WO2019116303A1 - Composition for the treatment of alopecia - Google Patents

Composition for the treatment of alopecia Download PDF

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Publication number
WO2019116303A1
WO2019116303A1 PCT/IB2018/060020 IB2018060020W WO2019116303A1 WO 2019116303 A1 WO2019116303 A1 WO 2019116303A1 IB 2018060020 W IB2018060020 W IB 2018060020W WO 2019116303 A1 WO2019116303 A1 WO 2019116303A1
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Prior art keywords
composition
treatment
amount
alopecia
present
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PCT/IB2018/060020
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French (fr)
Inventor
Umberto DI MAIO
Original Assignee
Neilos S.r.l.
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Application filed by Neilos S.r.l. filed Critical Neilos S.r.l.
Priority to EP18830956.1A priority Critical patent/EP3723734A1/en
Publication of WO2019116303A1 publication Critical patent/WO2019116303A1/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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 present invention relates to a composition for the treatment and/or prevention of alopecia.
  • Androgenetic alopecia is a pathology that leads to progressive atrophy of the hair follicle, with a consequent reduction in the number of hairs. It is a disorder characterised by progressive hair loss, prevalently in the central part of the scalp, with a hair loss pattern which varies from individual to individual.
  • Androgenetic alopecia is one of the most widespread dermatological problems. It is an age-related disorder, which affects 80% of men and 42% of women over 70 years of age. Although this disorder is more likely to be found in individuals of advanced age, cases of onset during puberty have been reported. Patients with a reduction in the amount or thickness of hair are perceived as older and this causes a reduction in self-esteem and may lead to psychosocial distress.
  • Androgenetic alopecia is a pathology that leads to progressive atrophy of the hair follicle, with a consequent reduction in the number of visible hairs. It affects at least 50% of men under 50 years of age and 70 % of men more advanced in age.
  • DHT 5a-dihydrotestosterone
  • DHT has an affinity for the androgen receptor that is 5 times greater than that of testosterone.
  • DHT has been demonstrated to be involved in the pathogenesis of other pathologies, such as benign prostatic hyperplasia, prostate cancer, hirsutism and acne.
  • the enzyme involved in the conversion of testosterone into DHT is 5a-reductase (3-oxo-5a-steroid 4- dehydrogenase). Its inhibition should lead to a reduction in the progression of the pathology. The importance of inhibiting it also derives from the fact that the hair follicles in the front area of the scalp express high levels of this enzyme, whereas the follicles in the occipital area express high levels of aromatase (which catalyses the synthesis of estradiol, which could have an effect that is opposite to that of DHT).
  • Type I expressed in the scalp, the skin, the sebaceous glands, the liver and the brain
  • Type II expressed in the prostate and in seminal vesicles
  • Type 111 overexpressed i n the case of prostate cancer.
  • Androgen-dependent therapeutic agents can be divided into 5a-reductase inhibitors, anti-androgens and oestrogens.
  • Finasteride is presently the only 5a-reductase inhibitor approved for the treatment of androgenetic alopecia. It is an inhibitor of isoform 2 of this enzyme, which blocks the conversion of testosterone into 5a- dihydrotestosterone (DHT).
  • DHT dihydrotestosterone
  • Dutasteride is an inhibitor of isoforms 1 and 2 of 5a-reductase. This drug is associated with greater efficacy, but also a greater occurrence of side effects.
  • spironolactone and cyproterone acetate are widely used. Their effectiveness is rather modest and the side effects include postural hypotension, electrolytic imbalances, mood disorders and liver toxicity.
  • minoxidil a hypertensive agent that promotes hair growth. It is the only active ingredient approved for the topical treatment of androgenetic alopecia. Minoxidil can lead to a statistically significant increase in the number of hairs after 24 weeks of treatment. This active ingredient, too, is not devoid of side effects, which include contact dermatitis, facial hypertrichosis and temporary hair loss in the initial phase. Moreover, the effectiveness is limited to the duration of the treatment: an interruption in treatment provokes a hair loss, known as "telogen effluvium”, within 4-6 months. Other therapeutic agents are represented by prostaglandin analogues, ketoconazole, melatonin and platelet-rich plasma. All of these treatments have shown very limited effectiveness in the treatment of androgenetic alopecia.
  • the present invention provides a composition for use according to the appended claims.
  • the present invention relates to a composition
  • a composition comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum for use in the preventive or curative treatment of alopecia in a subject, wherein said treatment comprises the administration of said composition to the subject.
  • the present invention relates to a pharmaceutical or cosmetic composition, dietary supplement or medical device comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum and at least one excipient acceptable for pharmaceutical, cosmetic, nutraceutical and/or dietary use.
  • composition according to the invention is particularly advantageous in the treatment of androgenetic alopecia, the treatment of which must generally be carried out for years.
  • treatment of a pathology or disorder means a therapy aimed at restoring the conditions of health of a subject, maintaining the existing conditions and/or preventing a worsening of said health conditions.
  • prevention of a pathology or disorder means a therapy aimed at preventing the onset of such a pathology or disorder in a subject, also, but not only, as a complication or effect of a pre-existing pathological condition or disorder.
  • percentages and amounts of a component in a mixture refer to the weight of such component relative to the total weight of the mixture.
  • the indication "from X to Y” comprises the extremes, i.e. X and Y, as well as all of the possible intermediate numerical values.
  • composition (s) is intended to include a pharmaceutical composition, a composition for cosmetic use, a composition for a dietary supplement, a composition for a food product or a composition for a medical device.
  • the present invention provides a composition comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum for use in the preventive or curative treatment of alopecia in a subject, wherein said treatment comprises the administration of said composition to the subject.
  • Ornithine is an amino acid which can be used in the composition according to the present invention in the L-form (CAS number 70-26-8), D-form or in a racemic or scalemic mixture of the isomers, preferably in the L-form. It is one of the products of the enzyme arginase on L-arginine, which creates ornithine and urea. Ornithine is therefore a fundamental product of the urea cycle, which enables the elimination of excess nitrogen.
  • Ornithine is not an amino acid involved in protein synthesis. However, in the non-hepatic tissues of mammals, the main metabolic role of the urea cycle is to synthesise arginine. Ornithine is thus very important as an intermediate product of metabolic processes. It has effects which are similar to those of arginine, but seems to have double the effectiveness. Its numerous functions include effectiveness as an ammonia detoxifying agent in several diseases with hyperammonaemia and for the cicatrisation of wounds.
  • Polyamines have long been known as important cell growth factors, though their role has not yet been completely clarified. Polyamine concentrations are strictly regulated by synthesis, transport and degradation. Their synthesis is mainly regulated by the enzymes ornithine decarboxylase (ODC1) and adenosylmethionine decarboxylase, whereas degradation is regulated by the enzyme spermidine/spermine N1-acetyltransferase (SSAT). Ornithine decarboxylase is the enzyme that catalyses the step limiting the synthesis of polyamines and has shown its importance in the development of various tissues, such as those of brain, teeth, testicles and pancreas.
  • ODC1 ornithine decarboxylase
  • SSAT spermidine/spermine N1-acetyltransferase
  • Polyamines are important in the hair growth process, as well as in the regulation of their growth cycle, but the mechanism of their physiological action is not yet known.
  • the levels of ornithine decarboxylase increase during the anagen phase of hair growth and are drastically reduced during the catagen phase.
  • the up-regulation of SSAT or ODC1 can lead to hair loss and cutaneous cysts in rats.
  • composition for use according to the present invention can also comprise, in addition or as an alternative to ornithine, salts thereof, such as, without limitation, the hydrochloride or dihydrochloride thereof or ornithine alpha-ketoglutarate, or derivatives such as, without limitation, esters or amides.
  • salts thereof such as, without limitation, the hydrochloride or dihydrochloride thereof or ornithine alpha-ketoglutarate, or derivatives such as, without limitation, esters or amides.
  • the treatment with the composition for use according to the present invention preferably comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg.
  • Millet Panicum miliaceum, L.
  • Poaceae or Gramineae
  • It falls within the grouping of the minor cereals. It represents an important food source for millions of people, in particular for the populations that live in less developed countries, such as those of sub-Saharan Africa. This is due to the ability of millet to grow even under adverse climate conditions.
  • Millet is a unique cereal because of its high content of calcium, dietary fibre, polyphenols and proteins. This cereal generally contains high amounts of essential amino acids, sulphurated amino acids (cysteine and methionine) in particular. The content of essential fatty acids is greater than that of other cereals, such as maize, rice and sorghum.
  • Millet is associated with numerous nutritional and therapeutic properties.
  • the extract used in the composition for use according to the present invention is preferably an aqueous extract of the caryopses (fruits, improperly called seeds) of Panicum miliaceum.
  • the treatment with the composition for use according to the present invention preferably comprises the administration of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg, preferably 20 to 250 mg.
  • the treatment with the composition for use according to the present invention preferably comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, and of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg, preferably 20 to 250 mg.
  • Cystine is a sulphurated amino acid characterised by the molecular formula C 6 H 12 N 2 O 4 S 2 and obtained through the oxidative reaction of two molecules of cysteine, which, in the structure, are bound through a disulphide bridge.
  • Cystine is an amino acid that is non-essential for humans and performs various biological functions in the body. It is an essential component of many proteins, of which it determines the tertiary structure, and can be involved in the redox reactions occurring in the body. It is particularly present in keratin, a protein present mainly in the hair, in which it is responsible, among other things, for the curvature: the latter derives, in fact, precisely from the number of disulphide bridges formed by cystine.
  • the treatment with the composition for use according to the present invention preferably comprises the administration of at least one among cystine, cysteine, N-acetyl cysteine, and mixtures thereof, or analogues and derivatives thereof.
  • the treatment according to the invention comprises the administration of a daily dose of at least one among cystine, cysteine, N-acetyl cysteine, and mixtures thereof in an amount of 50 to 5000 mg, preferably 300 to 1000 mg.
  • the present composition is advantageously used for the prevention and/or treatment of at least one disorder or pathology among androgenetic alopecia, alopecia areata, psychogenic alopecia and/or telogen effluvium.
  • the effectiveness of the composition may derive from the synergism of the following activities of the components:
  • Ornithine serves as a substrate for the synthesis of polyamines, which act as growth factors for hair follicles;
  • Extract of Panicum miliaceum is capable of preventing alopecia and nourishing hair follicle cells; Cystine serves as a substrate for the synthesis of keratin and is capable of reinforcing the hair structure.
  • the synergism is obtained particularly when ornithine is present in an amount comprised between 1 mg and 1000 mg, extract of Panicum miliaceum is present in an amount comprised between 1 mg and 2000 mg and cystine, if present, is in an amount comprised between 50 mg and 5000 mg.
  • composition according to the present invention can be for use in human subjects or for veterinary use, for example, but without limitation, in pets such as dogs or cats, or in other mammals.
  • the composition according to the present invention is preferably for use in humans.
  • the administration of the composition to the subject takes place orally, for example in the form of a pill, tablet, which may also be coated, a hard or soft gelatine capsule, also comprising microgranules, solution, suspension, syrup, granules, food containing (a), (b) and, optionally, (c) or in any other form known to the person skilled in the art.
  • composition for use according to the present invention may comprise, in addition to (a), (b) and, optionally, (c), at least one inert ingredient, such as at least one excipient among those commonly used and known to the person skilled in the art.
  • “Inert ingredient” means any substance, or combination of substances, auxiliary to the production of a pharmaceutical, dietary or nutraceutical form, which is to be found in the product and in the finished product and that is not the active ingredient, although it can modify the stability, release or other characteristics thereof.
  • Non-limiting examples of such ingredients are diluent excipients, absorbents, adsorbents, lubricants, glidants, colourants, surfactants, antioxidants, sweeteners, flavourings, binders, disintegrating agents, plasticisers, viscosity enhancing agents, emulsifiers, humectants, wetting agents, preservatives, chelating agents and the like.
  • the composition for use according to the present invention comprises, in addition to (a), (b) and, optionally, (c), at least one further active ingredient of natural or synthetic origin.
  • active ingredients are methionine, niacin, cholecalciferol, ergocalciferol, biotin, zinc, iron, copper, molybdenum, betaine and mixtures thereof.
  • the treatment of a subject comprises, in addition to the administration of the composition comprising (a), (b) and, optionally, (c), as identified above, also at least one among extracts of Ginkgo biloba L, Bambusa vulgaris Schrad., Saccharum offidnarum L, Eguisetum arvense L., Citrus aurantium L, Citrus iimon Burm., Trifolium pratense L, Glydne max (L.) Merr, and Cimidfuga racemosa Nutt.
  • the composition for use according to the present invention is for the treatment of at least one disorder or pathology among androgenetic alopecia, alopecia areata, psychogenic alopecia and/or telogen effluvium.
  • the present invention provides a pharmaceutical or cosmetic composition, dietary supplement or medical device comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum and at least one excipient which is acceptable for pharmaceutical, cosmetic, nutraceutical and/or dietary use.
  • the pharmaceutical or cosmetic composition, dietary supplement or medical device according to the present invention preferably comprises, in addition to (a) and (b), at least one among cystine, cysteine, N- acetyl cysteine and mixtures thereof (c).
  • ornithine (a) is preferably in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, and/or the extract of Panicum miliaceum (b) is present in an amount of 1 mg to 500 mg, preferably 20 to 250 mg, and cystine, cysteine or N-acetyl cysteine (c), if present, is in an amount of 50 to 5000 mg, preferably 300 to 1000 mg.
  • the term "medical device” is used with the meaning according to Italian Legislative Decree no. 46 of 24 February 1997 and Directive 93/42/EEC of 14 June 1993, i.e. it indicates a substance or another product, whether used alone or in combination, intended by the manufacturer to be used for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease, and the product of which does not achieve its principal intended action, in or on the human body, with pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.
  • the pharmaceutical or cosmetic composition, dietary supplement or medical device of the present invention can be solid, liquid or semisolid, for example as a suspension or gel, and can be in any form known the person skilled in the art of food, pharmaceutical or nutraceutical formulations, such as, by way of non-limiting example, in the form of a capsule, tablet, or powder that is at least partially dissolvable in the mouth or water soluble, granules, pellets or microparticles optionally contained in a sachet or in a capsule or in a mini-tablet, a liquid or semisolid preparation, gel, suspension, solution, two-phase liquid system and equivalent forms.
  • composition 1000 mg capsules.
  • EXAMPLE 10 Pharmaceutical form: 1800 mg sachets.
  • composition 1900 mg sachets.
  • the anagen phase of the hair present on the back of the mice was induced by following one of the procedures described in the literature (S. MCiller-Rover, B. Handjiski, C. Van Der Veen, S. EichmCiller, K. Foitzik, I. A. McKay, K. S. Stenn, and R. Paus, "A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages", Journal of Investigative Dermatology, vol. 117, no. 1. pp. 3-15, lug-2001).
  • the anagen phase was induced by shaving the hair on the back, so as to synchronise the anagen phase in all animals. Starting from the day after shaving, the formulations were applied on the skin of each animal, 2 times a day for 28 days, using a specific vehicle. The promotion of hair growth was evaluated by means of photographs of the rats and histological examination.
  • mice taken from each group was sacrificed after 14, 21 and 28 days from the beginning of the treatment.
  • the skin of the back was cut into a section with a diameter of 5 pm, fixed in formalin, embedded in paraffin and stained with hematoxylin/eosin for the histological examination.
  • FDPCs follicle dermal papilla cells
  • the cells are plated in 96-well multiwell plates at a density of 5000 cells/well (5 wells for each individual component or for the composition, technical replicates).
  • the cells are treated for 24 hours with the individual components of the present composition separately and with the components of the composition jointly, precisely with the aim of identifying a synergistic strengthening of the composition compared to the individual components thereof.
  • cell survival is evaluated with a colorimetric assay.
  • the absorbance of the reaction product is measured at a wavelength of 490 nm by means of a specific reader.
  • a morphological evaluation of the cells is also performed with a microscope.
  • the selected cellular model is represented by follicle dermal papilla cells (FDPCs).
  • the cells are plated to confluency in 96-well multiwell plates.
  • Oxidative stress is evaluated using a fluorimetric kit.
  • At least three independent experiments are performed for every component and for the composition of the invention and their statistical significance is verified using a non-parametric test.
  • the tests include an internal control condition (solvent) and a positive control condition.

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Abstract

The present invention relates to a composition for the treatment of alopecia.

Description

DESCRIPTION of the invention having the title:
“COMPOSITION FOR THE TREATMENT OF ALOPECIA”.
The present invention relates to a composition for the treatment and/or prevention of alopecia.
Androgenetic alopecia is a pathology that leads to progressive atrophy of the hair follicle, with a consequent reduction in the number of hairs. It is a disorder characterised by progressive hair loss, prevalently in the central part of the scalp, with a hair loss pattern which varies from individual to individual.
Androgenetic alopecia is one of the most widespread dermatological problems. It is an age-related disorder, which affects 80% of men and 42% of women over 70 years of age. Although this disorder is more likely to be found in individuals of advanced age, cases of onset during puberty have been reported. Patients with a reduction in the amount or thickness of hair are perceived as older and this causes a reduction in self-esteem and may lead to psychosocial distress.
Androgenetic alopecia is a pathology that leads to progressive atrophy of the hair follicle, with a consequent reduction in the number of visible hairs. It affects at least 50% of men under 50 years of age and 70 % of men more advanced in age.
The mechanism that leads to a reduction in the anagen phase (of hair follicle cell proliferation), and to progressive atrophy of the follicle following the death of the cells making it up, is undoubtedly very complex and has not yet been completely clarified.
An involvement of androgens in the process of pathogenesis of alopecia has been demonstrated. The hormone mainly involved is 5a-dihydrotestosterone (DHT), which has an affinity for the androgen receptor that is 5 times greater than that of testosterone. In addition to alopecia, DHT has been demonstrated to be involved in the pathogenesis of other pathologies, such as benign prostatic hyperplasia, prostate cancer, hirsutism and acne.
The enzyme involved in the conversion of testosterone into DHT is 5a-reductase (3-oxo-5a-steroid 4- dehydrogenase). Its inhibition should lead to a reduction in the progression of the pathology. The importance of inhibiting it also derives from the fact that the hair follicles in the front area of the scalp express high levels of this enzyme, whereas the follicles in the occipital area express high levels of aromatase (which catalyses the synthesis of estradiol, which could have an effect that is opposite to that of DHT).
Three isoforms of 5a-reductase have been identified to date:
• Type I: expressed in the scalp, the skin, the sebaceous glands, the liver and the brain
• Type II: expressed in the prostate and in seminal vesicles
• Type 111 : overexpressed i n the case of prostate cancer. Notwithstanding the high prevalence of androgenetic alopecia, the therapeutic options are very limited, with few pharmacological treatments and numerous over-the-counter products that are sold as being effective in the treatment of this disorder, but without any experimental evidence to support this indication. Androgen-dependent therapeutic agents can be divided into 5a-reductase inhibitors, anti-androgens and oestrogens.
Finasteride is presently the only 5a-reductase inhibitor approved for the treatment of androgenetic alopecia. It is an inhibitor of isoform 2 of this enzyme, which blocks the conversion of testosterone into 5a- dihydrotestosterone (DHT). Long-term treatment with finasteride at a dose of 1 mg is capable of reducing androgenetic alopecia, with a 30% increase in the number of hairs. In male androgenetic alopecia a greater response is found in the hair of the vertex than in hair in the frontal/centroparietal region.
Numerous side effects are associated with treatment with finasteride, including erectile dysfunction, reduction in libido and ejaculatory dysfunctions. These side effects are observed even for several years following the interruption of the treatment.
One of the most worrying side effects consists in the predisposition to breast cancer, probably due to an increase in the oestrogen/testosterone ratio occurring as a result of the blocking of 5a-reductase.
The use of finasteride in women is contraindicated due to its teratogenicity.
Dutasteride is an inhibitor of isoforms 1 and 2 of 5a-reductase. This drug is associated with greater efficacy, but also a greater occurrence of side effects.
Among anti-androgen agents, spironolactone and cyproterone acetate are widely used. Their effectiveness is rather modest and the side effects include postural hypotension, electrolytic imbalances, mood disorders and liver toxicity.
There are also various androgen-independent therapeutic agents for the treatment of androgenetic alopecia.
The main one is minoxidil, a hypertensive agent that promotes hair growth. It is the only active ingredient approved for the topical treatment of androgenetic alopecia. Minoxidil can lead to a statistically significant increase in the number of hairs after 24 weeks of treatment. This active ingredient, too, is not devoid of side effects, which include contact dermatitis, facial hypertrichosis and temporary hair loss in the initial phase. Moreover, the effectiveness is limited to the duration of the treatment: an interruption in treatment provokes a hair loss, known as "telogen effluvium”, within 4-6 months. Other therapeutic agents are represented by prostaglandin analogues, ketoconazole, melatonin and platelet-rich plasma. All of these treatments have shown very limited effectiveness in the treatment of androgenetic alopecia.
Given the limited effectiveness and - above all - the marked side effects of the present pharmacological treatments, there is a felt need for an innovative treatment that is effective in preventing and/or treating alopecia, particularly androgenetic alopecia, and which is not associated with the undesirable effects of the therapeutic agents presently available.
As a solution for said need, the present invention provides a composition for use according to the appended claims.
The present invention relates to a composition comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum for use in the preventive or curative treatment of alopecia in a subject, wherein said treatment comprises the administration of said composition to the subject.
The present invention relates to a pharmaceutical or cosmetic composition, dietary supplement or medical device comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum and at least one excipient acceptable for pharmaceutical, cosmetic, nutraceutical and/or dietary use.
Preferred embodiments of the present invention will appear clear from the detailed description that follows and are indicated in the appended claims.
Following extensive experimentation, the inventors have developed a composition containing an effective amount of a mixture which comprises at least two substances of natural origin, i.e. (a) ornithine and (b) an extract of Panicum miliaceum, and which has demonstrated high activity in the curative or preventive treatment of alopecia and is practically devoid of the side effects associated with the treatment of alopecia with the presently available active ingredients, mainly of synthetic origin.
The composition according to the invention is particularly advantageous in the treatment of androgenetic alopecia, the treatment of which must generally be carried out for years.
In the context of the present invention, "treatment” of a pathology or disorder means a therapy aimed at restoring the conditions of health of a subject, maintaining the existing conditions and/or preventing a worsening of said health conditions.
In the context of the present invention, "prevention” of a pathology or disorder means a therapy aimed at preventing the onset of such a pathology or disorder in a subject, also, but not only, as a complication or effect of a pre-existing pathological condition or disorder. Unless indicated otherwise, in the context of the present invention the percentages and amounts of a component in a mixture refer to the weight of such component relative to the total weight of the mixture.
Unless specified otherwise, in the context of the present invention, with respect to intervals of numerical values for a certain characteristic, the indication "from X to Y” comprises the extremes, i.e. X and Y, as well as all of the possible intermediate numerical values.
In the context of the present invention, the term "composition (s)” is intended to include a pharmaceutical composition, a composition for cosmetic use, a composition for a dietary supplement, a composition for a food product or a composition for a medical device.
In one aspect, the present invention provides a composition comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum for use in the preventive or curative treatment of alopecia in a subject, wherein said treatment comprises the administration of said composition to the subject.
Ornithine is an amino acid which can be used in the composition according to the present invention in the L-form (CAS number 70-26-8), D-form or in a racemic or scalemic mixture of the isomers, preferably in the L-form. It is one of the products of the enzyme arginase on L-arginine, which creates ornithine and urea. Ornithine is therefore a fundamental product of the urea cycle, which enables the elimination of excess nitrogen.
Ornithine is not an amino acid involved in protein synthesis. However, in the non-hepatic tissues of mammals, the main metabolic role of the urea cycle is to synthesise arginine. Ornithine is thus very important as an intermediate product of metabolic processes. It has effects which are similar to those of arginine, but seems to have double the effectiveness. Its numerous functions include effectiveness as an ammonia detoxifying agent in several diseases with hyperammonaemia and for the cicatrisation of wounds.
Structurally speaking, it is considered the lower analogue of lysine, as it has an amino group in position d, rather than e.
Polyamines have long been known as important cell growth factors, though their role has not yet been completely clarified. Polyamine concentrations are strictly regulated by synthesis, transport and degradation. Their synthesis is mainly regulated by the enzymes ornithine decarboxylase (ODC1) and adenosylmethionine decarboxylase, whereas degradation is regulated by the enzyme spermidine/spermine N1-acetyltransferase (SSAT). Ornithine decarboxylase is the enzyme that catalyses the step limiting the synthesis of polyamines and has shown its importance in the development of various tissues, such as those of brain, teeth, testicles and pancreas.
Its action is also crucial in hair growth, as demonstrated in 1983 by Takigawa, who observed that the inhibition of this enzyme by a-difluoromethylornithine led to the inhibition of hair growth. Numerous other studies have demonstrated the correlation between the inhibition of this enzyme by difluoromethylornithine and a marked reduction in hair growth. In one study it led to the onset of alopecia and dermatitis in rats and dogs. In other studies it has been demonstrated that the overexpression of this enzyme in hair follicles is associated with hair loss, excessive skin folds and tumour formation. These studies demonstrate that hair follicles can be sensitive to changes in the concentration of this enzyme.
Polyamines are important in the hair growth process, as well as in the regulation of their growth cycle, but the mechanism of their physiological action is not yet known.
The levels of ornithine decarboxylase increase during the anagen phase of hair growth and are drastically reduced during the catagen phase. The up-regulation of SSAT or ODC1 can lead to hair loss and cutaneous cysts in rats.
Recent studies have begun to delineate a possible mechanism of action of putrescine in hair growth. Luke et al. demonstrated the existence of a negative loop between the overexpression of ODC1 and hair loss (C. T. Luke, A. Casta, H. Kim, and A. M. Christiano, "Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis.”, Exp. Dermatol., vol. 22, no. 10, pp. 644-649, October 2013). The composition for use according to the present invention can also comprise, in addition or as an alternative to ornithine, salts thereof, such as, without limitation, the hydrochloride or dihydrochloride thereof or ornithine alpha-ketoglutarate, or derivatives such as, without limitation, esters or amides.
The treatment with the composition for use according to the present invention preferably comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg.
Millet ( Panicum miliaceum, L.) is an annual herbaceous plant belonging to the family Poaceae (or Gramineae). It falls within the grouping of the minor cereals. It represents an important food source for millions of people, in particular for the populations that live in less developed countries, such as those of sub-Saharan Africa. This is due to the ability of millet to grow even under adverse climate conditions.
Millet is a unique cereal because of its high content of calcium, dietary fibre, polyphenols and proteins. This cereal generally contains high amounts of essential amino acids, sulphurated amino acids (cysteine and methionine) in particular. The content of essential fatty acids is greater than that of other cereals, such as maize, rice and sorghum.
Millet is associated with numerous nutritional and therapeutic properties.
The extract used in the composition for use according to the present invention is preferably an aqueous extract of the caryopses (fruits, improperly called seeds) of Panicum miliaceum.
The treatment with the composition for use according to the present invention preferably comprises the administration of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg, preferably 20 to 250 mg.
The treatment with the composition for use according to the present invention preferably comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, and of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg, preferably 20 to 250 mg.
Cystine is a sulphurated amino acid characterised by the molecular formula C6H12N2O4S2 and obtained through the oxidative reaction of two molecules of cysteine, which, in the structure, are bound through a disulphide bridge.
It appears as a colourless solid with a melting point of 260-261 °C.
Cystine is an amino acid that is non-essential for humans and performs various biological functions in the body. It is an essential component of many proteins, of which it determines the tertiary structure, and can be involved in the redox reactions occurring in the body. It is particularly present in keratin, a protein present mainly in the hair, in which it is responsible, among other things, for the curvature: the latter derives, in fact, precisely from the number of disulphide bridges formed by cystine.
Given its important structural role for the health of hair, it is clear that an inadequate dietary intake of this molecule may give rise to a dysfunction in the production of keratin, with a consequent increase in the fragility of hair. Supplementing the diet with this amino acid may therefore lead to a reinforcement of the hair structure. Cystine has a greater bioavailability than cysteine, so it is often preferred to the latter as a supplement for hair health.
The treatment with the composition for use according to the present invention preferably comprises the administration of at least one among cystine, cysteine, N-acetyl cysteine, and mixtures thereof, or analogues and derivatives thereof.
If present in the composition, the treatment according to the invention comprises the administration of a daily dose of at least one among cystine, cysteine, N-acetyl cysteine, and mixtures thereof in an amount of 50 to 5000 mg, preferably 300 to 1000 mg. The present composition is advantageously used for the prevention and/or treatment of at least one disorder or pathology among androgenetic alopecia, alopecia areata, psychogenic alopecia and/or telogen effluvium.
Without wishing to be limited by theory, the effectiveness of the composition may derive from the synergism of the following activities of the components:
Ornithine serves as a substrate for the synthesis of polyamines, which act as growth factors for hair follicles;
Extract of Panicum miliaceum is capable of preventing alopecia and nourishing hair follicle cells; Cystine serves as a substrate for the synthesis of keratin and is capable of reinforcing the hair structure.
It has been surprisingly found that in the present invention a synergistic action occurs between ornithine, extract of Panicum miliaceum and, optionally, cystine.
The synergism is obtained particularly when ornithine is present in an amount comprised between 1 mg and 1000 mg, extract of Panicum miliaceum is present in an amount comprised between 1 mg and 2000 mg and cystine, if present, is in an amount comprised between 50 mg and 5000 mg.
The composition according to the present invention can be for use in human subjects or for veterinary use, for example, but without limitation, in pets such as dogs or cats, or in other mammals. The composition according to the present invention is preferably for use in humans.
In one embodiment, the administration of the composition to the subject takes place orally, for example in the form of a pill, tablet, which may also be coated, a hard or soft gelatine capsule, also comprising microgranules, solution, suspension, syrup, granules, food containing (a), (b) and, optionally, (c) or in any other form known to the person skilled in the art.
It remains understood that the administration of (a), (b) and, optionally, (c) according to the invention can take place simultaneously, for example in a single formulation, or in rapid sequence, for example by means of two or more formulations taken by the subject in any order, in a sequence closely spaced over time (e.g. within 1 to 10 minutes) in two distinct compositions. The composition for use according to the present invention may comprise, in addition to (a), (b) and, optionally, (c), at least one inert ingredient, such as at least one excipient among those commonly used and known to the person skilled in the art.
"Inert ingredient” means any substance, or combination of substances, auxiliary to the production of a pharmaceutical, dietary or nutraceutical form, which is to be found in the product and in the finished product and that is not the active ingredient, although it can modify the stability, release or other characteristics thereof.
Non-limiting examples of such ingredients, as known to the person skilled in the art of formulations in the pharmaceutical, nutraceutical or food sectors, are diluent excipients, absorbents, adsorbents, lubricants, glidants, colourants, surfactants, antioxidants, sweeteners, flavourings, binders, disintegrating agents, plasticisers, viscosity enhancing agents, emulsifiers, humectants, wetting agents, preservatives, chelating agents and the like.
In one embodiment, the composition for use according to the present invention comprises, in addition to (a), (b) and, optionally, (c), at least one further active ingredient of natural or synthetic origin. Non-limiting examples of such active ingredients are methionine, niacin, cholecalciferol, ergocalciferol, biotin, zinc, iron, copper, molybdenum, betaine and mixtures thereof.
In one embodiment of the present invention, the treatment of a subject comprises, in addition to the administration of the composition comprising (a), (b) and, optionally, (c), as identified above, also at least one among extracts of Ginkgo biloba L, Bambusa vulgaris Schrad., Saccharum offidnarum L, Eguisetum arvense L., Citrus aurantium L, Citrus iimon Burm., Trifolium pratense L, Glydne max (L.) Merr, and Cimidfuga racemosa Nutt.
In a preferred embodiment, the composition for use according to the present invention is for the treatment of at least one disorder or pathology among androgenetic alopecia, alopecia areata, psychogenic alopecia and/or telogen effluvium.
The present invention provides a pharmaceutical or cosmetic composition, dietary supplement or medical device comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum and at least one excipient which is acceptable for pharmaceutical, cosmetic, nutraceutical and/or dietary use. The pharmaceutical or cosmetic composition, dietary supplement or medical device according to the present invention preferably comprises, in addition to (a) and (b), at least one among cystine, cysteine, N- acetyl cysteine and mixtures thereof (c).
In said pharmaceutical or cosmetic composition, dietary supplement or medical device according to the present invention, ornithine (a) is preferably in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, and/or the extract of Panicum miliaceum (b) is present in an amount of 1 mg to 500 mg, preferably 20 to 250 mg, and cystine, cysteine or N-acetyl cysteine (c), if present, is in an amount of 50 to 5000 mg, preferably 300 to 1000 mg.
In the context of the present invention, the term "medical device” is used with the meaning according to Italian Legislative Decree no. 46 of 24 February 1997 and Directive 93/42/EEC of 14 June 1993, i.e. it indicates a substance or another product, whether used alone or in combination, intended by the manufacturer to be used for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease, and the product of which does not achieve its principal intended action, in or on the human body, with pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.
The pharmaceutical or cosmetic composition, dietary supplement or medical device of the present invention can be solid, liquid or semisolid, for example as a suspension or gel, and can be in any form known the person skilled in the art of food, pharmaceutical or nutraceutical formulations, such as, by way of non-limiting example, in the form of a capsule, tablet, or powder that is at least partially dissolvable in the mouth or water soluble, granules, pellets or microparticles optionally contained in a sachet or in a capsule or in a mini-tablet, a liquid or semisolid preparation, gel, suspension, solution, two-phase liquid system and equivalent forms.
Some preferred, but non-limiting, embodiments of the invention are the following:
EXAMPLE 1
Figure imgf000010_0001
Pharmaceutical form: 400 mg tablets. EXAMPLE 2
Figure imgf000011_0001
Pharmaceutical form: 500 mg tablets.
EXAMPLE 3
Figure imgf000011_0002
Pharmaceutical form: 600 mg tablets.
EXAMPLE 4
Figure imgf000011_0003
Pharmaceutical form: 800 mg capsules.
EXAMPLE 5
Figure imgf000011_0004
Pharmaceutical form: 1000 mg capsules.
EXAMPLE 6
Figure imgf000011_0005
Figure imgf000012_0005
Pharmaceutical form: 1200 mg tablets.
EXAMPLE 7
Figure imgf000012_0001
Pharmaceutical form: 1200 mg capsules.
EXAMPLE 8
Figure imgf000012_0002
Pharmaceutical form: 1600 mg sachets.
EXAMPLE 9
Figure imgf000012_0003
Pharmaceutical form: 1700 mg sachets.
EXAMPLE 10
Figure imgf000012_0004
Pharmaceutical form: 1800 mg sachets.
EXAMPLE 11
Figure imgf000013_0001
Pharmaceutical form: 1900 mg sachets.
EXAMPLE 12
Figure imgf000013_0002
Pharmaceutical form: 2200 mg sachets.
EXAMPLE 13
Figure imgf000013_0003
Pharmaceutical form: 350 mg tablet.
EXAMPLE 14
Figure imgf000013_0004
Pharmaceutical form: 1000 mg tablet. The following experimental part provides examples of practical embodiments of the invention, without limiting the scope thereof.
EXPERIMENTAL PART 1
In order to be able to evaluate the synergistic effect of the formulation, the rate of hair growth in a mouse model, as previously described in the literature (J. Y. Lee, K. R. Im, T. K. Jung, M.-H. Lee, and K.-S. Yoon, “Medicinal Herbal Complex Extract with Potential for Hair Growth-Promoting Activity", J. Soc. Cosmet. Sci. Korea, vol. 38, no. 4, pp. 277-287, 2012; K. Shin, T. Kim, J. Kyung, D. Kim, D. Park, and E. Choi, “Effectiveness of the combinational treatment of Laminaria japonica and Cistanche tubulosa extracts in hair growth", Lab Anim Res, vol. 31, no. 1, pp. 24-32, 2015) was evaluated.
For the study, use was made of C57BL/6 mice, which were housed in temperature-controlled rooms, with a temperature of 23 ± 2 °C, relative humidity of 45-65% and with light/dark cycles of 12 hours. The animals had free access to water and food, consisting in a standard diet. All experiments were performed in observance of Legislative Decree no. 116 of 27 January 1992 and according to the guidelines of the Council of the European Union (86/609/EEC and 2010/63/EU).
The anagen phase of the hair present on the back of the mice was induced by following one of the procedures described in the literature (S. MCiller-Rover, B. Handjiski, C. Van Der Veen, S. EichmCiller, K. Foitzik, I. A. McKay, K. S. Stenn, and R. Paus, "A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages", Journal of Investigative Dermatology, vol. 117, no. 1. pp. 3-15, lug-2001). In short, after having adapted the mice to the new environment for a week, the anagen phase was induced by shaving the hair on the back, so as to synchronise the anagen phase in all animals. Starting from the day after shaving, the formulations were applied on the skin of each animal, 2 times a day for 28 days, using a specific vehicle. The promotion of hair growth was evaluated by means of photographs of the rats and histological examination.
For an objective comparison of the rate of hair regrowth, photographs were taken of the back of the rats, after having anesthetized them, and the percentage area of hair growth was calculated by means of specific software.
One mouse taken from each group was sacrificed after 14, 21 and 28 days from the beginning of the treatment. The skin of the back was cut into a section with a diameter of 5 pm, fixed in formalin, embedded in paraffin and stained with hematoxylin/eosin for the histological examination.
EXPERIMENTAL PART 2
As an alternative test for evaluating the synergistic action of the active ingredients of the present invention, cell viability is analysed in vitro by means of the test described below. The selected cellular model is represented by follicle dermal papilla cells (FDPCs).
Specifically, the cells are plated in 96-well multiwell plates at a density of 5000 cells/well (5 wells for each individual component or for the composition, technical replicates).
12 hours after plating, the cells are treated for 24 hours with the individual components of the present composition separately and with the components of the composition jointly, precisely with the aim of identifying a synergistic strengthening of the composition compared to the individual components thereof. At the end of the 24 hours of treatment, cell survival is evaluated with a colorimetric assay.
The absorbance of the reaction product is measured at a wavelength of 490 nm by means of a specific reader.
At the end of treatment, a morphological evaluation of the cells is also performed with a microscope.
EXPERIMENTAL PART 3
Finally, with the aim of demonstrating the synergistic action of the components of the present invention, their antioxidant activity is evaluated in vitro.
The selected cellular model is represented by follicle dermal papilla cells (FDPCs).
Specifically, the cells are plated to confluency in 96-well multiwell plates.
Oxidative stress is evaluated using a fluorimetric kit.
At least three independent experiments are performed for every component and for the composition of the invention and their statistical significance is verified using a non-parametric test.
Differences having a p-value (probability value) < 0.05 are considered significant.
The tests include an internal control condition (solvent) and a positive control condition.

Claims

1. A composition comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum for use in the preventive or curative treatment of alopecia in a subject, wherein said treatment comprises the administration of said composition to the subject.
2. The composition for use according to claim 1 , wherein the treatment comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg and/or of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg.
3. The composition for use according to one of the claims 1 or 2, wherein the mixture comprises, in addition to (a) and (b), at least one among cystine, cysteine, N-acetyl cysteine or mixtures thereof (c).
4. The composition for use according to claim 3, wherein the treatment comprises the administration of a daily dose of at least one among cystine, cysteine, N-acetyl cysteine or mixtures thereof (c) in an amount of 50 to 5000 mg.
5. The composition for use according to at least one of the preceding claims, wherein said treatment comprises the administration of a daily dose of ornithine (a) in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, a daily dose of extract of Panicum miliaceum (b) in an amount of 1 mg to 500 mg, preferably 20 to 250 mg, and at least one among cystine, cysteine, N-acetyl cysteine or mixtures thereof (c), if present, in an amount of 50 to 5000 mg, preferably 300 to 1000 mg.
6. The composition for use according to any one of the preceding claims, for the treatment of at least one disorder or pathology among androgenetic alopecia, alopecia areata, psychogenic alopecia and/or telogen effluvium.
7. A pharmaceutical or cosmetic composition, dietary supplement or medical device comprising or, alternatively, consisting of an effective amount of a mixture which comprises at least (a) ornithine, (b) extract of Panicum miliaceum and at least one excipient acceptable for pharmaceutical, cosmetic, nutraceutical and/or dietary use.
8. The pharmaceutical or cosmetic composition, dietary supplement or medical device according to claim 7, which comprises, in addition to (a) and (b), at least one among cystine, cysteine, N-acetyl cysteine or mixtures thereof (c).
9. The pharmaceutical or cosmetic composition, dietary supplement or medical device according to one of the claims 7 or 8, wherein ornithine (a) is in an amount of 1 mg to 2000 mg, preferably 200 to 1000 mg, and/or the extract of Panicum miliaceum (b) is present in an amount of 1 mg to 500 mg, preferably 20 to 250 mg, and cystine, cysteine, N-acetyl cysteine or mixtures thereof (c), if present, is in an amount of 50 to 5000 mg, preferably 300 to 1000 mg.
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