Delivery of Smart, Functional Innovative Materials: A Supramolecular Chemistry Approach to Anti-Aging & Acne Products
Published on Euro Cosmetic Magazine, p38-42, Vol. 3, 2015
Shao Xiang Lu and Letian Liu
Broda Tech, LLC
Broda Technologies Co., Ltd.
Recently, the importance of introducing supramolecular chemistry to cosmetics and personal care has become evident. Rather than synthesize a new molecule by linking the covalent chemical bonds in the desired arrangement of different atoms or groups via a series of chemical reactions, the two or more molecules chosen are designed in such a way that they self-assemble into organized entities. These generate new or enhanced functionality useful for cosmetic and personal care applications. Based on this concept, a smart hydrogel delivery system has been created which undergoes transformation from a liquid at room temperature to a shear sensitive hydrogel upon contact with skin.
最近针对超分子化学在化妆品和个人护理用品应用方面的研究，已日趋重要，而且也确实获得了业界的重视。在传统的化学概念中，分子是由不同原子之间通过化学 反应来合成的，原子与原子间的链接是共价键，而超分子化学与传统化学不同的是：超分子化学是分子之间通过选择性自组装的方式形成一种有序的聚集体，而这种 有序的聚集体可以为化妆品和个人护理用品提供一种崭新的功能性运用；例如，基于这一理念开发成功的新型智能水凝胶输送体系可以在室温下呈现液体状态，但接触皮肤后，在皮肤温度下迅速转变成剪切敏感的凝胶态。
Further, supramolecular salicylic acid has also been developed which is soluble in water without the need of any other solvents at low pHs. This material can be readily incorporated into either unbuffered or buffered formulations.
Supramolecular chemistry has expanded the scope of synthetic chemistry and grown rapidly in the last few decades. The technology provides an approach to formation of Nano scale systems and allows design and development of smart, functional materials with applications ranging from biology to materials science. While traditional synthetic chemistry deals with covalently bonded molecules, supramolecular chemistry deals with organized entities of intermolecular complexes. Such complexes consist of the association of two or more molecules held together by non-covalent intermolecular bonds. Examples of these include: hydrogen bonds, dipole-dipole interactions, van der Waals forces, cation-pi interactions, pi-pi bonds, CH/pi interactions, or hydrophobic effects, and etc.
超分子化学扩展了经典合成化学的范围，并在过去几十年中迅速发展。该技术提供了制造纳米尺度体系的新方法，并可以设计出智能化、功能性 新材料，具有从生物学到材料科学的广泛应用前景。传统的合成化学涉及的是含共价键的分子，而超分子化学涉及的是分子间有序复合聚集体。这种超分子复合聚集 体是由两个或更多分子通过分子间非共价键选择性地结合在一起，这种分子间非共价这种分子间非共价键包括氢键、偶极-偶极的相互作用，范德华力，阳离子-π，π-π键，CH/PI的相互作用或疏水效应等。
Supramolecular chemistry may be defined as “chemistry beyond the molecule”. Its development requires the use of multidisciplinary science- combined with the specific manipulation of selective non-covalent intermolecular interactions. The most important benefits of such complexes, especially in the field of cosmetics and personal care, are their reversibility and the fact that one or more properties that can be changed in a controlled manner by external stimuli, such as temperature, pH, moisture, stress and etc.
超分子化学可以定义为“超越分子的化学”。其发展需要多学科的共同协作，并且，结合特定选择性非共价分子间相互作用。 这种超分子复合聚集体最重要的益处是具有可逆特性，特别是在化妆品和个人护理用品应用方面，也就是说，可以以受控的方式通过外部刺激,比如温度、pH值、 水分、压力等，来改变这种复合聚集体的一种或是多种物理性能。
2. Water-Soluble Supramolecular Salicylic Acid
Salicylic Acid is a naturally occurring active ingredient and can be found in many plants, such as willow bark. It is also known as beta hydroxy acid or BHA and has both cosmetic and medicinal benefits. Salicylic acid has been introduced as a key ingredient in many cosmetic products and also OTC (over-the-counter) drug products over the last several decades. The use of salicylic acid for the treatment of acne, skin wrinkling, skin pigmentation, warts, freckles, dandruff or other skin-related problems is well known in the preparation of cosmetic, personal care and dermatological formulations. Salicylic acid is lipophilic and works as an exfoliating agent to penetrate into the pores, dissolve dead skin cells and enhance skin cell turnover. This cell renewal is accompanied by an overall improvement in the appearance of the skin texture with smoothing effect in a reduction of fine lines and wrinkles.
水杨酸是一种天然活性成分,存在于许多植物中,如柳树皮。它也被称为β-羟基酸或BHA，同时具有美容和药用价值。在过去的几十年中，水杨酸作为一种非常 重要的活性成分被广泛应用于化妆品和非处方（OTC）药品中。利用水杨酸治疗头皮屑，粉刺，皮肤皱纹，皮肤色素沉着，疵，雀斑或皮肤有关问题在皮肤病和化 妆品配方的制备上是众所周知的。水杨酸是亲脂性的,是去角质剂，能渗透毛孔，溶解死皮细胞，增强肌肤细胞活力。伴随着这种细胞的更新，皮肤会变得光滑细 腻、细纹减少，从而全面改善皮肤外观。
Studies have shown that salicylic acid is less irritating than skin care products containing alpha-hydroxy acids but has similar or better results in improving skin conditions. A recent clinical study also demonstrates that salicylic acid is as effective as benzoyl peroxide in acne treatment while provides additional skin care benefits not achievable with acne treatment products containing benzoyl peroxide.
Salicylic acid is a weak acid in a colorless crystalline form and is poorly soluble in water (2 g/L at 20 °C). It is soluble in ethanol, propanol, acetone, ethers and other organic solvents that are usually unsafe for use on human skin.
水杨酸是一种弱酸,呈无色结晶形态，难溶于水（2 g/L, 20 °C）,易溶于乙醇、丙醇、丙酮、乙醚等有机溶剂,而这些有机溶剂在人体皮肤上使用时通常是不安全的。
Typical problems that occur when using salicylic acid in preparing cosmetic and personal care products are that the salicylic acid tends to form crystals on standing and precipitate out within various un-buffered formulations. The recrystallization of salicylic acid in the formulation not only significantly reduces the bioavailability of the active ingredient but also cause skin irritation. It is a common practice in the industry to increase the pH with sodium hydroxide.. This technique neutralizes part of the free salicylic acid to form water soluble salicylates which increases solubility and therefore reduces recrystallization of salicylic acid in the formula. This approach avoids possible skin irritation caused by low pH systems. Although this common practice helps formulation chemists achieve stable products containing salicylic acid and avoids possible skin irritation; it reduces the efficacy of the salicylic acid and results in a product that is therapeutically less effective.
水杨酸在化妆品配方中应用的最大问题是水杨酸在非缓冲、低pH值溶液中倾向于结晶沉淀。配方中水杨酸的再结晶不仅减少了活性成分的有效生物利用度，同时也 会导致皮肤刺激，因而在业内添加氢氧化钠以提高溶液pH值是常见的做法。该技术可以中和部分游离的水杨酸形成水溶性的水杨酸盐以提高水杨酸溶解度，从而减 少了配方中水杨酸再结晶的可能，同时也避免了由于低pH值可能导致的皮肤刺激。尽管这种常见的做法有助于配方师提高含有水杨酸产品配方的稳定性，并避免了 可能的皮肤刺激,但这同时降低了水杨酸的功效。
It is well known that changes in pH have a profound influence on many aspects of the action of therapeutically active ingredients. Salicylic acid is a weak acid in which the proportion of the unionized and ionized components is dependent on the pH of the medium according to the well-known Henderson-Hasselbalch equation (1):
Here, [HA] is the molar concentration of the unionized weak acid, [A⁻] is the molar concentration of ionized base and Ka is the acid dissociation constant.
Salicylic acid has a pKa of 3 with a pH value well below 3. Table 3 lists calculated molar percentage of unionized salicylic acid form as a function of pH value based on Henderson-Hasselbalch equation (1). The calculation indicates that it will have only 50% un-ionized salicylic acid at pH 3.0, 23.8% unionized salicylic acid at pH 3.5 and 9.1% unionized salicylic acid at pH 4.0.
水杨酸的pKa是3，其pH值一般远远低于3。如表3所示，根据Henderson-Hasselbalch方程式计算得出的水杨酸pH值所对应的非离子 化水杨酸摩尔浓度百分比。计算表明，当水杨酸的pH值=3时，非离子化的水杨酸浓度为50%，pH=3.5时，非离子化的水杨酸浓度为23.8%，当 pH=4时，非离子化的水杨酸浓度只有9.1%。
Table 3: Unionized salicylic acid (mole %) as a function of pH
Unionized salicylic acid (mole %)
The therapeutic action of salicylic acid may be attributed to that of either the ionized or the un-ionized acid fractions alone, or to a combination of both types of fractions and depends on the routes of administration. The efficacy of the skin care product containing salicylic acid depends mainly on the availability of free salicylic acid, which is limited with buffers and high pHs. The un-ionized salicylic acid is lipid-soluble and thus diffuses more effectively across the hydrophobic skin epidermal barrier. This allows it to penetrate the pores. By contrast, the ionized fraction is water-soluble, and therefore transfer across the skin’s epidermal layer is either zero or negligible. This affects the distribution of the salicylic acid or alters the rate of transfer and attainment of equilibrium concentration at the site of action on the skin.
水杨酸的功效可能是由离子化或者是非离子化的部分作用有关，又或是两者共同作用有关，且取决于实施方式。含水杨酸的护肤产品功效主要取决于游离水杨酸，其 与缓冲液和高pH值的条件下只能有有限的浓度。非离子化的水杨酸是脂溶性的，更容易透过皮肤的表皮屏障，也更容易渗透到毛孔中。相反，离子化的水杨酸是水 溶性的，因此，其渗透进皮肤的表皮层的可能性很小，甚至可以忽略。这会影响水杨酸的分布或会改变水杨酸传输速率和达到皮肤作用位置能够达到的平衡浓度。
A number of strategies have been developed for the delivery of salicylic acid in the past. These include encapsulation of salicylic acid particles and the esterification of salicylic acid with polymeric polyols for controlled release. However, these approaches provide only partial solutions for the delivery of salicylic acid with limitations in formulation freedom and reduced therapeutically efficacy. To overcome technical challenges, a recent advancement in supramolecular chemistry has been developed to selectively self-assemble poorly water- soluble salicylic acid into water- soluble organized entities in the form of intermolecular complexes.6 This novel technological approach utilizes non-covalent, reversible, intermolecular bonding to form water- soluble supramolecular salicylic acid complexes. These properties are quite useful for the delivery of salicylic acid to achieve maximum efficacy and reduced skin irritation at low pHs.
过去，为了解决上述水杨酸配方输送问题，已开发了多种不同的技术，这包括水杨酸颗粒的包裹技术，以及酯化含多元醇聚合物达到缓控释。然而，这些方 法只提供了水杨酸配方的部分解决方案，并限制了配方自由度，降低了其功效。为克服这种技术上的难题，一种结合了现代超分子化学的新技术应运而生，该技术可 以选择性地将非水溶性水杨酸分子以自组装的方式形成分子与分子之间的可溶性超分子聚集体。这种新颖的技术通过分子间可逆的、非共价键形成超分子水杨酸复合 物。这种超分子技术能够使水杨酸在较低的pH值下发挥最大功效的同时，减少其副作用。
One such complex is a water- soluble supramolecular salicylic acid, such as SupraSalix™-16 Supramolecular salicylic acid is readily soluble in water to form a clear and transparent solution with a pH below 3. The release of salicylic acid can be achieved through the dissociation of hydrogen bonded water soluble complexes in water. Aqueous solutions or hydrogels containing salicylic acid intermolecular complexes are stable over a wide temperature range without recrystallization or discoloration. Such complexes provide water-soluble salicylic acid at low or controlled pHs to help achieve maximum efficacy with virtually no skin irritation. By contrast, Salicylic acid can cause irritation even at low use level in the formulation at low pHs. Clinical evaluations of Human Repeat Insult Patch Test (RIPT) for skin irritation and skin sensitization on 50 subjects indicates that there are no identifiable signs or symptoms of primary irritation or sensitization noted for the formulation containing 2% effective salicylic acid at pH 2.5-2.8. This makes it an effective raw material to delivery water soluble salicylic acid at low pHs for people with sensitive skin. The supramolucular salicylic acid provides benefits of salicylic acid with high efficacy at low pHwithout typically associated skin irritation.
这种水杨酸复合物是一种可溶于水的超分子聚集体，比如SupraSalix™-16 超分子水杨酸，它易溶于水，并在pH值低于3的情况下形成清澈透明的溶液。水杨酸的释放可以通过水溶性复合物氢键在水中的离解来实现。含有水杨酸复合物的 水溶液或水凝胶在较大的温度范围内都是稳定的，且不会出现重结晶和变色的现象。
The water-soluble supramolecular salicylic acid can meet one of the most demanding formulation challenges typically associated with the use of salicylic acid at low pHs. It can be formulated into various existing products, or newly developed formulations, by simply dissolving SupraSalix* in water without the need for any additional solvents, such as ethyl alcohol, followed by incorporating into various systems either in unbuffered or buffered formulations. However, caution must be exercised when formulating at low pH to avoid ingredients that are susceptible to hydrolytic degradation in acidic conditions.
这种超分子水杨酸复合物能够在较低或者可控pH值下，使非水溶性水杨酸溶于水中，并减少对皮肤的刺激性，同时最大限度地发挥活性成分的功效。传统剂型的水 杨酸在低pH的情况下，即使剂量很低，也仍然可能引起皮肤刺激。在一项有50名志愿者参与的人体多次重复斑贴临床试验评估中，含有2%有效水杨酸体系的 pH值在2.5-2.8之间，没有发现明显的皮肤刺激及过敏症状。这使得该超分子水杨酸成为对有皮肤过敏症状的人在低pH值下使用水杨酸的有效原材料。该 超分子水杨酸体系在低pH值下提供了较高水杨酸功效，而避免了常见的水杨酸皮肤刺激性。
Supramolecular salicylic acid shows high efficacy in reducing blemishes, soothing inflammation, improving skin appearance and accelerating skin's clarifying process without skin irritation comparing with other OTC acne products on the market. Studies on an OTC acne treatment product, containing 2% effective salicylic acid, demonstrate superior overall performance than existing products. Figure 2 shows pictures of before and after acne treatment with formula containing 2% effective salicylic acid at a pH below 3.
Salicylic acid is a multifunctional active ingredient and can be used in a variety of cosmetic and personal care products. The potential applications of supramolecular salicylic acid include, but not limited to skin care, anti-acne, anti-dandruff shampoo, hands and foot care, anti-bacteria hand soap bars and cleansers, and etc.
For example, salicylic acid can relieve inflammation and redness. Supramolecular salicylic acid can be easily incorporated into shaving products that contain salicylic acid to help get a closer shave and prevent breakouts. Shaving products containing salicylic acid will help prevent pores from clogging and avoid razor burn while shaving. Aftershave products containing salicylic acid will help to reduce oil secretion, control the enlarged pores and tighten the skin, prevent inflammation and redness caused by close shaving, and kill bacteria. In addition, alcohol-free shave and aftershave products formulated with supramolecular salicylic acid will help keep skin better hydrated.
例如，由于水杨酸可以减轻炎症和红肿症状，故超分子水杨酸可以很容易地加入到剃须产品中，以帮助达到更好地贴近皮肤剃刮，防止皮肤痘痘的生长。含有水杨酸 的剃须产品能够有效防止毛孔堵塞，避免剃须时对皮肤的伤害。含有水杨酸的须后护理水产品将有助于减少油脂分泌，收缩毛孔，紧致肌肤，防止剃须引起的炎症和 红肿，并杀死细菌。此外，加入了超分子水杨酸的、不含酒精的须后产品可以帮助皮肤更好地保持滋润。