Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
• • 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
• • 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
  • 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
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
  • A61Q5/02—Preparations for cleaning the hair

Definitions

• the invention concerns the use of compounds to promote hair growth and/or inhibit or delay hair loss in humans, and compositions for such use comprising such compounds as active principles.
• sandalwood is referred to a class of woods from trees of the genus San- talum.
• the essential oil of sandalwood is usually extracted by steam distillation of wood from matured sandalwood trees, and is a well-known valued component for perfumes.
• sandalwood oil is also the subject of patent publications regarding officinal and empirical preparations for a number of different uses, including a generic treatment of hair loss and dandruff, such as for example the patent publication CN1075250A describing a medicinal extract, defined in fact as Chinese medicine, comprising sandalwood mixed with flower bud of magnolia, rose flower, liquorice root, peony bark powder, kaempferia, lilac, herba asari, ginseng and root of angelica dahurica.
• CN102000293 and CN103735443 describe similar Chinese medicines, the former made of a mixture of sandal wood, angelica roots, rhizoma kaempferiae seeds, talc, holy basil, natural indigo and spike nard, the latter made of a mixture of sandal wood, fleece flower root, pine needles and salvia miltiorrhiza, to be applied on hair.
• the Indian patent publication IN00177MU2002A describes a composition for the prevention of hair falling which comprises sandalwood oil mixed with coconut oil, eucalyptus oil, clove oil, lavender oil and rosemary oil.
• sandalwood oil the main components of sandalwood oil are a-santalol e ⁇ -santalol, which are alcohols basically showing a sesquiterpenic type chain.
• the structural formula of a-santalol is:
• sandalore is a synthetic odorant having a fragrance similar to sandalwood and consequently used in perfumes, emollients and skin cleaning agents as a less expensive ingredient mimicking the sandalwood scent.
• Sandalore, as well as the structurally similar compound named brahmanol, are alcohols having a chemical structure quite distinct from the said ingredients of natural sandalwood oil, that is, ⁇ -santalol e ⁇ -santalol.
• sandalore or sandal entanol, having formula:
• brahmanol or sandal cyclopentane, having formula:
• EP1561476 describes deodorant compositions for improving deodorizing effects where, among a broad number of substances and a broad number of uses, the use of sandalore and brahmanol is also described as deodorizing fragrances in hair care products such as shampoos, conditioners, hair rinse, hair coloring agents, permanent-wave agents, wax, hair spray and mousse.
• fragrance materials of natural origin to be used as fragrances in EP1561476 include sandalwood oil, and sandalore and brahmanol are defined as trade names of the above materials, thus meaning that according to this document there is no distinction between the fragrance provided by the natural extract and its synthetic substitutes.
• EP1346720 relates to a deodorant composition for hair color having a similar scope. There is no description in such publications, not even generically, of such synthetic odorants for the treatment of hair loss, or for promoting hair growth.
• Olfactory receptors (ORs) expression is not restricted to the nasal epithelium but it is also present in different human tissues, see Feldmesser E, Olender T, Khen M, Yanai I, Ophir R, Lancet D., Widespread ectopic expression of olfactory receptor genes.
• Ri and R2 form together a double bond, or Ri and R2 form together a cyclopropyl group;
• Fb, R4 are the same or different and independently chosen from hydrogen, methyl, or R3 and R 4 form together a double bond;
• R5 and Re are the same or different and independently chosen from hydrogen, methyl; or R5 and Re form together a double bond, or R5 and Re form together a cyclopropyl group;
• R7 methyl, or ethyl
• compositions for use in promoting hair growth, and/or inhibiting or delaying hair loss suitable for topical administration on the human scalp, in which one or more compounds of formula (I) are used as active prin- ciples, preferably in a quantity between 0.1 and 10% by weight (w/w %), formulated with ingredients suitable for a topical administration.
• compositions of the invention are suitable both for a cosmetic and a therapeutic use in promoting hair growth and/or the treatment of hair loss in the human scalp, wherein at least one compound of general formula (I) is comprised as active princi- pie.
• polyquaternium-1 1 0.0025-0.025 aqua q.s. to 100 g
• Fig. 1 shows immunofluorescence images taken from samples of human scalp skin tissues and hair follicles (HFs).
• Fig. 2 shows a diagram relating to hair shaft elongation.
• Fig. 3 shows a diagram relating to hair growth cycle, with particular reference to the catagen phase.
• Fig. 4 shows a diagram relating to hair matrix keratinocyte proliferation and apopto- sis.
• Fig. 5 shows a diagram relating to the catagen-promoting growth factor TGF 2.
• Figures 1 to 5 concern the results obtained in the following experimental study, and are thus described in detail in the following description.
• the said compound 1 according to the invention i.e. sandal pentanol
• sandal pentanol was chosen among the compounds of formula (I) to be tested for experimental purposes as follows.
• Sandal pentanol is named Sandalore in the diagrams of Figs. 2-5.
• HFs were treated with either the vehicle, sandal pentanol, Phenirat or a mixture of sandal pentanol and Phenirat.
• Ki67/TUNEL were performed and used to evaluate hair cycle score and hair matrix keratinocytes proliferation and apoptosis.
• TGF 2 a potent catagen inducer
• Temporal and occipital normal human scalp skin was obtained from healthy donors (in an age range 38 - 69 years) undergoing routine face-lift surgery after informed consent and ethical approval.
• OCT embedded samples were sectioned (6 ⁇ thickness) with a cryostat. Sections were fixed in 4% paraformaldehyde, pre-incubated with 1 0% of goat serum (for OR2AT4) or 5% goat serum +0,3% Tritton X-1 00 (for cleaved-caspase 3) and incubated with the corresponding primary antibody at 4°C overnight (1 /100 for OR2AT4 and 1 /400 for cleaved-caspase 3). Secondary antibody incubation was performed at RT for 45 min. Counterstaining with DAPI (1 ⁇ g/mL) was performed to visualize nuclei.
• TGFb2 For TGFb2, samples were fixed in acetone and the endogenous peroxidases were blocked with 3% of H2O2. This step was followed by an avidin-biotin blocking step and a preincubation with TNB buffer (Tris HCI+NaCI+Casein). The corresponding primary antibody was incubated at 4°C overnight (1 ⁇ 000 for TGFb2). Secondary antibody incubation was performed at RT for 45 min before using the Tyramide sig- nal amplification kit (Perkin Elmer). Counterstaning with DAPI was performed to visualize nuclei. To stain apoptotic and proliferating cells, we have used the apoptag kit (Merck Milipore) following manufacture's protocol followed by Ki67 staining.
• TNB buffer Tris HCI+NaCI+Casein
• the primary antibody was incubated overnight (Ki67, 1 /20) after the TdT-enzyme step.
• the secondary antibody was incubated for 45 min at RT after the fluorescent- labelled anti-Digoxigenin step of the apoptag kit. Counterstaining with DAPI was performed to visualize nuclei. Negative controls were performed by omitting the primary antibody. Images were taken using a Keyence fluorescence microscope (Osaka, Japan) maintaining a constant set exposure time throughout imaging for further analysis.
• Human scalp samples were obtained after face-lifting procedure and used at the same day for microdissecting human anagen VI scalp HFs.
• Microdissected human scalp HFs were cultured at 37°C with 5% CO2 in a minimal media of William's E media (Gibco, Life technologies) supplemented with 2mM of L-glutamine (Gibco), 10ng/ml hydrocortisone (Sigma-Aldrich), 10pg/ml insulin (Sigma- Aldrich) and 1 % penicillin/streptomycin mix (Gibco) (WEM) as previously described (Philpott, 1990; Kloepper, 2010; Langan et al, 2015).
• HFs were treated with the corresponding substances for 6 days following experimental conditions. HFs were treated either with vehicle (0.1 % DMSO), sandal pentanol (500 ⁇ ), Phenirat (in a ratio 1 :1 to the agonist), or a mixture sandal pentanol+Phenirat.
• Phenirat was added 30 min before sandal pentanol. Hair shaft elongation was measured daily using an inverted binocular microscope (Philpott et al., 1990) and culture medium was replaced every second day. HFs were then embedded in cryomatrix (Fisher Scientific) and snap frozen in liquid nitrogen. Sections of 6 ⁇ thickness were cut with a cryostat and stored at -80 °C for further immunohistochemical analysis.
• Staining intensity was evaluated in well-defined reference areas by quantitative (im- muno-)histomorphometry, as previously described (Bertolini et al., 2014) using NIH IMAGE software (NIH, Bethesda, MD, USA).
• OR2AT4 olfactory receptor 4
• ORS suprabulbar outer root sheath
• keratino- cytes of human scalp anagen HFs as shown by immunofluorescence in Figure 1 .
• CTS connective tissue sheath
• DP dermal papilla
• HM hair matrix
• IRS inner root sheath
• ORS outer root sheath
• HS hair shaft
• HB hair bulb
• HF hair follicles.
• Dotted lines delineate the IRS (inner root sheath), ORS (outer root sheath) and DP (dermal papilla).
• Fig. 1 shows that OR2AT4 is expressed in suprabulbar ORS keratinocytes of anagen scalp HFs and in suprabulbar and bulbar ORS, and in hair matrix tips keratinocytes in microdissected anagen HFs.
• Microdissected anagen HFs revealed OR2AT4 cells in the hair bulb, namely in ORS and hair matrix (HM) tips, see Fig.1 B, in addition to the characteristic suprabulbar intrafollicular expression, see Fig. 1 D.
• OR2AT4 The activation of OR2AT4 by sandal pentanol significantly delays catagen induction and decreases apoptosis in human hair matrix keratinocytes
• FIG. 3 shows that the compound of the invention significantly delays catagen development.
• Sandal pentanol significantly decreases hair matrix keratinocytes apoptosis
• Ki67/TUNEL staining was performed. Proliferating (diagram of Figure 4A) and apoptotic (diagram of Figure 4B) hair matrix keratinocytes were counted in the hair matrix of treated and vehicle HFs. Representative pictures of Ki67/TUNEL are shown in Fig. 4 from C to E.
• hair matrix keratinocyte proliferation did not change in HFs treated with sandal pentanol or Phenirat alone.
• co-administration of the specific antagonist of OR2AT4, Phenirat, together with sandal pentanol induced a significant decrease on the hair matrix keratinocyte proliferation as shown in Fig. 4A.
• Sandal pentanol treatment significantly decreased hair matrix keratinocyte apoptosis, whilst co-administration of sandal pentanol+Phenirat significantly increased hair matrix keratinocyte apoptosis, as shown in Fig.4B. 5)
• Specific stimulation of OR2AT4 by sandal pentanol significantly decreased the catagen-promoting growth factor TGF32
• FIG. 5 Corresponding representative pictures of TGF 2 immunofluorescence are shown in Fig. 5, B (vehicle), C (sandalore), D (sandalore+ Phenirat).
• OR2AT4 is a hair growth modulator and the compound of the invention is an anagen-prolonging agent. Stimulation of OR2AT4 by the compound of the invention increases hair shaft elongation and delays catagen phase transition, while the effect is not obtained with the OR2AT4 inhibitor Phenirat, and is substantially counteracted when the compound of the invention is co-administered with Phenirat.
• Stimulation of OR2AT4 by the compound of the invention modulates apoptotic signalling pathways and significantly decreases apoptosis in human hair matrix keratinocytes, while this effect is not obtained with Phenirat and is substantially counteracted when the compound of the invention is co-administered with Phenirat.
• Stimulation of OR2AT4 by the compound of the invention significantly decreases the relevant catagen-promoting growth factor, TGF 2, while this effect is not obtained with Phenirat.
• TGF 2 catagen-promoting growth factor

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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