Compounds for preventing and treating skin or mucosal affections having an inflammatory component

Abstract

The present invention concerns the use of selected compounds in a cosmetic skincare treatment or in the treatment of certain skin, scalp or mucosal diseases. The invention also provides a composition for topical use incorporating a pharmaceutically or cosmetically effective amount of a compound for preventing or treating skin or mucosal diseases having an inflammatory component or for reducing the redness or irritation of skin or mucosae.

Claims

1. A method of treating a skin, scalp, or mucosal inflammatory disease, said method comprising: administering topically, to a subject having a skin, scalp or mucosal inflammatory disease, sandal pentanol in an amount effective to promote anti-inflammatory activity mediated by dermcidin, wherein said disease is selected from the group consisting of psoriasis, rosacea, folliculitis, and skin rashes.

2. The method of claim 1, wherein the sandal pentanol is in a composition further comprising a physiologically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 shows dermcidin protein expression in the epithelium of human scalp Hair Follicles (HFs) with Sandalore treatment

(2) Representative images show dermcidin (white arrows) in Sandalore and vehicle human treated scalp microdissected hair follicle for 5 days (a,b) or 3 days (c,d) ex vivo. Qualitative observation deriving from the analysis of n=3 independent experiments (3 donors) (a,b) or 1 independent experiment (1 donor) (c, d). HS, hair shaft; IRS, inner root sheath; ORS, outer root sheath.

(3) The experimental data indicate the number of positive cells (DCD+cells). In the vehicle are present 4.444±0.623 (mean±SEM) DCD+ cells, whereas in the treatment with 500 microM the DCD+ cells are 7.786±0.596 (mean±SEM). Sandalore induces statistical significant increase of the number of DCD+ cells with respect to vehicle (p<0.001).

DETAILED DESCRIPTION OF THE INVENTION

(4) According to certain aspects of the invention, the inventors founds that specific compounds activate certain immune defense mechanisms of the skin and/or promote an immune-stimulating activity which is mediated by dermcidin, a peptide which is constitutively secreted in human sweat and which typically plays a role in the regulation of the innate immune response as evidenced by Echo Wang et al. on Shock, 2016 January; 45(1): 28-32.

(5) In accordance with a first aspect the present invention provides compounds of formula (I) for use as claimed in appended claim 1.

(6) Further embodiments of the pharmaceutical use of compounds of formula (I) invention are defined in appended claims 2-4.

(7) Compounds of formula (I) were developed as synthetic substitutes of natural sandalwood. They provide a fragrance similar to that of Sandalwood.

(8) In general, the terminology sandalwood is referred to a class of woods from trees of the genus Santalum. The essential oil of sandalwood commonly is extracted by steam distillation of wood from matured sandalwood trees, and is a well-known valued component for perfumes.

(9) The main components of sandalwood oil are α-santalol e β-santalol, which are alcohols basically showing a sesquiterpenic type chain.

(10) The structural formula of α-santalol is the following

(11) ##STR00002##

(12) The structural formula of β-santalol, which is as follow,

(13) ##STR00003##

(14) The above chemical structures includes a terminal tricyclohept-3-yl or a bicyclohept-2-yl group, respectively.

(15) One of the preferred compounds for the topical uses according to the invention is sandal pentanol, also known as Sandalore®. This is a synthetic odorant having a fragrance similar to sandalwood and commonly used as component of perfumes or as emollient or skin cleaning agent or as an ingredient mimicking the sandalwood scent.

(16) Typically, Sandalore, and its analogue derivatives, are alcohols having a chemical structure different from α-santalol e β-santalol which origin from natural sandalwood oil.

(17) Sandalore, or sandal pentanol, have the following formula:

(18) ##STR00004##

(19) Typically, the above referred molecules are synthetic.

(20) In accordance with certain embodiments the compounds of formula (I) contain a terminal cyclopenten-1-yl group and have no polycyclic structure typical of natural sandalwood oil constituents.

(21) In accordance with certain embodiments, the compounds of formula (I) are selected from the compounds illustrated in the following Table:

(22) TABLE-US-00001 Formula/ Compound IUPAC Name CAS No Structural formula MW 1 sandal pentanol 3-methyl-5-(2,2,3- trimethylcyclopent-3-en-1- yl)pentan-2-ol  65113-99-7 C.sub.14H.sub.26O 210.36 2 sandal pentenol (4Z)-3-methyl-5-(2,2,3- trimethylcyclopent-3-en-1- yl)pent-4-en-2-ol  67801-20-1 C.sub.14H.sub.24O 208.35 3 sandal cyclopropane 1-methyl-2-((1,2,2- trimethylbicyclo(3.1.0)hex-3- yl)methyl)-cyclopropane- methanol 198404-98-7 C.sub.15H.sub.26O 222.37 4 Santol pentenol (E)-3,3-dimethyl-5-(2,2,3- trimethylcyclopent-3-en-1- yl)pent-4-en-2-ol 107898-54-4 C.sub.15H.sub.26O 222.37 5 sandal cyclopentane 2-Methyl-4-(2,2,3-trimethyl-3- cyclopenten-1-yl)butanol  72089-08-8 C.sub.13H.sub.24O 196.34 6 sandalrome (E)-2-ethyl-4-(2,2,3- trimethylcyclopent-3-en-1- yl)but-2-en-1-ol  28219-61-6 0 C.sub.14H.sub.24O 208.35 7 sandal butenol (E)-2-methyl-4-(2,2,3- trimethyl-3-cyclopenten-1-yl)- 2-buten-1-ol  28219-60-5 C.sub.13H.sub.22O 194.32

(23) A preferred compound falling in formula (I) and illustrated in the above Table is sandal pentanol (compound 1).

(24) In accordance with certain embodiments the compounds of formula (I) have a 2,2,3-trimethylcyclopent-3-en-1yl moiety bearing a C.sub.4-C.sub.5 alkyl or C.sub.4-C.sub.5 alkenyl group in the 1-position of the ring. Preferred compounds falling in this embodiments are those with the moiety bearing a C.sub.4-C.sub.5 alkyl group in the 1-position of the ring, for example compounds 1, 2, 4, 5, 6, 7 referred in the above Table.

(25) In accordance with certain embodiments, sandal cyclopentane is excluded from the compounds of formula (I).

(26) It has been found that the selected compounds of formula (I) or the compounds falling in anyone of the above referred embodiments, when applied on the skin activates or promotes an immune defense response or an immune modulation action which is at the basis of their anti-inflammatory action.

(27) Typically, the referred immune modulation action is mediated by dermcidin (DCD), a protein secreted by eccrine gland.

(28) In contrast to antimicrobial peptides (AMPs), dermcidin is constitutively secreted in human sweat and is not inducible by inflammation or skin injury.

(29) In addition, contrary to the more common AMPs, such as defensins and cathelicidin, which are cationic peptides which bind to and permeabilize the bacterial membranes, dermcidin is an anionic peptide and kill bacteria through a different molecular mechanism.

(30) These properties make the dermcidin-mediated anti-inflammatory activity of the selected compounds of formula (I) in skin diseases underivable from the antimicrobial peptides having cationic nature allowing them to bind and disrupt bacterial membrane molecules.

(31) Medical Uses

(32) The inventors have also evidenced that the application on the skin of compounds of formula (I) stimulates the expression of dermcidin, a specific peptide provided with a local/topical anti-inflammatory action.

(33) These compounds exert an action on inflammatory skin diseases which makes them useful in the treatment of certain skin diseases with an inflammatory component especially psoriasis, folliculitis, rosacea and bromhidrosis especially severe bromhidrosis.

(34) The compounds of formula (I) are also useful in the treatment of bromhidrosis because one of the factor from which this disorder origins is the dysregulation of skin secretion from eccrine sweat glands which are regulated by dermcidin which is the biological target of compounds of formula (I).

(35) It has been also observed that the topical application to the skin of the compounds of formula (I) alters the composition of the microbiome from a pathological to healthy state thus resulting effective in many different skin diseases wherein inflammation is a component.

(36) In accordance with these aspects, a therapeutically effective amount of a pharmaceutical composition containing a compound of formula (I) is applied on the area of the skin in need of treatment. The treatment may include the application of the composition at least once a day, preferably twice until full recovery or until the symptomatology of the related diseases is substantially reduced or resolved.

(37) The present disclosure also provides a method of treatment of inflammatory diseases of the skin said method comprising the topical administration of an effective amount of a compound of formula (I) or a composition containing said compound and a pharmaceutically acceptable carrier.

(38) In accordance with this aspect, the method is useful in the treatment of folliculitis.

(39) The methods and compositions disclosed herein may be used for a wide range of skin disorders in which an inflammatory component is present including psoriasis, rosacea and folliculitis.

(40) Problems with current treatments for these disorders include antibiotic resistance, side effects, complicated regimens, and lack of long-term effectiveness. Treatments disclosed herein may provide alternatives to antibiotic and/or anti-inflammatory therapy, the use of compounds of formula (I) according to the invention, presenting very few or absence of side effects with simple treatment regimens and long-term effectiveness.

(41) Cosmetic Uses

(42) It has been observed that the compounds of formula (I) ameliorated the aesthetic aspect of flushed skin, red skin, skin rashes and the redness of skin.

(43) Thus, in accordance with another aspect of the invention the cosmetic, non-therapeutic use of compounds of formula (I) as cosmetic skincare treatment is provided in accordance with claims 5 to 10.

(44) In accordance with some embodiments it is provided the cosmetic, non therapeutic, use of compounds of formula (I) for the topical prevention and/or treatment of imperfection or blemish of the skin, for example for ameliorating the aesthetic aspect of flushed skin, or for reducing skin rashes or discoloring red skin or blotches.

(45) Within the cosmetic uses of the compounds of formula (I) or composition containing the same, also fall mild acne and the excessive sebum production.

(46) The term “cosmetically acceptable” as used herein means that the components of the compositions are suitable for cutaneous or mucosal application in general, and when applied they do not cause an unwanted toxicity, allergic response, redness, incompatibility, instability, and similar reactions.

(47) Compositions

(48) In accordance with another aspect of the invention, a composition is provided, comprising an effective amount of one of the compounds of formula (I) according to anyone of the embodiments referred herein above and a physiologically acceptable carrier.

(49) The composition may be a pharmaceutical composition or a cosmetic composition. A suitable carrier is a pharmaceutically, phisiologically or cosmetically acceptable carrier.

(50) Typically, the composition are suitable for topical application on the skin or on mucosa.

(51) In the present specification, the term “carrier” refers to an excipient, carrier, diluent or adjuvant which has no activity and which may be present in the composition of the invention. Any carrier and/or excipient suitable for the form of preparation desired for administration is contemplated in the uses described herein.

(52) Typically, cosmetically acceptable carrier are used for the cosmetic uses of the compounds of formula (I) of the invention.

(53) In accordance with certain embodiments, the composition of the invention contains a pharmaceutically acceptable and/or physiologically acceptable carrier or, and a compound of formula (I) in an amount ranging from 0.1 to 20% by weight, from 0.5 to 15%, from 1 to 10% by weight.

(54) Typically, the composition of the invention either for cosmetic and pharmaceutical uses are in any forms suitable for topical/local application and may be in solid, fluid or semifluid form.

(55) Suitable compositions in solid form comprise creams, pastes, ointments, gel, bandages for pharmaceutical or cosmetic applications and sticks, make-up.

(56) In accordance with a preferred embodiment, the composition is a cream for topical application.

(57) Suitable compositions in fluid form include water-based formulations such as suspensions, solutions, lotions, gels, shampoos.

(58) Suitable compositions in semi-fluid form include foams and emulsions.

(59) For cosmetic application suitable forms include masks, transdermal paste or patch. In the composition of the invention, one or more excipients typically used in the basic formulation of pharmaceutical or cosmetic formulations may be incorporated, such as oils, glycerin, emollients, emulsifiers, dispersing agent, in amounts which are typical for the desired use.

(60) In the formulation of the composition of the invention may be present additional ingredients such as a Bisabolol, inositol, betaine, allantoins, ceramides for the creamy formulation.

(61) In some embodiments, the fluid or semifluid composition of the invention may contain lipophilic substances such as oils, for example Hydrogenated castor oil.

(62) In the case of formulations in liquid form, water is present as a diluent or solvent, optionally mixed with other liquids used for the formulation of pharmaceutical or cosmetic compositions.

(63) According to another embodiment, the cosmetic composition further comprises one or more amongst thickeners, solubilizers, preservatives, water, alcohols, glycerin, stabilizers, cosmetically acceptable antioxidants and antibacterials in amounts according to the common pharmaceutical or cosmetic practice.

(64) The present description is further described herein below with reference to the following examples which represent embodiments of the invention.

Example No. 1

(65) TABLE-US-00002 Cream Component Q.ty (% w/w) PEG-8 Beeswax  6-18 Octyldodecanol  4-11 Diisopropyl sebacate 3-8 Mixed triglyceirdes decanoyl and octanoyl 2.3-6.8 Isostearyl isostearate 2-6 Sandalore (sandal pentanol) 1-2 Butyrospermum parkii butter 1-3 Dicaprylyl ether 1-3 Pentylene glycol 1-3 Glycerin 1-2 Polymethyl methacrylate 1-2 Potassium cetyl phosphate 1-2 Symdiol 68T 0.4-1.1 Alphaa Bisabolol 0.3-0.8 Betaine monohydrate 0.3-0.8 Inositol 0.3-0.8 Trehalose 100 0.3-0.8 Poloxamer 407 0.18-0.53 Dissolvine GL-38 0.2-0.5 Carbomer 0.1-0.3 Hydrogenated soy lecithin 0.1-0.3 Oxynex ST Liquid 0.1-0.3 Tromethamine 0.09-0.27 Allantoin 0.08-0.23 Disodium EDTA dihydrated 0.1-0.2 Pentaerytritol Tetrakis 0.03-0.08 (3-(3.5-di-tert-butyl-4 hydroxyphenyl) propionate Lactic acid 80% 0.018-0.053 Dimethylmethoxy chromanol 0.01-0.03 Water q.s. to 100 g

Example No. 2

(66) TABLE-US-00003 Lotion Component Q.ty (% w/w) Ethanol 10-20 Disodium EDTA 0.03-0.09 PEG-40 Hydrogenated castor oil 0.75-2.25 Sandalore (sandal pentanol) 0.5-2.5 Water q.s. to 100 g

Example No. 3

(67) TABLE-US-00004 Deodorant Component Q.ty (% w/w) Ethanol 20-30 Sandalore (sandal pentanol)  0.1-10.0 PEG-40 Hydrogenated castor oil 1-3 Tocopheryl acetate 0.1-0.2 D-Panthenol 0.3-0.8 1.2 Propandiol  5-15 Triethyl citrate 0.2-0.5 Water q.s. to 100 g

Example No. 4

(68) TABLE-US-00005 Body cream Component Q.ty (% w/w) Isopropyl myristate  5-10 Polisorbato 60 4.5-7.5 Sandalore (sandal pentanol)  0.1-10.0 Sodium hydroxide 0.05-0.15 Alcool benzilico 1-2 Sorbitan monostearate 1.5-2.5 Cetyl palmitate 2-3 Cetyl alcohol 3-5 Stearyl Alcohol 3-5 Water q.s. to 100 g

Example No. 5

(69) TABLE-US-00006 Face cream Component Q.ty (% w/w) C12-13 alkyl lactate 3-5 Gemseal 25 3-5 Sandalore (sandal pentanol)  0.1-10.0 PEG-30 Dipolyhydroxystearate 1.3-3.8 Magnesium sulphate heptahydrate 0.4-1.2 Silica dimethyl silylate 1-2 Hydrogenated castor oil 1-2 Super sterol esters 0.3-0.8 Ethylhexyl palmitate 3-8 Allantoin 0.1-0.3 Fenossiethanol 0.4-0.6 Glycerin 2.3-6.8 PPG-15 Stearyl ether 1-3 Nylon-12 1-3 Ceramide Omega 9 0.1-0.3 Collageneer 0.2-0.5 Water q.s. to 100 g

Example No. 6

(70) TABLE-US-00007 Spray solution Component Q.ty (% w/w) Ethanol 30-50 Propylene glycol 2.5-8.0 Sandalore (sandal pentanol)  0.1-10.0 Water q.s. to 100 g

Example No. 7

(71) TABLE-US-00008 Vaginal solution Component Q.ty (% w/w) Poloxamer 30-50 Propylene glycol 30-50 sandalore 0.1-10  water q.s. to 100 g

Example No. 8

(72) Experimental evidence of regulation (promotion) of dermcidin by sandal pentanol. This experimental evidence is also based on the antinflammatory activity of dermcidin as evidenced in the article “The in vitro immune modulating properties of a swedt gland-derived anti-microbial peptide dermcidin” to Echo Wang et al., published on Shock, 2016 January; 45(1): 28-32.doi.1097/SHK0000000000000488, especially FIG. 3 showing that dermcidin modulated LPS- and HMGB1-induced chemokine (pro-inflammatory cytokines) release by human monocytes.

(73) HF Organ Culture:

(74) Human scalp samples were obtained 1 day after face-lifting procedure (i.e. after overnight transport from collaborating surgeons) and used at the same day for microdissecting human anagen VI scalp HFs. The HF microdissection technique employed for setting up the classical Philpott assay used in the current study, removes all perifollicular tissue with the sole exception of the HF's dermal sheath and thus does not contain any other skin appendage structures (e.g. eccrine gland elements). Microdissected human scalp HFs were cultured at 37° C. with 5% CO.sub.2 in a minimal media of William's E media (WEM, Gibco, Life technologies) supplemented with 2 mM of L-glutamine (Gibco), 10 ng/ml hydrocortisone (Sigma-Aldrich), 10 μg/ml insulin (Sigma-Aldrich) and 1% penicillin/streptomycin mix (Gibco) (WEM). After microdissection, the HFs were first incubated in WEM for 24 hrs for re-equilibration.

(75) Chemical Stimulation of Human Microdissected HFs with Sandal Pentanol

(76) After 24 hours, WEM medium was replaced and HFs were treated with vehicle (0.1% DMSO), sandal pentanol 500 μM, for 3 or 5 days for (immuno-)histology or 6 hours for microarray. Culture medium was replaced every second day and after 6 days, HFs were then embedded in cryomatrix (Fisher Scientific), and snap frozen in liquid nitrogen for (immuno-)histology.

(77) Microarray Analysis

(78) Expressional alteration was considered to be significant only when ≥1.8-fold and equidirectional changes were observed in at least 3 of 4 patients (independent experiments).

(79) Dermcidin Immunofluorescent Staining

(80) OCT embedded samples were sectioned with a Leica cryostat. Dermicidin protein was detected using tissue sections fixed in 4% paraformaldehyde, pre-incubated with 10% of goat serum, and incubated with a mouse anti-human Dermcidin (Novus Biologicals, G-81, 1:200). Secondary antibody (Goat anti-mouse Alexa fluor 488) incubation was performed at room temperature for 45 min. Counterstaning with DAPI (1 μg/mL) was performed to visualize nuclei.

(81) Results

(82) Dermicidin protein expression is increased in hair follicle outer root sheath keratinocytes ex vivo after sandal pentanol (500 μM) treatment for 3 and 5 days (FIG. 1). Data are confirmed in following Table 1.

(83) Microarray analysis revealed that Sandalore significantly promotes AMPs secretion since transcripts of AMPs genes were up-regulated, particularly Dermcidin expression increased by 77.6 folds.

(84) TABLE-US-00009 TABLE 1 Dermcidin positive cells Vehicle 500 μM Sandalore Mean 4.444 7.786*** SEM 0.6232 0.5962   ***p < 0.001