WO2022185228A1 - Composition ou formulation comprenant un ou plusieurs inhibiteurs de 5-alpha-réductase et un ou plusieurs acides biliaires - Google Patents

Composition ou formulation comprenant un ou plusieurs inhibiteurs de 5-alpha-réductase et un ou plusieurs acides biliaires Download PDF

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WO2022185228A1
WO2022185228A1 PCT/IB2022/051834 IB2022051834W WO2022185228A1 WO 2022185228 A1 WO2022185228 A1 WO 2022185228A1 IB 2022051834 W IB2022051834 W IB 2022051834W WO 2022185228 A1 WO2022185228 A1 WO 2022185228A1
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acid
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Carlo Clerici
Graziano CLERICI
Gabriele Cruciani
Bernard Fioretti
Lucio Leonardi
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S&R Farmaceutici S.P.A.
G&C Biotech S.R.L.
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Publication of WO2022185228A1 publication Critical patent/WO2022185228A1/fr

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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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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la fourniture d'une composition topique destinée au traitement de dermatoses dépendantes des androgènes caractérisés par l'association d'un ou de plusieurs acides biliaires et d'un ou plusieurs inhibiteurs de l'enzyme 5 alpha réductase. Une composition ou une formulation comprenant un ou plusieurs inhibiteurs de 5 alpha réductase et un ou plusieurs acides biliaires est utile pour le traitement des pathologies liées au déséquilibre androgénique (dermatoses androgéniques) avec la capacité de limiter les effets secondaires des inhibiteurs, de 5 alpha-réductase et d'améliorer les effets cytoprotecteurs des acides biliaires.
PCT/IB2022/051834 2021-03-02 2022-03-02 Composition ou formulation comprenant un ou plusieurs inhibiteurs de 5-alpha-réductase et un ou plusieurs acides biliaires WO2022185228A1 (fr)

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IT102021000004898A IT202100004898A1 (it) 2021-03-02 2021-03-02 Formulazione per uso topico caratterizzata da una combinazione di acidi biliari ed inibitori della 5 alfa reduttasi per la il trattamento delle dermatosi androgeno-dipendenti.
IT102021000004898 2021-03-02

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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN110200838A (zh) * 2019-06-21 2019-09-06 武汉百思凯瑞生物科技有限公司 一种复合多肽纳米囊泡及其制备方法和应用

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ITPG20120030A1 (it) 2012-06-27 2013-12-29 Bernard Fioretti Resveratrolo inorganico ibrido
KR20180036580A (ko) 2016-09-30 2018-04-09 주식회사 유스바이오팜 수가용화(水加溶化)된 우르소데옥시콜산을 함유하는 염증성 피부질환 또는 중증 소양증 예방 또는 치료용 조성물
US10703761B2 (en) * 2016-10-18 2020-07-07 City Of Hope Bile acid receptor modulators and methods of use thereof
CN107582899B (zh) * 2017-10-21 2021-01-15 内蒙古民族大学附属医院 一种清热止血的蒙药及其制造工艺

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CN110200838A (zh) * 2019-06-21 2019-09-06 武汉百思凯瑞生物科技有限公司 一种复合多肽纳米囊泡及其制备方法和应用

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IT202100004898A1 (it) 2022-09-02

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