Clinical and cosmeceutical uses of hydroxyacids

Clinics in Dermatology (2009) 27, 495–501

Clinical and cosmeceutical uses of hydroxyacids Barbara A. Green, RPh, MS a,⁎, Ruey J. Yu, PhD, OMD b , Eugene J. Van Scott, MD c a

NeoStrata Company, Inc, 307 College Road, Princeton, NJ 08540, USA 655 Stump Road, Chalfont, PA 18914 USA c 3 Hidden Lane, Abington, PA 19001 USA b

Abstract The hydroxyacids are represented by the α-hydroxyacids, β-hydroxyacids, polyhydroxy acids, and bionic acids. Together, these ingredients form a class of compounds with unparalleled benefits to the skin and unprecedented usage in the cosmeceutical market in cosmetic and therapeutic formulations alike. The most commonly used hydroxyacid is glycolic acid, an α-hydroxyacid that has been used extensively in cosmetic antiaging formulations, moisturizers, and peels, and in treatment products to improve hyperpigmentation and acne. The newer polyhydroxy and bionic acids offer the benefits of αhydroxyacids without irritation, making them suitable for use on sensitive skin, rosacea, and after cosmetic procedures. They also provide additional antioxidant/chelation, barrier strengthening, and moisturizing effects. Bionic acids inhibit matrix metalloproteinase enzymes in skin, providing a preventative antiaging benefit. The hydroxyacids as a class can be combined with therapeutically active materials and cosmetic procedures to increase therapeutic effects and improve tolerability and outcomes of medicinal agents and procedures. © 2009 Elsevier Inc. All rights reserved.

Introduction About three decades ago, Van Scott and Yu found that hydroxyacids (HAs) with a hydroxyl group at the α- or βposition, when applied topically, had a very specific effect on hyperkeratinization. This effect was clinically expressed by an initial abrupt detachment of the hyperkeratotic stratum corneum at its innermost level, stratum compactum, distal to the stratum granulosum, providing beneficial effects for ichthyosis, dry skin, keratoses and warts, and follicular hyperkeratosis, including that occurring in acne.1-3 Later work found that sustained applications of α-HAs (AHAs) and β-HAs (BHAs) resulted in plumping of the skin. Although some epidermal thickening occurred, dermal thickening accounted for the measurable effects on skin ⁎ Corresponding author. E-mail address: [email protected] (B.A. Green). 0738-081X/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.06.023

plumping, which was correlated with biosynthesis of glycosaminoglycans (GAGs), collagen, and improved quality of elastic fibers.4 These dermal changes were accompanied by improvement in fine lines and wrinkles. Although some skin diseases and disorders seem to be innate, appearing simply with the passage of time, “innate” may not be tantamount to “inevitable.” HAs are known to modulate form and function of skin, providing therapeutic benefits for skin diseases and aging. This contribution summarizes clinical uses and antiaging effects of HAs, including AHAs, BHAs, polyhydroxy acids (PHAs), and bionic acids (BAs).

α-Hydroxyacids The AHAs are organic carboxylic acids with one hydroxyl group attached to the α-position of the carboxyl

496 group. The hydroxyl and carboxyl groups are both directly attached to an aliphatic or alicyclic carbon atom. The hydroxyl group in the AHA is neutral, and only the carboxyl group provides an acidic property. Many AHAs are present in foods and fruits and, therefore, are called fruit acids. Glycolic acid, the smallest AHA, occurs in sugar cane and is the most widely used HA in skin care. Lactic acid, the next smallest AHA, is also widely used in topical formulations to exfoliate and provide antiaging effects. Some AHAs contain a phenyl group as a side-chain substituent. This changes the solubility profile of the AHA, providing increased lipophilicity over conventional watersoluble AHAs and can be used to target oily and acne-prone skin (Figure 1). Examples include mandelic acid (phenyl glycolic acid) and benzilic acid (diphenyl glycolic acid).

β-Hydroxyacids The BHAs are organic carboxylic acids having one hydroxyl group attached to the β-position of the carboxyl group. The hydroxyl group in the BHA is neutral in nature and the carboxyl group provides the acidic property. Some BHAs, such as β-hydroxybutanoic acid, are present in body tissues as metabolic intermediates and energy sources; however, they have not yet been commercialized in dermatologic formulations. Some molecules are both an AHA and BHA because they contain a hydroxyl group in the α-position to one carboxyl group and in the β-position to

B.A. Green et al. another carboxyl group. Malic acid (apple acid), for example, contains one hydroxyl and two carboxyl groups, and citric acid contains one hydroxyl and three carboxyl groups, making both molecules an AHA and a BHA. Citric acid is widely used in topical formulations as an antioxidant and pH adjustor, and its antiaging benefits are well established.5 Although some have termed salicylic acid a BHA, we do not consider it to be a BHA; for that reason, it is not included in this discussion. Salicylic acid behaves differently on skin than other HAs, presumably due to its phenolic hydroxyl attachment that renders the hydroxyl acidic rather than neutral.1

Polyhydroxy acids The PHAs are organic carboxylic acids with two or more hydroxyl groups in the molecule attached to carbon atoms of an aliphatic or alicyclic chain. All the hydroxyl groups in the PHA are neutral, and only the carboxyl group provides its acidity. To be both an AHA and PHA, also known as a polyhydroxy AHA, it is essential that at least one hydroxyl group be attached to the α-position. Many PHAs are naturally occurring, endogenous metabolites, or intermediate products from carbohydrate metabolism in body tissues. For example, gluconic acid and gluconolactone are important metabolites formed in the pentose phosphate pathway from glucose during the biosynthesis of ribose for ribonucleic acid.

Fig. 1 Face of a 24-year-old woman with acne at (left) baseline and (right) after three peels administered during a 2-month period. Peels consisted of 20% mandelic acid plus 10% citric acid booster peels, followed by application of free acid glycolic acid peel solutions of 20%, 50%, and 70%, respectively.

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Bionic acids

Fig. 2 A gel matrix containing 14% water formed upon evaporation of water from the bionic acid (BA) lactobionic acid solution.

Gluconolactone is the most commercialized PHA in skin care products, because it is readily available and delivers the antiaging benefits of HAs, in addition to strengthening skin barrier function6 and being a gentle, moisturizing, antioxidant/chelating substance.7,8 For example, an in vitro cutaneous model of photoaging demonstrated that gluconolactone protects against ultraviolet (UV) radiation. These findings were attributed to the ability of gluconolactone to chelate oxidation-promoting metals and trap free radicals.9 In addition, pretreatment of skin with gluconolactone does not lead to an increase in sunburn cells after UVB irradiation, as has been shown to occur with glycolic acid; this is thought to be due to its antioxidant effects.9 Gluconolactone can also be formulated with oxidative drugs, such as benzoyl peroxide, to help reduce irritation potential and erythema caused by the oxidative drug.10

The BAs are chemically classified as aldobionic acids. They consist of one carbohydrate monomer chemically linked to an aldonic acid PHA; examples are lactobionic acid, maltobionic acid, and cellobionic acid. BAs are commonly obtained from their disaccharide through chemical or enzymatic oxidation; for example, lactobionic acid is obtained from lactose, maltobionic acid from maltose, and cellobionic acid from cellobiose. Although the BAs are larger molecules than traditional AHAs, they are small enough to penetrate skin at approximately 358 daltons, and their pKa is roughly equivalent to smaller AHA molecules; for example, the pKa of lactobionic acid is 3.8, which matches that of glycolic acid. BAs are hygroscopic materials that readily attract and retain water, forming a gel matrix when their aqueous solution is evaporated at room temperature (Figure 2). The transparent gel contains certain amounts of water, forming a clear gel matrix. Formation of a gel matrix may add protective and soothing effects for inflamed skin. Indeed, formulations containing BA are well tolerated and help calm skin when applied after cosmetic procedures that weaken the skin’s barrier, including superficial HA peels and microdermabrasion.11 One notable protective use of lactobionic acid, a BA used in some commercial skin care formulations, is as an antioxidant chelator in organ transplantation preservation solutions. Lactobionic acid reportedly inhibits hydroxyl radical production by forming a complex with the oxidationpromoting metal Fe(II).12 Furthermore, gluconolactone (a PHA) and lactobionic acid and maltobionic acid (BAs) inhibit oxidative degradation of hydroquinone and banana peel.13 Lactobionic acid also functions as an inhibitor of the matrix metalloproteinase (MMP) enzymes.14 Excessive

Fig. 3 Photomicrographs show histology staining for matrix metalloproteinase-9 (original magnification ×400). (Left) Specimen shows staining of untreated control forearm skin. (Right) Specimen shows staining after topical application of 8% lactobionic acid cream (pH, 3.8) for 12 weeks. Decreased density of brown color demonstrates a reduction in matrix metalloproteinase-9 staining. Reprinted with permission from Cosmetic Dermatology 2008;21(2):76-82.

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Fig. 4 Hyperkeratotic heels (left) before and (right) after once-daily use for 3 weeks of a 20% α-hydroxyacid/polyhydroxy acid/bionic acid combination cream (pH, 3.7). The cream contains 5% lactic acid, 5% glycolic acid, 5% mandelic acid, and a 5% blend of gluconolactone and maltobionic acid.

activity of MMPs occurs with age and sun exposure, contributing to wrinkle formation, skin laxity, and visible telangiectasia.15 The use of BAs to inhibit MMPs may provide a significant benefit in the prevention of photodamage (Figure 3).

Clinical uses of HAs Dry skin and hyperkeratinization One of the more frequently encountered skin problems is xerosis, commonly known as dry skin. It can be improved momentarily with application of water. It can be improved for longer periods with the simultaneous use of common water-retaining substances such as glycerin and propylene glycol, and improved still more with occlusive measures to

Fig. 5 Lamellar ichthyosis. Left side of image shows untreated skin, and the right side shows skin after twice-daily use for 2 weeks of a 20% α-hydroxyacid/polyhydroxy acid/bionic acid combination cream (pH, 3.7). The cream contains 5% lactic acid, 5% glycolic acid, 5% mandelic acid, and a 5% blend of gluconolactone and maltobionic acid.

retard evaporative water loss. The condition of dry skin persists, however, despite these hydrating procedures because corneocyte production, desquamation, and waterretaining capacity are not performing optimally. Topical use of AHA formulations on xerotic skin restores the stratum corneum and epidermis to a more normal clinical and histologic state. Combination HA formulations that contain PHAs and BAs are found to have unparalleled efficacy for treating xerosis and for treating otherwise treatment-resistant conditions such as callused fissured plantar and palmar skin (Figures 4 and 5).

Sensitive skin and rosacea One of the distinguishing benefits of the PHAs and BAs is their gentleness on skin. Compared with glycolic acid and lactic acid, PHAs and BAs do not sting or burn. Product use studies have demonstrated compatibility with sensitive skin, even on rosacea and atopic dermatitis.16,17 Moreover, partly because of their gentleness, concurrent use of products with gluconolactone and a topical drug containing azelaic acid has been shown to improve therapeutic outcomes for rosacea by reducing skin redness and diminishing the appearance of telangiectasia. The latter effect may occur as a result of the ability of gluconolactone

Fig. 6 Adult woman with hyperpigmentation (left) before and (right) after twice-daily use of a skin-lightening formulation for 12 weeks. The topical formulation contains 2% hydroquinone, 3% kojic acid, and a 10% polyhydroxy acid/bionic acid blend of gluconolactone and lactobionic acid.

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499 dermis also increased in thickness, with increased prominence of dermal papillae. Increased thickness of skin without further topical applications persists for months.19 These clinical and histologic findings are consistent with in vivo and in vitro observations of others showing the AHA glycolic acid increases production of collagen, hyaluronic acid, and fibroblast proliferation.20,21 As a result of the ability to increase dermal biosynthesis of matrix components, AHAs, PHAs, and BAs are used widely as topical antiaging substances. Benefits to patients include diminished dyspigmentation and an increase in total skin thickness and firmness, which in turn diminishes clinical wizened appearances (Figure 8).1,4,22

Fig. 7 Forearms of 62-year-old woman. The right forearm (left side of image; control) was treated for 6 months with a placebo lotion twice daily. The left forearm (right side of image), which was treated for 6 months with 25% lactic acid lotion twice daily, is more plump, has fewer lentigines, and has less mottled hyperpigmentation.

to increase skin thickness. Patient tolerability of medication containing azelaic acid was also improved.18

Hyperpigmentation Some of the most visibly obvious changes to photoaged skin are a variety of localized hyperkeratotic and hyperpigmented lesions that include seborrheic keratoses, actinic keratoses, lentigines, and mottled pigmentation. Most of these are popularly recognized under the common name of “age spots,” spots that cluster on the face, back of hands, and the extensor aspect of forearms. The predominant lesion of this category is the lentigo, often accompanied by persistent mottled pigmentation and thin pigmented keratoses, each a consequence of past over-exposures to sunlight. Hyperpigmented lesions are diminished in degree of clinical visibility quite readily by topical AHA treatment, with or without the combined use of adjuvant depigmenting agents such as hydroquinone (Figure 6). Lesions of the chest and forearms are next in rank of responsiveness (Figure 7). Lesions of the back of the hands respond most slowly. Nevertheless, with sustained treatment, substantial lightening and even complete resolution of hyperpigmentation can and does occur.

Uses as a peeling agent Effects from topically applied HAs may be compared and evaluated in connection with the method of use. One method is that used in peeling procedures, where effects are from short intense exposures. Glycolic acid and lactic acid are AHAs that have been used commonly as peeling agents. In contrast to other topical peeling agents, including phenol, trichloroacetic acid, and salicylic acid, many of the AHAs are nutritive and physiologic. In high concentrations of up to 70% or greater, they can be applied to the skin for short times23 to achieve substantial desquamation and initiate accelerated epidermal and dermal renewal for use in antiaging and adjunctive care of acne, rosacea, and hyperpigmentation (Figure 1). AHAs are primarily used as superficial peeling agents in practice, offering the benefit of safety and effectiveness over the course of a series of peels. Superficial AHA peels are increasingly being used in combination with

Wrinkles and photoaging Significant normalizing, antiaging benefits occur in the dermal layers with daily application of AHAs to the skin. In studies on forearm skin where AHAs were applied daily for extended periods, 4,5,19 substantial increases in dermal thickness occurred (Figure 7) that were correlated with increased amounts of hyaluronic acid and other GAGs as well as with qualitative improvements in collagen fibers and improved histologic quality of elastic fibers.4 The papillary

Fig. 8 Adult man with hyperpigmentation and photoaging at (left) baseline and (right) after twice-daily use of an αhydroxyacid (AHA)/polyhydroxy acid (PHA)/bionic acid (BA) skin care regimen for 12 weeks. Use of the skin care products resulted in significantly less hyperpigmentation and improved radiance. The product regimen included: 20% AHA/BA cleanser, 10% PHA/BA SPF 15 cream for daytime use, and 15% AHA lotion for nighttime use.

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other dermatologic devices to provide complementary benefits and enhance outcomes of procedures, including injectable fillers and botulinum toxin type A, microdermabrasion, intense pulsed light, and nonablative laser.

Synergy with topical drugs HAs can be used to enhance and improve therapeutic effects of certain medicinal agents (Figure 9). In some cases, the biologic effect is intuitive due to the known functions of HAs. For example, the AHA lactic acid and its ammonium salt prevent dermal atrophy associated with the topical use of corticosteroids.24 This is presumably due to AHA stimulation of collagen and GAG synthesis; however, mechanisms of how HAs complement or supplement the efficacy for other ingredients are, for the most part, unknown. We do know that most pharmaceutical agents produce pharmacologic effects by first interacting or binding with their receptors in the target tissues. Many receptors are functional macromolecules, such as enzymes, cell membranes, or certain components of cells. It is possible that HAs may increase the affinity of the receptor molecule toward the topical agent, acting as a better and more efficient coenzyme or as an activator by disrupting barriers and removing inhibitors for better binding of the agent toward its receptor molecule; for example, enzyme activation by removal of natural inhibitors. Such may be the case when AHAs are combined with topical corticosteroids in the treatment of psoriasis (Figure 10). In most cases, the enhanced therapeutic effects are not due to increased penetration and can be achieved by the use of a combination formulation or by an alternative use of separate formulations, such as one formulation in the morning and another in the evening.

Conclusions As we strive to reverse the clinical signs of aging and improve overall skin health, one class of compounds continues to emerge as ingredients with important benefits.

Fig. 9 Onychomycosis (Trichophyton rubrum) of the thumb nail, (left) before topical treatment and (right) after 6 months topical treatment, once daily at bedtime, with clotrimazole 1% and glycolic acid 15% in an aqueous alcoholic solution.

Fig. 10 Psoriasis. The right side of the body was treated twice daily with clobetasol propionate 0.05% ointment for 2-week intervals, with 1-week intervening periods of no treatment. The left side was treated likewise, but 0.5% benzilic acid was added to clobetasol propionate 0.05% ointment. After 2 months, lesions of the right side had improved incompletely, whereas lesions of left side improved completely.

The hydroxyacids, mainly α-hydroxyacids, polyhydroxy acids, and bionic acids, remain timeless in their ability to modulate skin structure and performance, providing both clinical and cosmetic benefits to skin. Moreover, the hydroxyacids continue to be important topical cosmeceutical and therapeutic tools because they offer significant epidermal and dermal benefits to skin and are also safe for skin and the body, even after full body application over long periods of time, such as for the treatment of ichthyosis. Hydroxyacids can be used alone or with other topicals to target specific symptoms of photoaging and various conditions of hyperkeratosis, while also offering the flexibility for combination use with other cosmetics, drugs, and devices in dermatology.

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Clinical and cosmeceutical uses of hydroxyacids 8. Edison BL, Green BA, Wildnauer RH, et al. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alphahydroxyacid regimen. Cutis 2004;73(suppl 2):14-7. 9. Bernstein EF, Brown DB, Schwartz MD, et al. The polyhydroxy acid gluconolactone protects against ultraviolet radiation in an in vitro model of cutaneous photoaging. Dermatol Surg 2004;30:1-8. 10. Kakita LS, Green BA. A review of the physical and chemical properties of alpha-hydroxyacids (AHAs) and polyhydroxy acids (PHAs) and their therapeutic use in pharmacologics. J Am Acad Dermatol 2006;54: AB107. 11. Briden E, Jacobsen E, Johnson C. Combining superficial glycolic acid (AHA) peels with microdermabrasion to maximize treatment results and patient satisfaction. Cutis 2007;79(suppl 1):13-6. 12. Charloux C, Paul M, Loisance D, et al. Inhibition of hydroxyl radical production by lactobionate, adenine, and tempol. Free Radical Bio Med 1995;19:699-704. 13. Briden ME, Green BA. The next generation hydroxyacids. In: Draelos ZD, Dover J, Alam M, editors. Procedures in cosmetic dermatology: cosmeceuticals. Philadelphia: Elsevier Saunders; 2005. p. 205-12. 14. Upadhya GA, Strasberg SM. Glutathione, lactobionate, and histidine: cryptic inhibitors of matrix metalloproteinases contained in University of Wisconsin and histidine/tryptophan/ketoglutarate liver preservation solutions. Hepatology 2000;31:1115-22. 15. Thibodeau A. Metalloproteinase inhibitors. Cosmet Toilet 2000;115: 75-6.

501 16. Rizer R, Turcott A, Edison B, et al. An evaluation of the tolerance profile of a complete line of gluconolactone-containing skin care formulations in atopic individuals. Skin Aging 2001;9(suppl):18-21. 17. Rizer R, Turcott A, Edison B, et al. An evaluation of the tolerance profile of gluconolactone-containing skin care formulations in individuals with rosacea. Skin Aging 2001;9(suppl):22-5. 18. Draelos ZD, Green BA, Edison BL. An evaluation of a polyhydroxy acid skin care regimen in combination with azelaic acid 15% gel in rosacea patients. J Cosmet Dermatol 2006;5:23-9. 19. Van Scott EJ, Yu RJ. Actions of alpha hydroxy acids on skin compartments. J Geriatr Dermatol 1995;3(suppl A):19-24. 20. Kim SJ, Park JH, Kim DH, et al. Increased in vivo collagen synthesis and in vitro cell proliferative effect of glycolic acid. Dermatol Surg 1998;24:1054-8. 21. Bernstein EF, Lee J, Brown DB, et al. Glycolic acid treatment increases type I collagen mRNA and hyaluronic acid content of human skin. Dermatol Surg 2001;27:1-5. 22. Green BA, Edison BL, Wildnauer RH, et al. Lactobionic acid and gluconolactone: PHAs for photoaged skin. Cosmet Dermatol 2001;9: 24-8. 23. Van Scott EJ, Ditre CM, Yu RJ. Alpha-hydroxyacids in the treatment of signs of photoaging. Clin Dermatol 1996;14:217-26. 24. Lavker RM, Kaidbey K, Leyden J. Effects of topical ammonium lactate on cutaneous atrophy from a potent topical corticosteroid. J Am Dermatol 1992;26:535-44.