CoValence is among the pioneers who have brought to focus the application of “Chirally-Correct” ingredients in skin care formulations to maximize their efficacy and avoid any potential or pitfalls in the alteration or instability of their chemical structure during their formulation. Our article (Chiral Skin Care, GCI, November 2010) and patents (US Patents 8,211,873; 8,227,426; 8,410,079; and 8,859,269) are attest to it.
Briefly stated, our article and patents bring to focus that:
Not ALL optically active ingredients possess selectivity or variability in their topical attributes. A number of ingredients, in their stereoselective state, can possess differential skin care attributes. The combinations of two optically active ingredients that can form a bond (ionic or covalent) that leads to a new combination compound may not necessarily have any difference in its skin penetration rates (as we know today), but may have significantly different biological affects upon their release as original individual components after their penetration into skin, the latter depending upon the stereochemistry of the two combining moieties. Our article simply brings to the attention of formulators and marketers that the selection of stereospecific molecules can be of value in targeted skin care applications. While the concept of the stereospecificity in pharmaceutical industry has been known for a very long time, CoValence is proud to having introduced this concept in skin care applications since year 2000 as the phraseology: “Chirally-Correct”. In a cosmic sense, the Earth came to existence over 2 billion years ago. All chemical entities that we know today can be traced to their evolution or creation beliefs. Thus, nothing may be considered fundamentally new, irrespective of those millions of patents that have issued so far. Everything is applications based, in this cosmic sense. “Chirally-Correct” is an example of this applications-based concept of natural and other right- or left-handed ingredients.
In an article published in Dermascope (February 2014), “Chirally Correct Skin Care… Or Is It?” several points have been brought to the attention of readers that need further clarification entertained herein.
Breaking Down the Science: Our main point is that chiral molecules can have dissimilar biological activity. Upon their penetration into skin and diffusion into dermis and bloodstream such differential biological activity can be an important consideration relative to their efficacy and safety (toxicology). We do need to focus on what is happening beyond the visible layer of skin. Skin, after all, is a three-dimensional structure composed of stereospecific molecules (L-amino acids in proteins, and optically-active nucleotides, among others) that can be very selective in terms of what is permitted through it.
We are not proposing that all chiral molecules have different rates of skin penetration upon their topical application. However, this can actually happen if there are other ingredients in the formulation (added intentionally or inadvertently) that can form a complex with the chiral ingredient used in that formulation. Prudent, informative chemical considerations of all ingredients in a topical formulation are thus necessary. The comment in Dermascope that “the bottom line is there’s not one iota of science to support the premise of chirally-correct ingredients in skin care products” is like saying that “it does not exist if I do not see it”. The discovery of stereospecific topical skin penetrative ingredients is on the horizon. It may require future inventive minds of electron chemists and pharmaceutical biochemists, among other concordant disciplines.
Pharmaceutically Correct; Cosmetically Questionable: The case of retinoic acid presented is a good example. Although retinoic acid itself does not have any optically active carbon atoms its complexation with a “chirally-correct” molecule, such as an L-amino acid, can result in a “chirally-correct” retinoic acid derivative, which, depending on the three-dimensional stereochemistry of such complexing agent may have a differential skin penetration. Whether this difference is due to selective permeability of L-isomer, or its inherent biological property may require the inventive minds of disciplines mentioned above.
Absorption: Function of Chirality or Other Factors? It is stated that “Penetration is more a function of the size of the molecule and the strength of the liposome or technology of the delivery system.” The possibility that the three-dimensional stereochemistry of such ingredients or their derivatized complexes may have a differential skin penetration needs to be recognized, albeit perhaps theoretically at the moment.
Allergens or Just an Irritating Distraction? We do not imply that “non-chirally correct formula can cause an allergic reaction”. A particular optically-active ingredient may itself have allergenic properties or be biologically inactive, while its optical counterpart may not have the same issues. Our focus is to be selective in that “chirally-correct” direction. To illustrate this point, Kosari et al. (Dermatitis, 2010;21(3):148-153; http://www.medscape.com/viewarticle/723147_3) state : “Studies have confirmed that dl-α-tocopherol (of synthetic origin) induces dermatitis more frequently than d-α-tocopherol (of natural origin). Adams et al. (Dermatitis, 2010;21(4):199-202) state: “The North American Contact Dermatitis Group (NACDG) reported a 1.1% rate of positive patch-test reaction to dl-α-tocopherol 100% in 2003 to 2004 and a relative rate of 1.00 in 2001 to 2002. dl-α-Tocopherol was on the NACDG’s list of the 20 most common allergens in cosmetics from 2001 to 2004; 3.1% of women and 0.6% of men had positive patch test reactions to vitamin E that were attributed to a cosmetic not otherwise specified (Warshaw et al., J Am Acad Dermatol 2009;60:23–38). Additionally, documentation from The Linus Pauling Institute states: “The biological activity of vitamin E in animals is defined by its influence on symptoms of deficiency, including neuropathy, fetal death, or myopathy (muscle disease), and is dependent upon distinct regulatory processes. These regulatory processes largely explain why RRR-alpha-tocopherol, or d-alpha-tocopherol, is the most biologically potent of the eight naturally occurring forms of vitamin E”. This is directive of possible biological specificity of the optical isomers of an ingredient that cosmetic chemists need to be cognizant of.
Unstable in its Foundation. The comments: “most chirally correct ingredients degrade rather easily and change their chiral activity, which can then affect their penetration ability.” “Even if you put a chirally active in a cosmetic preparation, you cannot be sure that it will stay that way”. “These are very mobile materials. They are not inert and can change their rotations”, is obviously a non-chemist interpretation. Most optically active materials that are currently being used in cosmetic products have fairly stable chemical structure. The process of racemization that can affect the stereochemistry and optical rotation of a “chirally-correct” molecule are usually possible under harsher chemical reaction or pH conditions. For example, peptide synthesis with “chirally-correct” amino acids using dicyclohexylcarbodiimide or mixed anhydride technology can cause racemization (conversion of a D or L compound into a mixture of D and L). Extremely low or high pH conditions (especially very high pH) can also cause such racemizations. Such conditions are not typically encountered in cosmetic formulations or manufacturing processes. Then, there is the process of mutarotation, which changes only the optical rotation of a compound in a solution state, but it does not change their D or L structure or their biological properties.
We eagerly anticipate that the interest ignited by the concept of “Chirally-Correct” may help us better understand these ingredients, and additionally paving the path for future development of stereoselective skin penetrating ingredients and delivery systems with targeted topical attributes. The researchers, marketers, and consumers shall all reap the benefits of such a coordinated endeavor.