Transcending the Boundaries of Cosmetics: A Novel Ionic Liquid Inspired Skin Penetration System as an Alternative to Medical Beauty Treatments
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Presented by: Toru Okamoto
Introduction
Cosmeceuticals are an emerging category of beauty products that utilize the benefits of cosmetic active ingredients. However, until now they have not yet been able to transcend the boundaries of conventional cosmetics. Although consumers believe that the applied active drugs in cosmeceuticals are highly effective, in reality, almost all hydrophilic cosmeceutical drugs applied on the skin cannot reach the active site in the deeper layers of the skin due to the presence of the stratum corneum. Furthermore, there is still the question of whether enhancing drug penetration leads to more even skin tone and/or wrinkle appearance improvement. Thus, there are unmet needs for an innovative technology that enhances the skin penetration of cosmetic active ingredients and leads to improvement in consumers’ skin health and appearance.
Drug penetration can be described by both partitioning into and diffusion through the stratum corneum (SC), which is a robust lipophilic barrier. For cosmeceuticals, because there are a limited number of useable active drugs, standard strategies to improve partitioning such as prodrugs are of no use. In addition, penetration enhancers that break the barrier function of SC may result in toxicity. Such standard techniques are based on the capability of single molecules, which have a limit. To overcome these limitations, here we present two strategies to enhance skin penetration inspired by the principles of ionic liquids (ILs): the fluidization of the drug itself and the design of a new penetration-enhancer that utilizes intermolecular interactions.
Methods
Fluidization of Active Drugs: In this study, potassium 4-methoxysalicylate (4MSK) was used as a model to explore the potential of fluidizing drugs inspired by ILs for enhancing penetration in cosmeceutical products. First, cations and hydrogen bond acceptors were screened. Next, complexes were synthesized by salt-metathesis reactions. The interaction of the complexes was confirmed by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Drug penetration experiments were conducted using human skin and a Franz diffusion cell system.
Fluidization of SC Sheets: To obtain higher safety and enhanced penetration capabilities for cosmeceutical uses, we adopted novel liquid phases such as ILs consisting of an amphoteric surfactant. The mechanisms underlying penetration enhancement were investigated by measuring SC sheets with ATR-FTIR and differential scanning calorimetry (DSC).
Result and Discussion
Fluidization of Active Drugs: A clear viscous liquid was obtained by the reaction of 4MSK with basic amino acid salts. The glass transition temperature of the obtained complexes was below 0°C. The complex obtained from 4MSK and arginine hydrochloride, 4MS-Arg, was fluidized due to strong interactions between 4MS and Arg. Compared with 4MSK, 4MS-Arg showed drastically higher penetration. The calculated partition coefficient showed a tenfold increase by fluidization with complex formation. Furthermore, visual observation showed that the crystallization of 4MS-Arg upon water evaporation was slower than that of 4MSK. This suggests that 4MS-Arg is a promising alternative to 4MSK for maintaining a supersaturated state over a long period of time. From a penetration study using human skin, results suggested that 4MS-Arg formed a drug-containing reservoir in the SC due to both the supersaturation effect and improved partitioning, and efficiently delivered 4MSK to the target site.
Fluidization of SC Sheets: In addition, we successfully synthesized complexes composed of alkyl betaine and xylitol that are strongly assisted by hydrogen bonding. ATR-FTIR and DSC results suggested that they temporarily disorganized the intercellular lipids in the SC and enhanced their fluidity. Furthermore, the synthesized complexes can improve drug solubility, which leads to higher chemical potential. Hydrophilic drugs can easily pass through the SC with increased fluidity and are safe due to the reversibility of the reactions.
Conclusion
We have developed two novel technologies to enhance the skin penetration of hydrophilic drugs in cosmeceutical formulations: drug fluidization and a new penetration-enhancing co-solvent that utilizes intermolecular interactions. These technologies not only allow the use of any target drug but also minimize toxicity towards the skin. Furthermore, by using a novel fluidization technique inspired by ILs, we demonstrated the enhancement of penetration and skin effects for an existing and proven drug without using any chemical reactions. These technologies can give cosmeceuticals great potential to transcend the scope of cosmetics and help consumers stay healthy, beautiful, and unworried about aging.
Cosmeceuticals are an emerging category of beauty products that utilize the benefits of cosmetic active ingredients. However, until now they have not yet been able to transcend the boundaries of conventional cosmetics. Although consumers believe that the applied active drugs in cosmeceuticals are highly effective, in reality, almost all hydrophilic cosmeceutical drugs applied on the skin cannot reach the active site in the deeper layers of the skin due to the presence of the stratum corneum. Furthermore, there is still the question of whether enhancing drug penetration leads to more even skin tone and/or wrinkle appearance improvement. Thus, there are unmet needs for an innovative technology that enhances the skin penetration of cosmetic active ingredients and leads to improvement in consumers’ skin health and appearance.
Drug penetration can be described by both partitioning into and diffusion through the stratum corneum (SC), which is a robust lipophilic barrier. For cosmeceuticals, because there are a limited number of useable active drugs, standard strategies to improve partitioning such as prodrugs are of no use. In addition, penetration enhancers that break the barrier function of SC may result in toxicity. Such standard techniques are based on the capability of single molecules, which have a limit. To overcome these limitations, here we present two strategies to enhance skin penetration inspired by the principles of ionic liquids (ILs): the fluidization of the drug itself and the design of a new penetration-enhancer that utilizes intermolecular interactions.
Methods
Fluidization of Active Drugs: In this study, potassium 4-methoxysalicylate (4MSK) was used as a model to explore the potential of fluidizing drugs inspired by ILs for enhancing penetration in cosmeceutical products. First, cations and hydrogen bond acceptors were screened. Next, complexes were synthesized by salt-metathesis reactions. The interaction of the complexes was confirmed by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Drug penetration experiments were conducted using human skin and a Franz diffusion cell system.
Fluidization of SC Sheets: To obtain higher safety and enhanced penetration capabilities for cosmeceutical uses, we adopted novel liquid phases such as ILs consisting of an amphoteric surfactant. The mechanisms underlying penetration enhancement were investigated by measuring SC sheets with ATR-FTIR and differential scanning calorimetry (DSC).
Result and Discussion
Fluidization of Active Drugs: A clear viscous liquid was obtained by the reaction of 4MSK with basic amino acid salts. The glass transition temperature of the obtained complexes was below 0°C. The complex obtained from 4MSK and arginine hydrochloride, 4MS-Arg, was fluidized due to strong interactions between 4MS and Arg. Compared with 4MSK, 4MS-Arg showed drastically higher penetration. The calculated partition coefficient showed a tenfold increase by fluidization with complex formation. Furthermore, visual observation showed that the crystallization of 4MS-Arg upon water evaporation was slower than that of 4MSK. This suggests that 4MS-Arg is a promising alternative to 4MSK for maintaining a supersaturated state over a long period of time. From a penetration study using human skin, results suggested that 4MS-Arg formed a drug-containing reservoir in the SC due to both the supersaturation effect and improved partitioning, and efficiently delivered 4MSK to the target site.
Fluidization of SC Sheets: In addition, we successfully synthesized complexes composed of alkyl betaine and xylitol that are strongly assisted by hydrogen bonding. ATR-FTIR and DSC results suggested that they temporarily disorganized the intercellular lipids in the SC and enhanced their fluidity. Furthermore, the synthesized complexes can improve drug solubility, which leads to higher chemical potential. Hydrophilic drugs can easily pass through the SC with increased fluidity and are safe due to the reversibility of the reactions.
Conclusion
We have developed two novel technologies to enhance the skin penetration of hydrophilic drugs in cosmeceutical formulations: drug fluidization and a new penetration-enhancing co-solvent that utilizes intermolecular interactions. These technologies not only allow the use of any target drug but also minimize toxicity towards the skin. Furthermore, by using a novel fluidization technique inspired by ILs, we demonstrated the enhancement of penetration and skin effects for an existing and proven drug without using any chemical reactions. These technologies can give cosmeceuticals great potential to transcend the scope of cosmetics and help consumers stay healthy, beautiful, and unworried about aging.