Physiological cooling agents, commonly known as coolants, continue to gain popularity for use in various consumer applications due to their recognized ability for improving desirable sensate properties in consumer products. The desired sensate properties are generally explained by the chemical action of such coolant compounds on the nerve endings responsible for the sensation of cold. Common applications and uses for these compounds include, but are not limited to foods, beverages, flavors, pharmaceuticals, perfumes, and miscellaneous cosmetic goods.
One of the most well-known physiological coolants is l-menthol, a compound having the structure shown below, and which has been widely used in several of the above mentioned applications. In particular, l-menthol has an excellent cooling strength, low sensitivity threshold, and is relatively inexpensive compared to other coolant compounds.
However, menthol also exhibits several undesirable properties, such as a strong “stinging” smell, a somewhat bitter taste, and it has a relatively high volatility. These disadvantages of l-menthol have limited its acceptance for use in various applications and therefore have stimulated intense research for suitable physiological cooling agents that possess a low volatility and exhibit a relatively weak odor or even no odor at all.
The primary focus of physiological coolant compound research has been toward the synthesis of compounds having a hydrocarbon skeleton similar to menthol, but which also comprise a “heavier” functional group than the hydroxyl functional group of menthol. As a result, a number of synthetic menthol substitutes have been developed and commercialized.
One commercially important group of synthetic coolants are the N-substituted 3-p-menthane carboxamides, commonly referred to as p-MCA and having the following structure:
Originally disclosed by Wilkinson Sword Ltd., UK, in a number of patents world wide, i.e. GB 1,351,761, DE 2,205,255, U.S. Pat. No. 4,033,994, U.S. Pat. No. 4,136,163, and U.S. Pat. No. 4,150,052, N-substituted 3-p-menthane carboxamides p-MCA represent a larger group of cyclohexane carboxamides of the general structure 1:
also disclosed by Wilkinson Sword Ltd. in DE 2,413,639, GB 1,422,998, U.S. Pat. No. 4,248,859 and U.S. Pat. No. 4,296,093. This larger group of cyclohexane carboxamides not only includes coolants having a carbon skeleton similar to menthol, but also coolants structurally unrelated to menthol.
A second commercially important group of synthetic coolants, and a group that is structurally unrelated to menthol, are the N-monosubstituted acyclic carboxamides of the general structure 2:
also first disclosed by Wilkinson Sword Ltd. in GB 1,421,743, GB 1,421,744, DE 2,317,538, and U.S. Pat. No. 4,153,679.
Substituents X and X1 as referred to in general structures 1 and 2 above are typically lower linear or branched alkyl groups, such as methyl, ethyl, tertiary butyl; aryl groups such as p-methoxyphenyl; or functionally substituted alkyl groups such as ethoxycarbonylmethyl, and the like. Substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, as used in general structures 1 and 2 above, are typically independently hydrogen atoms, lower linear or branched alkyl groups, such as methyl, ethyl, isopropyl, tertiary butyl, and the like.
Commercially successful members of these two groups of synthetic physiological cooling agents are N-ethyl-3-p-menthane carboxamide (commonly referred to as WS-3) and N,2,3-trimethyl-2-isopropylbutanamide (commonly referred to as WS-23), both of which are available from Millennium Specialty Chemicals, Jacksonville, Fla.

Other important carboxamide type physiological coolants include N-(ethoxycarbonylmethyl)-3-p-menthane carboxamide (WS-5) and N-tert-butyl-3-p-menthane carboxamide (WS-14).

A third commercially important class of synthetic physiological cooling agents are l-menthol based esters and ethers, having the general structure:

As used herein, substituent Y typically represents a lactic acid residue —OC(O)CH(OH)CH3, a monosuccinate residue —OC(O)CH2CH2COOH, a monoglutarate residue —OC(O)CH2CH2CH2COOH, or a glycerin residue —OCH2CH(OH)CH2OH, and the like. To date, the most commercially important representatives of this class have been menthyl lactate (ML) available from Symrise, Givaudan, and Millennium Specialty Chemicals; menthoxypropanediol (MPD) available from Takasago; monomenthyl succinate (MMS) available from V.Mane Fils, and monomenthyl glutarate (MMG). In general however, esters and ethers are weaker cooling agents compared to the above mentioned carboxamides. To that end, the most commercially important member of the ester/ether class is Menthyl Lactate ML.

Lastly, menthone glycerin acetal (MGA) represents the commercially viable ketal group of synthetic coolants, and isopulegol (sold under the trade name Coolact® P) and p-menthane-3,8-diol (sold under the trade name Coolact® 38D) are two examples of the p-menthanol class of liquid coolants, both of which have also gained significant popularity as synthetic coolant compounds.

The spectrum of consumer products that incorporate physiological cooling agents continues to broaden and thus gives rise to a need for coolant compounds and compositions having more sophisticated and multifaceted physiological cooling properties. As a result, combinations of cooling agents are progressively attracting more attention. This trend is illustrated by numerous reports in the technical and patent literature, where several different coolants have been used in combination to arrive at a final consumer formulation.
Several attempts have been made to formulate compositions containing menthol and one or more synthetic coolant molecules. For example, U.S. Pat. Nos. 5,009,893 and 5,698,181 teach that combinations of l-menthol and p-menthane carboxamide in a chewing gum provide a long-lasting, breath-freshening perception without the bitterness of l-menthol taken alone. Similarly, U.S. Pat. No. 5,663,460 discloses that the organoleptic properties of a menthol composition improve when menthol is blended with pure isopulegol or with MPD.
Attempts have also been made to provide physiological cooling compositions that contain no menthol or at least insignificant amounts of menthol. These compositions are particularly desirable when the strong smell and taste of menthol have to be completely avoided. For example, U.S. Pat. Nos. 5,407,665, 5,681,549 and 5,686,063 teach combinations of MPD, WS-3 and WS-23, which are incorporated into a mouthwash composition together with an alkoxy or glycol ether and ethyl acetate or a polyhydric alcohol as co-solvents or solubilizers. Similarly, after shave lotions according to U.S. Pat. Nos. 5,449,512 and 5,527,530 contain WS-3 or WS-23, or mixtures thereof together with an alcohol and a low-molecular weight methylsiloxane or acyl lactylate.
Significantly, practically all physiological cooling agents of the carboxamide groups are solid materials at ambient temperature and atmospheric pressure, usually with relatively high melting points (see Table 1). A representative of the menthol-based esters and ethers group of physiological cooling agents, menthyl lactate (ML) is also a solid material, although with a relatively lower melting point (see Table 1). 1-Menthol itself is a solid with a melting point of approximately 40-44° C. Several other commercial cooling agents listed above (MPD, MSS, MMG, MGA, Coolact P® and Coolact® 38D) exist as liquids at ambient temperature and atmospheric pressure.
TABLE 1Melting points of commercially important solid cooling agentsMeltingTradepoint,nameChemical name° C.l-Mentholp-Menthan-3-ol40-44WS-3N-ethyl-3-p-menthane carboxamide 97-101WS-5Substantially pure N-(ethoxycarbonylmethyl)-3-p-80-82menthane carboxamide, same as N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycineWS-14N-tert-butyl-3-p-menthane carboxamide147-150WS-23N,2,3-trimethyl-2-isopropyl butanamide60-62Menthyll-Menthyl ester of lactic acid40-45Lactate
In order to be added into a cooling composition, solid cooling agents must first be melted and dissolved in a flavor blend or dispersed in the emulsion. For example, the manufacturer's product literature on Menthyl Lactate (Frescolat® ML Crystal) from Symrise (former Haarmann & Reimer GmbH) advises that the product must be incorporated in a melted state into the oils, fragrances or emulsions at approximately 40-45° C. (Jacobs et al., Parfümerie und Kosmetik, 1999, Vol. 80, # 4, pp. 26-31). This added step of melting, of course, adds difficulties during the blending stage. This melting step, especially in the case of solid materials with higher melting points, such as WS-3, WS-5, and WS-14, also raises safety concerns. For example, a 25-kg pail of solid WS-3 with a melting point of about 100° C. or just below 100° C., must be placed in a “hot room,” and heated to a temperature equal to or exceeding 100° C. In turn, the hot pail containing melted WS-3 has to be handled by personnel, introducing dangerous opportunities for burn related injuries to occur.
To that end, if the coolant is in the form of a free-flowing powder or crystalline form, it can be added to the composition as such. However, it is well-known that blending of a powder or crystalline material can cause inhomogeneity of the final blend. This is caused by an uneven distribution of the coolant, especially when the final blend is a solid, a semi-solid, or a viscous liquid. It also raises additional safety concerns due to the possible formation of explosive mixtures of the particulate dust and air. Therefore, additional attempts have been made to pre-dissolve the solid coolant agent in an additional food grade, flavor grade or pharmaceutical grade solvent such as ethanol or propylene glycol. However, as would be expected, the presence of an additional solvent in the final article is often undesirable. For example, with regard to propylene glycol, its presence in a final comestible article can impart an undesirable bitter taste nuance.
Currently, literature on solvent-free liquid compositions of physiological cooling agents is very limited. A recent pre-grant US Patent Application Publication 2004/0018954 (Su et al.) discloses that mixtures of l-menthol and menthyl lactate can be liquid under normal conditions, which is reasonably explained through a eutectic mixture. It should be noted that the best effect is achieved at 1:1 weight ratio, where the crystallization point of the mixture is 8.2° C. In the winter season, such mixtures would certainly solidify during shipping and the need for thawing or melting would still exist. Moreover, these mixtures are based on menthol as the major component which, as mentioned above, is often undesirable.
Therefore, there is still a need in the art for new and improved physiological cooling compositions comprising one or more carboxamide class cooling agents, wherein the composition is capable of existing as a liquid under normal or ambient conditions, even in the substantial absence of a solvent and even when all of the individual components of such composition exist as a solid at ambient temperature and atmospheric pressure, when taken separately.