, in British Journal of Dermatology, vol.
152, n. 3, 2005, pp. 579-581)
During puberty, the increase in androgens causes the growth of the sebaceous glands, causing them to produce a greater quantity of sebum. Based on changes in the blood androgen rate, a correlation with the incidence of acneiform eruptions associated with menstruation and pregnancy is attributed to. Hormones act with hyperproliferative activity both towards the production of sebum and towards the keratinization of the infundibulum (Thiboutot D, Acne: hormonal concepts and therapy., In Clin Dermatol, n. 22, 2004, pp. 419-428). Several hormones have been associated with acne, among them the androgens testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEAS), Insulin-like Growth Factor (IGF-1) Somatotropin
(GH). Androgens and IGF-1 appear to be essential for the onset of acne, since this pathology does not manifest itself in individuals with androgen insensitivity syndrome
(CAIS) or with Laron syndrome (insensitivity to GH resulting in extremely low levels by IGF-1) (Gollnick and Zouboulis, 2014; Zouboulis et al., 2014, see above; Shalita,
Del Rosso, Webster. (2011), Carol Heughebaert, Alan R. Shalita: The role of androgens in the comedogenesis, p. 33). The biological events recognized as determining factors in the formation of acne lesions are hyperkeratization and occlusion of the pilosebaceous follicle, hyperactivity and hyperresponsiveness of the sebaceous gland and infection with Propionibacterium acnes.
HERSUTISM: defined as excessive hair growth in anatomical sites where such growth is considered a secondary male characteristic. It is generally believed to occur as a result of a slight overproduction of androgens locally in the skin (Bienenfeld A,
Azarchi S, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR. Androgens in women:
Androgen-mediated skin disease and patient evaluation. J Am Acad Dermatol. 2019
Jun; 80 (6): 1497-1506. doi: 10.1016 / j.jaad.2018.08.062. Epub 2018 Oct 10. PMID:
30312644).
ATOPIC DERMATITIS: Multifactorial syndrome with autosomal recessive transmission strongly influenced by environmental factors. Atopic dermatitis is widespread and is the most common inflammatory skin disease, with a prevalence of
10-20% among children and 2-5% among adults. In the first months of life, a yellowish flaking on the head, known as "cradle cap", can be a way of presenting AD. This disease can then spread to the face and extensor surfaces of the limbs of infants, sometimes showing widespread exudation and scabs. Atopic dermatitis is manifested by areas of dry and red skin, very itchy, prone to flaking and cracking. Skin lesions range from mild erythema to severe lichenification (skin thickening with accentuation of the normal skin texture; lichen results from repeated rubbing). Sex hormones (androgens and estrogens) appear to play an important role in the pathogenesis of atopic dermatitis (N. Kanda, T.
Hoashi, H Saeki 2019. International J. of molecular Science 20 (19): 4660). The role of sex hormones in the course of atopic dermatitis).
DELAYED SCALING OF SKIN WOUNDS: Endogenous androgens have important effects on the mechanisms responsible for wound healing in the skin.
Androgen receptors (ARs) are present in keratinocytes (Gilliver SC, Wu F, Ashcroft
GS. Regulatory roles of androgens in cutaneous wound healing. Thromb Haemost 2003;
90: 978-85) which lie at the edge of wounds and are able to respond to stimuli of endogenous androgens (Ashcroft GS, Mills SJ. Androgen receptor mediated inhibition of cutaneous wound healing. J Clin Invest 2002; 110: 615-24) RA are expressed in cheratinocytes located at the wound edges in the proximity of inflammatory cells and dermal fibroblasts present in the healing skin wound. Important clinical studies have also shown that the male hormone dihydrotestosterone DHT is able to reduce wound healing, while 5 a reductase inhibitors are able to improve it (Gilliver SC, Ashworth JJ,
Mills SJ, Hardman MJ, Ashcroft GS. Androgens modulate the inflammatory response during acute wound healing. J Cell Sci 2006; 119: 722-32 and Saika S, Ikeda K,
Yamanaka O, et al. Loss of tumor necrosis factor a potentiates transform- ing growth factor b-mediated pathogenic tissue response during wound healing. Am J Pathol 2006;
168: 1848-60).
HAIR TRANSPLANT: The hair transplant is a surgical operation with which the surgeon removes a part of the hair (including the root) from areas called donors to another where the density of the hair is very low, or zero, called recipient. The hair with the relative bulbs is taken, choosing them carefully, from the posterior and lateral regions of the patient's head, thus avoiding any risk of rejection and ensuring continuous regrowth in the areas where they are implanted. Mainly the FUT and FUE techniques have established themselves on the market, which differ in the ways in which the hair is taken from the scalp, each with its own advantages and disadvantages. With the FUE
(Follicular Unit Extraction) method, the individual follicular units each containing 1 to
4 hairs are removed from the patient under local anesthesia and transplanted into the areas of absence of hair (Novel technique of follicular unit extraction hair transplantation with a powered punching device, in Dermatol Surg, vol. 34, n. 34, Dec.
2008, pp. 1683-8.
FUT (or STRIP) is the most common technique for removing hair from the donor area. The surgeon takes a strip of scalp from the back of the head, where there is regular hair growth and is transplanted into the no hair area (Mohamed Mohamed EE, Younes
AK, Osmand A, Mohamed R, Makki M, Younis M. Punch graft versus follicular hair transplantation in the treatment of stable vitiligo. J Cosmet Laser Ther. 2017 Oct; 19
(5): 290-293; Gupta AK, Love RP, Harris JA. Old Friend or New Ally : A Comparison of Follicular Unit Transplantation and Follicular Unit Excision Methods in Hair
Transplantation. Dermatol Surg. 2020 Aug; 46 (8): 1078-1083).
After the hair transplant, special rules must be followed so that the grafted follicle can be correctly absorbed and rooted in the new chosen position. Alongside particular precautions to avoid hair rejection, adequate therapies must be considered to support hair regrowth. The treatments that are most used are those capable of inhibiting the action of the enzyme 5 a reductase type 1 and 2 responsible for the transformation of testosterone into dihydrotestosterone. Three are the most used drugs: minoxidil, finasteride and dutasteride, which are not without side effects when used alone in high doses (Banka, N; Bunagan, MJ; Shapiro, J (January 2013). "Pattern hair loss in men: diagnosis and medical treatment ". Dermatologic Clinics. 31 (1): 129-40). ROSACEA: Chronic dermatosis, that is a pathological alteration of the skin, which usually affects the central area of the face and manifests itself with erythema, with telangiectasias and with inflammatory lesions of the acneiform type (i.e. with papules and pustules similar to those of acne ) (Standard classification of rosacea:
Report of the National Rosacea Society Expert Committee on the Classification and
Staging of Rosacea, ournal of the American Academy of Dermatology, April 2002 -
Volume 46 - Number 4). The precise etiopathogenesis of the disease is still unknown
(Tiizun Y, Wolf R, Kutlubay Z, O, Engin B, Rosacea and rhinophyma, in
Clinics in Dermatology, vol. 32, Feb. 2014, p. 35-46). Among the many possible pathogenic factors studied, there are exposure to ultraviolet rays, andro-estrogenic hormonal imbalances, free radicals such as superoxide and hydroxyl radical, an increased reactivity of blood vessels, some neuropeptides, cathelicidins, infectious factors.
Not surprisingly, among the treatments used for androgen dependent dermatoses are 5 alpha reductase inhibitors, which are applied topically.
The "topical" application is an administration that can be in the form of solutions, lotions, ointments, creams, liposomes, sprays, gels, roller sticks, shampoos, foams, solid soaps, lip sticks or any other method that utilizes pharmaceutically acceptable micelles and penetration stimulators such as medical devices. Regarding the application site, these applications are applied to the scalp at bedtime and again after a shower in the morning for a total of two applications per day.
5-DHT is generated from testosterone through the activity of 5α-reductase (5α-R). Two isoforms of 5α were characterized, which differ both in the distribution at the tissue site, and in the optimal pH for enzymatic activity. While the type II isoform is considered the major isoenzyme in genital tissues, the type 1 isoform is most expressed in the skin and pilosebaceous unit (Russell DW, Wilson ID. Steroid 5 alpha-reductase: two genes
/ two enzymes. Annu Rev Biochem. 1994; 63: 25-61. Doi: 10.1146 / annurev.bi.63.070194.000325. PMID: 7979239 and Thiboutot D, Bayne E, Thome J,
Gilliland K, Flanagan J, Shao Q, Light J, Helm K. Immunolocalization of 5alpha- reductase isozymes in acne lesions and normal skin. Arch Dermatol. 2000 10 Sep; 136
(9): 1125-9. Doi: 10.1001 / archderm.136.9.1125. PMID: 10987868.
Dutasteride is a drug with 5 -alpha-reductase inhibiting action in the two isoforms I and II. It has been approved as a drug against benign prostatic hyperplasia.
Unlike finasteride and topical minoxidil, it has not been approved by the European
Medicine Agency or the Food and Drug Administration for use in androgenetic baldness.
Finasteride has shown very interesting results as anti-baldness, acting on the formation of dehydrotestosterone is indicated in case of androgenic baldness. Usually administered by general way, it is currently tested in the form of local application in hydroalcoholic lotion. It may be unwelcomed to male patients due to the presence of possible (temporary) side effects in the sexual sphere (from decreased libido, reduced volume of ejaculate, impotence) (Fertig RM, Gamret AC, Darwin E, Gaudi S. Sexual side effects of 5-a-reductase inhibitors finasteride and dutasteride: A comprehensive review. Dermatol Online J. 2017 Nov 11; 23 (11): 13030 / qt24k8q743. PMID:
29447628).
Progesterone is a weak 5 alpha reductase inhibitor, and was one of the first drugs with scientifically proven results. In the form of a lotion, it is used as an antiseborrheich drug and often associated with other substances in topical anti-baldness preparations (Krieg M, Schlenker A, Voigt KD. Inhibition of androgen metabolism in stroma and epithelium of the human benign prostatic hyperplasia by progesterone, estrone, and estradiol. Prostate. 1985; 6 (3): 233-40. doi: 10.1002 / pros. 2990060303).
Serenoa Repens, also known as Florida Palmetto, this plant has berries from which a phyto-derivative with antiandrogenic activity is obtained as it is capable of reducing the production of dehydrotestosterone. It acts generally and its effect is similar to that of finasteride; now known throughout the world, studies on its anti-baldness and antiseborrheic effect are very recent, while drugs and supplements based on serenoa repens have been on the market for some time for the treatment and prevention of prostatic hypertrophy. It also does not cause major side effects like other 5 alpha reductase inhibitors such as erectile dysfunction. (Buonocore D, Verri M, Cattaneo L,
Arnica S, Ghitti M, Dossena M. Serenoa repens extracts: In vitro study of the 5α- reductase activity in a co-culture model for Benign Prostatic Hyperplasia. Arch Ital Urol
Androl. 2018 Sep 30; 90 (3): 199-202. Doi: 10.4081 / aiua.2018.3.199).
Berberine and mono caffeil tartaric acid are compounds present in nature, effective and well tolerated by the body, able to inhibit particularly type 25 -a reductase
(Youn DH, Park J, Kim HL, Jung Y, Kang J, Lim S, Song G, Kwak HJ, Um JY.
Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro. Front Pharmacol. 2018
Jul 16; 9: 773. Doi: 10.3389 / fphar.2018.00773).
Resveratrol is a polyphenol with a stilbenic structure contained in micromolar concentration in red wine and grape skin as well as in some plant species such as poliginum cuspidatum. Resveratrol inhibits 5 alpha reductase at microM concentrations
(Wang Y, Sun J, Chen L, Zhou S, Lin H, Wang Y, Lin N, Ge RS. Effects of resveratrol on rat neurosteroid synthetic enzymes. Phytotherapy. 2017 Oct; 122: 61-66). The famacokinetic properties of resveratrol can be modified by formulations used in the field of cosmetics and dermatology such as the one in which the polyphenol is co-precipitated with at least one hydrocalcite or hydroxide as described in patent application EP
2679243, the content of which is fully incorporated here, for reference.
Azelaic acid is an antiacne par excellence, locally inhibits the transformation of testosterone into dehydrotestosterone. It has only recently been considered as an anti- baldness principle. (Stamatiadis D, Bulteau-Portois MC, Mowszowicz I. Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid. Br J Dermatol. 1988
Nov; 119 (5): 627-32. Doi: 10.1111 / j. 1365-2133.1988.tb03474.x.)
The Camellia Sinensis phyto-derivative also known as Green Tea extract has a proven antioxidant effect, effective against free radicals, co-responsible for the anti- aging of the skin and skin appendages including hair follicles. The recent hypothesis on its antiandrogenic effect (in particular it would inhibit the formation of dehydrotestosterone), has not yet been scientifically proven. (Dhariwala MY,
Ravikumar P. An overview of herbal alternatives in androgenetic alopecia. J Cosmet
Dermatol. 2019 Aug; 18 (4): 966-975. Doi: 10.1111 / joed.12930.).
Zinc and vitamin B6: topically applied zinc inhibits the production of dehydrotestosterone and tiie association with vitamin B6 enhances this anti-DHT effect
(it seems that vitamin B6 also has antiandrogenic effects on its own). It can also be used generally, associated with vitamin B6 in order to reduce the circulation of DHT.
(Stamatiadis D, Bulteau-Portois MC, Mowszowicz I. Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid. Br J Dermatol. 1988 Nov; 119 (5): 627-
32. Doi: 10.1111 / j. 1365-2133.1988.tb03474.x.)
The aminoacids Arginine and cysteine are used for the treatment of androgenetic alopecia; not because they have anti-DHT effects, but by acting: arginine as a stimulator of growth activity while cysteine as a nutrient necessary for hair formation and development. (Yazdani- Arazi SN, Ghanbarzadeh S, Adibkia K,
Kouhsoltani M, Hamishehkar H. Histological evaluation of follicular delivery of arginine via nanostructured lipid carriers: a novel potential approach for the treatment of alopecia. Artif Cells Nanomed Biotechnol. 2017 Nov; 45 (7): 1379-1387. Doi:
10.1080 / 21691401.2016.1241794; Adil M, Amin SS, Mohtashim M. N-acetylcysteine in dermatology. Indian J Dermatol Venereol Leprol. 2018 Nov-Dec; 84 (6): 652-659 . doi: 10.4103 / ijdvl.IJDVL_33_18.).
The phytocomplex of Poligonum multiflurum (PM) has been used as a component of hair loss treatments while in animal experiments it increases the number and size of hair follicles. The PM phytocomplex contains many active ingredients and among these emodin has been found to be a powerful inhibitor of 5 alpha reductase
(Shin et al., 2020).
In one study, PM extracts stimulate mitochondrial activity, proliferation and expression of bcl2. Furthermore, by altering the growth factors, it prolongs the anagenesis. It also reduces androgen receptors (Shin et al., 2020).
Surprisingly, it was found that emodin applied individually inhibits mitochondrial activity measured by MTT assay in a dose-dependent manner and induces a depolarization of the mitochondrial potential (Figure 1) This action is associated with an induction of apoptosis which could explain the numerous toxic effects associated with this substance. Unfortunately, these toxic actions do not allow to exploit the abilities that emodin has to inhibit 5 alpha dehydrogenase without inducing apoptosis which is the basis of the side effects.
Surprisingly, it has been found that bile acids protect the mitochondrion from inhibition of mitochondrial activity and emodin-induced depolarization (Figure 1), but these actions are observed only in the presence of divalent cations, in fact in their absence the emodin reduces the mitochondrial activity even in the presence of bile acid.
Bile acids show mitochondrial protective activity and are cytoprotective and anti- apoptotic by increasing the levels of bcl-2. Bile acids show an anti-apoptotic effect by stabilizing mitochondrial activity even when applied individually.
Therefore, the invention refers to a composition or formulation comprising one or more inhibitors of the 5 alpha reductase and one or more bile acids in the neutral or salified form in a weight ratio between these components comprised between 0.01 and
100, preferably between 0.1 and 10 still more preferably 1, wherein at least one inhibitor of the 5 alpha reductase and/or at least one bile acid is in the form of a salt of a bivalent
(metal) cation, such as an alkaline earth metal salt, preferably a calcium or magnesium salt.
In one embodiment, the salt of the divalent metal, such as the salt of an alkaline earth metal, is a direct salt between at least one 5 alpha reductase inhibitor and / or at least one bile acid with an alkaline earth metal, preferably a salt of calcium, or magnesium or zinc.
The composition of the invention is shown useful for use in the treatment of androgen-dependent dermatoses, in particular in the treatment of acne, alopecia, and seboroic dermatitis, and in the treatment of hair loss in dogs and cats. Furthermore, the composition of the invention can be used for topical use in the form of a medical device.
The invention also refers to a composition or formulation comprising one or more inhibitors of 5 alpha reductase and one or more bile acids in the neutral or salified form in a weight ratio between these components comprised between 0.01 and 100, preferably between 0.1 and 10. even more preferably 1, for use in association with a precursor compound of a divalent metal (cation), such as an alkaline earth metal salt, for the treatment of one or more of the aforementioned pathologies.
Bile acids (BA) are amphipathic molecules with steroid scaffolds produced in the liver from cholesterol from which the primary bile acids directly derive which in humans are represented by cholic acid (CA) and chenodeoxycholic acid (CDCA) and are represented by the following general formula (I) indicated below.
The de novo biosynthesis of BA uses about 90% of the cholesterol actively metabolized in the body, while the remaining 10% is part of the biosynthesis processes of steroid hormones.
The structure of BA varies widely between different vertebrate species and the observed chemical diversity of the pool is further expanded by the actions of anaerobic gut bacteria which convert primary bile acids into dozens of secondary and tertiary bile acids.
In application US 2019 / 0192539A1 it is shown that ursodeoxycholic acid
(UDCA) improves some skin diseases related to capacity anti-inflammatory only when molecularly dispersed in polysaccharides. This disclosure refers to a composition for the prevention or treatment of inflammatory skin diseases or severe itching including solubilized aqueous ursodeoxycholic acid (UDCA). In particular, the molecular dispersion is achieved through a composition containing polysaccharides with particular reference to maltodextrin.
Brief description of figures 1 and 2
Chenodexosycholic acid reduces mitochondrial damage of 5 alpha reductase inhibitors only in the presence of divalent cations in the extracellular solution: A) mitochondrial activity measured in human cells at various concentrations of emodin in absence (red bars) and presence (blue bars ) of 100 nM of chenodeoxycholic acid (Ac. CDC, experiments conducted in Ringer's solution). The differences are estimated by comparing the value of mitochondrial activity with the condition without emodin (* p
<0.05 each bar represents the average of 6 experiments). Surprisingly, the cytoprotective effect of bile acids is not observed if the test is performed in a modified Ringer solution by removing the cationic divalent ionic species (compare blue bars with green ones n =
6; * p <0.05, each bar represents the mean of 6 experiments),
Figure 2) Change in mitochondrial potential over time monitored by the nerstian probe tetramethylrodamine methyl ester (TMRM). The black line represents the trend of the mitochondrial potential in a control condition (no treatment) over time, while in red the mitochondrial potential following the application of emodin (application red bar): note the change in slope of the TMRM signal. In blue the same experiment described for the red line but in the continuous presence of 100 nM of Ac. CDC. Tracks are normalized to the maximum of the initial signal.
Among the 5 alpha reductase inhibitors can be chosen: Emodin, Dutasteride,
Finasteride, Progesterone, Berberine, pure Resveratrol and / or co-precipitate in with at least one hydrocalcite or hydroxide, monocaffeyltartaric acid, Azelaic acid, Zinc, vitamin, arginine and cisateine, phytocomplexes of Serenoa Repens and Poligonum
Multiflurum and their combinations.
Bile acids can be chosen from the compounds deriving from the formula (I)
and their ester derivatives with glycine (glycine derivatives), taurine (Tauro derivatives), glucuronic acid (glucuronate derivatives) and sulfuric acid (sulfates derivatives). Some examples of the above formula and their derivatives are:
CA = cholic acid CAS Number: 81-25-4
Cholic acid methyl ester CAS Number: 1448-36-8 5
Glico derivative of cholic acid CAS Number 475-31-0
Tauro derivative of cholic acid CAS Number: 81-24-3
Sulfur derivative of cholic acid CAS Number 60320-05-0
Cholic acid glucorinide CAS Number 76060-22-5
CDCA = Chenodeoxycholic acid CAS Number: 474-25-9
Glyco derivative of chenodeoxycholic acid CAS Number 640-79-9
Tauro derived from chenodeoxycholic acid CAS Number 516-35-8
Sulfo derivative of chenodeoxycholic acid CAS 59132-32-0
UDCA = ursodeoxycholic acid CAS Number: 128-13-2
Ursodeoxycholic acid methyl ester CAS Number: 10538-55-3
Glyco derivative of ursodeoxycholic acid CAS Number 64480-66-6
Tauro derived from ursodeoxycholic acid CAS Number: 14605-22-2
Sulfur derivative of ursodeoxycholic acid CAS 68780-73-4
Glucoronide of the disodium salt of ursodeoxycholic acid CAS Number 75672-30-9 MCA = muricolic acid CAS Number: 2393-58-0
DCA = deoxycholic acid CAS Number 83-44-3
Deoxycholic acid methyl ester CAS Number: 10538-55-3
Glico derivative of deoxycholic acid CAS Number 360-65-6
Tauro derived from deoxycholic acid CAS Number: 516-50-7
Sulfo derivative of lithocolic acid CAS 34669-57-3
Deoxycholic acid glucoronide CAS Number 72504-58-6
LCA = lithocolic acid CAS Number 434-13-9
Glico derivative of lithocolic acid CAS Number 474-74-8
Tauro derivative of lithocolic acid CAS Number 516-90-5
7-oxolithocolic acid CAS Number 4651-67-6
Lithocolic acid glucoronide CAS Number 75239-91-7
HDCA = iodesoxycholic acid CAS Number: 83-49-8
Methyl ester of iodesoxycholic acid CAS Number 2868-48-6
Glico derivative of iodesoxycholic acid CAS Number 13042-33-6
Tauro derived from iodesoxycholic acid CAS Number 2958-04-5
The salified forms of formula (I) are included in the definition of bile salts, specifically but not limited to, alkali metal salts selected from sodium, lithium or potassium salt or alkaline earth metal salts selected from calcium or magnesium. Base addition salts further include inorganic and organic amine salts including, but are not limited to, ammonium, methylammonium, ethylammonium, diethylammonium, triethylammonium, lysine, arginine, N-methylglucamine and choline.
The composition or formulation of the invention includes one or more inhibitors of 5 alpha reductase here inafter referred to as "inhibitory component of the enzyme 5 alpha reductase" and one or more of bile salts hereinafter referred to as "component of bile salts". The weight ratio (referred below to as the RATIO) between the "inhibitory component of the 5 alpha reductase enzyme" and the "bile salts component" is between
0.01 and 100, preferably between 0.1 and 10, even more preferably 1.
Preferably, in the formulation according to the invention, the amount of the inhibitory component of the 5 alpha reductase enzyme and of the "bile salts component", expressed as% by weight of the total formulation is between 0.01% and 20%, preferably between 0.01 and 10% even more preferably 5%.
Preferably, in the formulation according to the invention, the amount of the divalent metal, expressed as% by weight of the total formulation is between 0.01% and
10%, preferably between 0.1 and 5% even more preferably 3%.
The composition or formulation may further comprise pharmaceutically acceptable excipients. Among the excipients that can be used, the following can be used by way of example: lecithin, maltodextrin, isopropyl palmitate, lecithin organogel,
PLURONIC F-127 organogel, NDMS, ethoxyglycol: ethanol and / or water.
Examples
Example 1 of the formulation of the mixture of association with a ratio of 1
Example 2 of the formulation of the mixture of association with a ratio of 1
Example 13. AL., 35 years old, male, characterized by thinning alopecia of the vertex and the fronto-pariatal area: The trichogram shows the following formula: anagen 50%, catagen 5%, telogen 45%. The lotion as described in example 9 was applied every evening, lightly rubbed into dry hair. After six weeks the area showed initial hair regrowth and at the end of treatment (twelfth week) small light-colored hairs were present on 2/3 of the alopecic area, especially in the anterior area with reappearance of hair with normal trichogram (anagen 85 %, catagen 2%, telogen 13%). This aspect is surprising given that
AL had previously applied a lotion similar to the example, but without bile acids and had not observed beneficial effects on alopecia, on the contrary, erythema had appeared.

Claims

1. Composition or formulation comprising one or more inhibitors of 5 alpha reductase and one or more bile acids in the neutral or salified form in a weight ratio between these components comprised between 0.01 and 100, preferably between 0.1 and
10, still more preferably 1, wherein at least a 5 alpha reductase inhibitor and/or at least one bile acid is in the form of a salt with an alkaline earth metal, preferably a calcium or magnesium salt, and a salt of a divalent metal (cation), such as a salt of a alkaline earth metal, for example a salt of calcium, magnesium or zinc.
2. Composition or formulation as in claim 1, where the salt of an alkaline earth metal is a direct salt between at least one 5 alpha reductase inhibitor and/or at least one bile acid with an alkaline earth metal, preferably a calcium salt, of magnesium or zinc.
3. Composition or formulation as in claim 1 or 2, wherein the 5 alfa reductase inhibitors are selected from the following: Emodin, Dutasteride, Finasteride,
Progesterone, Berberine, pure Resveratrol and/or Resveratrol co-precipitated with at least one hydrocalcite or hydroxide, monocaffeyl tartaric acid, Azelaic acid, Zinc, vitamin, arginine and cysteine, phytocomplexes of Serenoa Repens and Poligonum Multiflurum and their combinations.
4. Composition or formulation as in one of the previous claims wherein the bile acid component is chosen from the compounds deriving from formula (I) and their ester derivatives with glycine (glycine derivatives), taurine (Tauro derivatives), glucuronic acid (glucuronate derivatives) and sulfuric acid (sulfate derivatives).
5. Composition or formulation as in claim 4, wherein the bile acid is selected from one or more of the following compounds;
A = cholic acid CAS Number 81-25-4
Methyl ester of cholic acid CAS Number: 1448-36-8
Glico derivative of cholic acid CAS Number 475-31-0
Tauro derivative of cholic acid CAS Number: 81-24-3
Sulfo derivative of cholic acid CAS Number 60320-05-0
Cholic acid glucorinide CAS Number 76060-22-5
CDCA = chenodeoxycholic acid CAS Number 474-25-9
Glico derivative of chenodeoxycholic acid CAS Number 640-79-9
Tauro derived from chenodeoxycholic acid CAS Number 516-35-8
Sulfo derivative of chenodeoxycholic acid CAS 59132-32-0
UDCA = ursodeoxycholic acid CAS Number 128-13-2
Ursodeoxycholic acid methyl ester CAS Number 10538-55-3
Glyco derivative of ursodeoxycholic acid CAS Number 64480-66-6
Tauro derived from ursodeoxycholic acid CAS Number: 14605-22-2
Sulfur derivative of ursodeoxycholic acid CAS 68780-73-4
Glucoronide of the disodium salt of ursodeoxycholic acid CAS Number 75672-30-9
MCA = muricolic acid CAS Number 2393-58-0
DC A = deoxycholic acid CAS Number: 83-44-3
Methyl ester of deoxycholic acid CAS Number: 10538-55-3
Glico derivative of deoxycholic acid CAS Number: 360-65-6
Tauro derived from deoxycholic acid CAS Number 516-50-7 Sulfo derivative of lithocolic acid CAS 34669-57-3
Glucoronide of deoxycholic acid CAS Number 72504-58-6
LCA = lithocolic acid CAS Number 434-13-9
Glyco derivative of lithocolic acid CAS Number 474-74-8
Tauro derived from lithocolic acid CAS Number 516-90-5
7-oxolithocolic acid CAS Number 4651-67-6
Lithocolic acid glucoronide CAS Number 75239-91-7
HDCA = iodesoxycholic acid CAS Number: 83-49-8
Methyl ester of iodesoxycholic acid CAS Number 2868-48-6
Glyco derivative of iodesoxycholic acid CAS Number 13042-33-6
Tauro derived from iodesoxycholic acid CAS Number 2958-04-55.
6. Pharmaceutical, dermatological or cosmetic composition or formulation as in one of the preceding claims for use in the treatment of androgen-dependent dermatoses.
7. Composition as in claim 6, for use in the treatment of acne.
8. Composition as in claim 6, for use in the treatment of alopecia
9. Composition as in claim 6, for use in the treatment of Seborrheic dermatitis.
10. Composition as in claim 6-9 for topical use in the form of solution, lotion, ointment, cream, ointment, liposomes, spray, gel, roller sticks, shampoo, soaps, lip sticks.
11. Composition as in claim 6-9 for topical use in the pharmaceutical form of a medical device.
12. Composition as in claim 6, for use in the treatment of hair loss in dogs and cats.
13. Composition as in claim 10 characterized in that it is topically administered daily, preferably twice a day for a treatment period from 1 to 12 months, preferably between 2 months and 9 months, even more preferably from 3 months to 6 months, even more preferably 3 months.
EP22713729.6A 2021-03-02 2022-03-02 Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids Pending EP4373496A1 (en)

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PCT/IB2022/051834 WO2022185228A1 (en) 2021-03-02 2022-03-02 Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids

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