NICOMENTHYL

NICOMENTHYL® is composed of pure MENTHYL NICOTINATE, with no residues of other nicotinates, obtained through a new and proprietary industrial synthesis process (patent pending), developed over 20 years of research by Dr. Gabriele Segalla at Multichem R&D Laboratories, in Milan, Italy.
NICOMENTHYL® represents a new and revolutionary substance for cosmetic use that can significantly activate the cutaneous microcirculation without causing bothersome hyperemia or irritations, on the contrary it generates a pleasant hot-cold sensation in the area of application.

It is derived from the chemical reaction (esterification) of two natural components:

  • Menthol, obtained from mint essential oil, has a refreshing and soothing effect on the skin.
  • Nicotinic acid, also known by the names of Niacin or Vitamin B3 or Vitamin PP (Pellagra-Preventing), is used by the organism for forming enzymes (NAD and NADP) that are essential for energy metabolism. These coenzymes take part in over 200 enzymatic reactions within the organism. Nicotinic acid helps break down and assimilate proteins, fats and glucosides. It plays a fundamental role in the formation of erythrocytes, in optimizing blood circulation and in providing oxygen to the cells. Its properties are used in topical applications for improving the barrier effect, oxygenating and nourishing the skin, accelerating cellular differentiation and cicatrization, as well as for its anti-inflammatory and detoxifying effects.

Nico-Menthyl

The molecule of Nico-Menthyl is composed of a “niacinic” part (derived from Niacin or Nicotinic Acid) and a “menthylic” part (derived from Menthol). The niacinic part tends to produce a warming vasodilating effect, while the menthylic part a fresh vasoconstricting effect. Thus, the application of a cosmetic product containing Nico-Menthyl on the skin results in an efficient activation of the cutaneous microcirculation and a simultaneous pleasant and persisting sensorial hot/cold effect or cool tingling.

FUNCTIONS

Multifunctional sensorial bioactive, activator of the cutaneous microcirculation, particularly indicated for:

  • Cellulitis treatment
  • Hair loss prevention treatment
  • Anti-age formulations (inhibit the slowdown of cutaneous microcirculation associated with ageing or slackening of the tissues)
  • Adjuvant in the treatment of gingivitis and sensitive gums
  • Sport massage products
  • Refreshing products for feet and legs
  • Intimate hygiene products
  • Lip plumping cosmetic treatments
  • Spa treatment products
  • Deodorant/antiperspirants
  • Pre/after shave products
  • Body lotions

ORIGIN

Obtained by a synthesis process from natural components

INCI (CTFA)

Menthyl Nicotinate.

COSMETIC FORMULATIONS

Liposoluble (add to oily phase). Can be processed either hot or cold (thermostable).
The sensorial effect is increased in water-based formulations, such as O/W emulsions, hydro-alcoholic lotions, water-based gels, etc.
Being a polar molecule, NICOMENTHYL®, supported by appropriate thickening agents, has self-emulsifying properties, which may result in the formation of stable micro-emulsions, without having to add any other emulsifier or solubilizer.

RECOMMENDED USAGE

0,5 - 3%


SAFETY TESTS

The following assessment tests were conducted on NICOMENTHYL®: in vitro cutaneous irritation testing on 3D reconstructed human epidermis and vaginal tolerability testing on reconstructed vaginal epithelium; in vitro model testing to predict skin sensitization through assessment of the stimulating potential on the immune cellular response mediated by monocyte/macrophage cells; in vitro assessment of the ocular irritancy potential through cytotoxicity assay Neutral Red Uptake on cell culture and Het Cam testing on fertilized chicken eggs.
All tests have confirmed the absence of irritative and/or sensitizing effects. An evaluation of the genotoxic potential of NICOMENTHYL® through the Ames test did not show any evidence of mutagenicity.

IN VIVO EFFICACY TESTS

Doppler Laser Blood-flow Velocity Meter on twenty volunteers of both sexes (9 males, 11 females), with an average age of 41.2 years, with a cosmetic cream containing 2% NICOMENTHYL®, in comparison with a placebo. The results obtained displayed a statistically significant increase in the microcirculatory flow values after 15, 30 and 60 minutes from application, as shown in the following bar chart. (Report dated 12/11/2014 N. REL/1819/2014/CLI/ST)

microcirculation graph

The bar chart shows a statistically significant increase in the microcirculatory flow values after 15 minutes (+62.8% with respect to the value of T0) and 30 minutes (+72.2% with respect to the value of T0). The effect persisted up to 60 minutes from application (+32.2% with respect to the value of T0).

The same test has been carried out on other 20 subjects of both sexes, with a mean age of 44,9 years, using a topical preparation containing 3% of NICOMENTHYL®, compared to a negative control (placebo). Results are shown in the following chart.

grafico nico-menthyl 3%

The test showed that a concentration of 3% increases the microcirculatory flow velocity at remarkable levels, i.e. +78,7% at 15 minutes, +147,1% at 30 minutes and +87,4% at 60 minutes after application, without causing any irritating and/or sensitizing effects.

ANTIMICROBIAL EFFICACY

The antimicrobial effectiveness of NICOMENTHYL® was assessed, i.e. its capacity to inhibit the proliferation of some human pathogenic microbial strains, through a contact inhibition assay on solid agar cultures. The strains tested were a Gram + bacteria or Staphylococcus aureus, a yeast, Candida albicans and a mould, Microsporum canis (S. aureus is a skin saprophyte that can become pathogenic in certain situations e.g. immunedepression. C. albicans as well can become pathogenic, while M. canis is a dermatophyte that causes various types of Tinea corporis).
NICOMENTHYL® has shown excellent antimicrobial effect towards all three of the strains:

Staphylococcus aureus (0,1 <MIC< 0,5%)
Microsporum canis (0,5 <MIC< 1,0%)
Candida albicans (MIC ≈ 0,5%)


NICOMENTHYL® - CHEMICAL CHARACTERISTICS

NICOMENTHYL® is composed of pure Menthyl nicotinate, a product of the reaction of Nicotinic acid (also called Niacina or Vitamin B3 or Vitamin PP) with natural Menthol (from Mint essential oil).

It has the following molecular structure:

Nicomenthyl_molecola_15fps_9.gif

Molecular formula: C16H23NO2
Molecular weight: 261.36
INCI name: Menthyl nicotinate
IUPAC Name: 5-Methyl-2-(isopropyl)cyclohexyl nicotinate
Other chemical denominations: (2-propan-2-ylcyclohexyl) 5-methylpyridine-3-carboxylate.
CAS Nbr. 40594-65-8
EINECS Nbr. 254-991-1

PROPERTIES AND TECHNICAL SPECIFICATIONS

ORGANOLEPTIC PROPERTIES
Appearance Liquid
Colour White transparent
Smell Odourless
PHYSICO-CHEMICAL PROPERTIES
Specific gravity (a 20°C) 1,04
Solubility Insoluble in water; soluble in alcohol, polar oils, esters
Boiling point at atmospheric pressure 292,23°C
Refractive index 1,5060-1,5074
Heavy metals (ppm) < 0,5
Arsenic (ppm) < 0,5
MICROBIOLOGICAL PROPERTIES
Total bacterial load (ufc/g) < 10
Moulds/Yeasts (cfu/g) < 10
Pathogens Absent

Shelf life: Thermostable. No added preservatives or antioxidants are required nor any special condition for storage.

Nicomenthyl_Carrier&Fixative.gif

Being a polar molecule with a very high boiling point (>292 °C), Nico Menthyl exercises an excellent fixative and carrier action over other liposoluble substances, making these latter ones more bioavailable and absorbable by the skin.

MECHANISM OF ACTION

Menthyl nicotinate is easily absorbed by the skin and hydrolyzed into its primary components: Menthol and Niacin. Since Menthol is a vasoconstrictor and Niacin is a vasodilator, their subcutaneous release produces a mild and pleasant sensation of freshness (due to the menthyl moiety component of the molecule of the molecule) and a simultaneous sensation of tingling warmth (due to the niacinic component moiety of the molecule) a few minutes following the application. These sensorial effects are quite different from those caused by products containing free menthol or the common methyl, ethyl or benzyl nicotinates or other menthol esters, which may occasionally cause skin irritations or excessive hyperemia and sensitivity.

SKIN THERMO-RECEPTORS AND COSMETIC SENSORIAL AGENTS

Several different kinds of cosmetic products nowadays contain specific ingredients that activate certain cutaneous thermo-receptors, which are then able to express such activations into different sensations depending on the specific substance used.

Examples of some “Sensorial Agents”, commonly used in cosmetic products:

COOLING AGENTS: menthol, menthyl lactate, isopulegol, camphor, etc.
WARMING AGENTS: capsaicin, vanillyl butyl ether, ginger oleoresin, etc.
VASODILATING AGENTS (warming/tingling): L-arginine, niacin, methyl nicotinate, ethyl nicotinate, hexyl nicotinate, etc.

All these sensorial agents contain functional groups in their molecular structure which, once in contact with the skin thermoreceptors, play key roles in inducing warming or cold sensations via the nervous system.

This area of research has recently received considerable attention with the identification of the family of trans-membrane proteins called Transient Receptor Potential (TRP) channels, which are essentially a kind of biochemical switches or cellular channels responsible for the sensory transduction of temperature and other stimuli. TRP are a group of protein ion channels located mostly on the plasma membranes of different kinds of cells. Each one of them is composed of 6 polypeptide sub-units.

To our ends, the four TRP channels that you see in the following graph are the most important ones and also the most studied ones:

TRP_Channels6.png

These TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold.

As also evidenced by the colours in the graph, TRPV1 & TRPV3 are activated by heat. TRPA1 and TRPM8 are activated by cold.

They are also activated by various molecules found in spices like: chilli pepper (capsaicin) (on TRPV1); wasabi (allyl isothiocyanate) and camphor (on TRPV3); peppermint, menthol (on TRPM8); garlic (allicin), cinnamom (on TRPA1).

NICOMENTHYL®: A NEW REVOLUTIONARY COSMETIC SENSORIAL ACTIVE

The molecule of NICOMENTHYL® (Menthyl Nicotinate) gets slowly hydrolyzed by skin enzymes (esterases) and so slowly releases Menthol and Niacin.

Menthol activates the cold TRP receptors TRPM8 and TRPA1 by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site.1

Niacin, on the contrary, in addition to its beneficial vitaminic supply to the skin, activates the heat-sensitive TRP receptors TRPV1 and TRPV3 channels, by lowering their activation threshold temperature, leading to their activation at body temperature.2

Nicomenthyl_TRP_GIF4.gif

The RESULT of this simultaneous activation on the relevant TRP channels, is: a very pleasant, unique, long lasting, sensory transduction i.e. a kind of fresh tingling turgidity sensorial effect.

The unicity of such sensation is due to NICOMENTHYL®being the only molecule, so far known, capable of simultaneously activating both the skin cold receptors (TRPM8, TRPA1) and the heat receptors (TRPV1, TRPV3).

For instance, sensorial agents as Menthol and its isomers or Isopulegol or Menthyl lactate or other esters of Menthol activate only the TRPM8 channel and thus they produce only a sensation of coldness (cooling sensorial agents).

Likewise, sensorial agents as Capsaicin or Vanillyl buthyl ether act only on the TRPV receptors and thus generate only a sensation of warmness (warming sensorial agents).

NICOMENTHYL® activates both types of thermoreceptors, thus causing a unique, composite, modulated sensation.

Furthermore, thanks to its extraordinary biochemical, chemical and physical properties (pourable liquid even at low temperatures, easier to incorporate into personal care formulation, very high boiling point, very high purity, biocompatible and easily absorbed through skin) and thanks to its slow hydrolysis into the skin, the resulting sensation (for instance in lip products) is milder, non-aggressive and LONG-LASTING.

This has been confirmed by several sensorial tests performed with cosmetic products containing 2 or 3% of NICOMENTHYL®. Most of the subjects have been able to perceive its typical pleasant fresh-warm sensation up to 60-90 minutes from the application. Just as a benchmark, let’s consider for instance that Menthyl lactate, largely used in toothpastes and skin care products, has a cooling strength (43) which is less than half of the menthol’s one (100) and is almost not perceivable any longer after 10 minutes (relatively low cooling longevity.3

The sensation caused instead by a warming sensorial agent like Vanillyl Butyl Ether can be felt immediately upon application, building up rapidly (for someone, too rapidly) within the first five minutes and then decreasing within the next 30 minutes.4

NICOMENTHYL®: “MODULATOR” & SYNERGISTIC EFFECT on other SENSORIAL AGENTS

Through the two moieties of its molecule (i.e. the niacinic warming moiety and the menthyl cooling one) NICOMENTHYL®, duly dosed and solubilized in cosmetic finished products, exerts also a kind of “modulator” and synergistic effect over several other sensorial agents. These, when used in combination with NICOMENTHYL®, even at lower concentrations than the ones usually recommended for such sensorial agents, extend their efficacy in time, with a less aggressive impact on the skin.

An example of this is the result obtained when NICOMENTHYL® is used in combination with Menthol: the refreshing effect of Menthol becomes sort of softened and dramatically extended, with less unpleasant side effects.

The sensorial effect of NICOMENTHYL® is optimized by all those solvents/carriers having a good lipophilicity and a high spreading value such as: Butylene glycol, Hexylene glycol, Pentylene glycol, Dipropylene glycol, Dicapryl ether, Dicaprylyl carbonate, Ethanol, etc. Furthermore, the effect is enhanced when NICOMENTHYL® is included in water based formulations (such as O/W emulsions or aqueous gels) or solubilized in microemulsions with Polysorbates, PEG-40 Hydrogenated castor oil or other hydrophilic solubilizers, while it is reduced in anhydrous formulations or W/O emulsions.

CONCLUSIONS

NICOMENTHYL® (Menthyl nicotinate)

  • Is a MULTIFUNCTIONAL SENSORIAL ACTIVE.
  • Is the only substance capable of generating 2 SENSORIAL RESPONSES IN 1 MOLECULE = A REALLY “UNIQUE” SENSATE.
  • Produces a PLEASANT, LONG-LASTING, EXOTIC, TINGLING SENSATION.
  • Acts as a SYNERGISTIC ENHANCER AND MODULATOR for other cosmetic sensorial agents.
  • Is a powerful, but non aggressive, SKIN MICROCIRCULATION ENHANCER.
  • NON-IRRITATING; NON SENSITIZING.
  • BIOCOMPATIBLE.
  • Thanks to its HIGH TRANSDERMAL DELIVERY OF VITAMIN B3 (the so called Skin Vitamin) is BENEFICIAL to skin and through skin.
  • Thanks to its chemical and physical properties (liquid even at very low temperatures, high boiling point, liposoluble, chemically stable at any temperature and pH), acts as an IDEAL FIXATIVE, CARRIER and BOOSTER for other lipophilic actives.

1 Cfr. “TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain” – BoyiLiu, LuFan, Shrilatha Balakrishna, Aiwei Sui, John B.Morris, Sven-Eric Jordt - NIH, Pain. 2013 October; 154(10): 2169–2177. doi: 10.1016/j. pain. 2013.06.043.

2 Cfr. “Nicotinic Acid is a Common Regulator of Heat-Sensing TRPV1-4 Ion Channels” - Linlin Ma, Bo Hyun Lee, Heather Clifton, Saul Schaefer, Jie Zheng - SCIENTIFIC REPORTS | 5 : 8906 | DOI: 10.1038/srep08906.

3 "http://www.leffingwell.com/cooler_than_menthol.htm" ; "http://www.sfiproducts.symrise.com/articles/download/cooling-agents" “Symcool® Cooling Agents Infinite Sensations”.

4 "http://lipochemicals.com/system/files/brochures/HotactVBE.pdf" ; "http://www.in-cosmetics.com/__novadocuments/69029?v=635538586717200000"


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NICOMENTHYL® is a registered trademark of MULTICHEM R&D Srl
Topical sexual stimulants containing NICOMENTHYL® (menthyl nicotinate) are protected by Italian, European and US patents.