The hydroxy acids: Where have we been and what's new?
Abstract
Background
Hydroxy Acids (HAs) have been used for the treatment of a variety of skin conditions over the past several decades. The use of HAs in both pharmaceutical and cosmetic products has increased dramatically, and recent studies have been undertaken to better understand their applications and therapeutic benefits.
Objective
The objective of this review is to study the uses of HAs and the emerging ingredients in the area of skin care. Relevant studies were reviewed and categorized by their molecular structure into alpha HAs (AHAs) beta HAs (BHAs) and poly HAs (PHAs).
Methods
A literature search on the use of HAs was performed and articles for review were selected from more recent dermatological studies published from 2018 to 2023. Older research was compared to the results of newer studies to identify the more recent developments in the application of HAs in skin care.
Results
The new research was concentrated in the area of new uses of the HAs, validating therapeutic concentrations and protocols, and combining different HAs and other chemicals to improve therapeutic outcomes for a variety of skin conditions and diseases.
Conclusion
The articles included for review demonstrate the continuing therapeutic relevance and developments in the application of HAs in skin care.
1 INTRODUCTION
Hydroxy acids (HAs) are naturally derived organic acids which have been utilized in the management of various dermatoses.1 Types of HAs include alpha HAs (AHAs), beta HAs (BHAs) and the newer generation of poly HAs (PHAs). For example, AHAs such as glycolic acid can be found in sugar cane, while lactic acid (LA) is present in milk and fruits. BHAs such as citric acid are naturally occurring in citrus fruits, and salicylic acid (SA) is derived from willow bark. HAs were first introduced five decades ago and were originally researched and documented as a treatment for ichthyosis.2 However, the market and therapeutic potential of HAs have expanded significantly since then.
1.1 Market value and consumer knowledge
Due to the influence of social media, the awareness of targeted ingredients for specific skin concerns has grown. For example, niacinamide has been shown to combat skin photoaging and dyspigmentation,3 hyaluronic acid may act as a humectant to draw moisture to the skin,4 and HAs have been shown to act as a keratolytic for acne and other hyperkeratotic disorders, increase epidermal turnover, and act as antioxidants to improve photoaged skin.5 Notably, HAs, which were once prescription-only, are now widely available in various over-the-counter skin care products and cosmeceuticals.6 Glycolic acid, LA, and SA are the most used in cosmetics.7 In lower concentrations, HAs are added to many cosmetics and skin creams such as exfoliants and moisturizers and antiaging lotions. In higher prescription-only concentrations (>20%), they can be used as peels to treat conditions such as acne and psoriasis.8 The market value for hydroxy acid products was valued at USD 1438.9 million in 2022 and is expected to grow at a rate of 9.1% from 2022 to 2028.9 An increasing public concern for natural beauty has also contributed to the increased demand for organically sourced ingredients.10
1.2 Types of HAs
1.2.1 AHAs
AHAs are carboxylic acids that have a hydroxyl group attached to the α-position of the carboxyl group. AHAs are water-soluble and thus work primarily on the skin's surface, exfoliating the outermost epidermal layer and promoting cell turnover. The most commonly used AHAs include glycolic, lactic, mandelic, malic, tartaric and citric acid.11, 12
1.2.2 BHAs
BHAs are carboxylic acids with a hydroxyl group attached to the β-position of the carboxyl group. BHAs are lipid-soluble and can penetrate into the pores which contribute to their exfoliative, comedolytic, and anti-inflammatory properties.1 The most common BHA is SA. Malic, tartaric and citric acids are BHAs which are classified as AHAs due to the position of another hydroxyl group at the a-position, which is dominant to the beta hydroxyl group.7
1.2.3 PHAs
PHAs are carboxylic acids with two or more hydroxyl groups attached at various positions within a molecular structure. The numerous hydroxyl groups enable PHAs to function as humectants, binding water within the epidermis and thus leading to enhanced moisturizing properties.13 PHAs are regarded as the new generation of AHAs, offering effects similar to AHAs without inducing the discomfort and irritation that is often associated with conventional AHAs.14 The three most frequently encountered PHAs include gluconolactone, lactobionic acid (LA), and galactose. These acids exhibit similar chemical characteristics including mild exfoliating effects, humectant properties, and are suitable for sensitive skin.
1.3 Mechanisms of action
The mechanism of action of HAs remain unclear, however, HAs are thought to influence epidermolysis and keratolysis. One theory is that AHAs reduce the Ca ion concentration in the epidermis and disrupt Ca ions that reduce cellular adhesion and induce exfoliation.15 Other studies suggest that glycolic acid promotes collagen production,16, 17 increases the hyaluronic content of skin,16 and modulates inflammatory cytokine and growth factor secretion.18 BHAs such as SA and its derivatives have also been found to have photoprotective and antimicrobial effects,19 Further studies have shown that topical HAs increase hydration, increasing epidermal thickness and levels of hyaluronic acid, and collagen gene expression to improve skin's appearance, texture and function.7 GA blocks UVB-induced inflammatory cytokines through the nuclear factor kappa B single pathway.
1.4 Objective
This review is intended to provide an overview of the prior and current uses of HAs in dermatological applications, and to review the most current studies to report recent developments in the knowledge and use of the HAs. Because they are ubiquitous in the cosmetic and skin care product industry, it is important keep up with the emerging literature about the safety and use of HAs. This review is intended to include new information on safety, efficacy, and applications of HAs as it pertains to dermatological health.7
2 METHODS
A literature search was performed using the PubMed database and Google Scholar. Articles for review were selected from more recent dermatological studies on the use of HAs with the criteria of those published from 2018 to August 2023. The search terms used in the Pubmed database included: HAs skin, AHAs skin, BHAs skin, PHAs skin. A search for older articles included those from 1997 onward were also accessed to determine the previous knowledge base.
3 DISCUSSION
3.1 AHAs
3.1.1 Old established uses
HAs have been used in cosmetics and dermatology for more than five decades. Their clinical use depends on pH, concentration, formulation, and application time. Research conducted over the years has studied their effectiveness and safety20; therapeutic regimens have been based on the results of this research. For example, a randomized controlled trial completed in 2007 demonstrated that 30% glycolic and 30% SA peels were similarly effective for the treatment of acne vulgaris.21 An article published in 2010 reviewed and summarized the literature up until that date.7 At that time, A number of clinical studies reported that topical application of glycolic acid can increase sensitivity of the skin to solar-simulated radiation (SSR).22
A published study that showed that glycolic acid not only directly accelerates collagen synthesis by fibroblasts, but that it also modulates matrix degradation and collagen synthesis through keratinocyte-released cytokines.17 This study suggested that glycolic acid contributes to the recovery of photodamaged skin. In another study, sun-damaged forearm skin was treated with 20% glycolic acid lotion or a lotion vehicle control (oil in water; pH 3.9) twice a day for 3 months. The authors found that the glycolic acid protocol increased epidermal thickness and levels of hyaluronic acid.16 The results of such studies have formed the basis of cosmetic and therapeutic indications of HAs.
What's New
3.1.2 Glycolic acid
AHAs make up the majority of HAs, such as GA on the skin, and of these, GA is the most prevalent. Newer studies attempt to determine the optimal and safe therapeutic concentration of GA. One animal study aimed to evaluate the dose dependent effects of GA on the skin.12 High (5 mM; pH 7.1) and low (0.1 mM; pH 7.4) concentrations of GA were utilized to examine the photoprotective or phototoxic properties of GA in UVB-radiated skin keratinocytes. This study found that GA may have an anti-inflammatory effect via epigenetic modifications at low concentrations, whereas GA at high concentrations (5 mM) will disrupt the cohesion of skin barrier corneocytes, and results in skin irritation or peeling, which will exacerbate photodamage of the skin.12
In a related study from 2021, the efficacy and biological effects of GA in a range of relative concentrations was evaluated.23 Human skin explants were topically treated with gel formulations and oil-in-water creams containing 8%, 10%, 15%, or 25% GA, adjusted to pH 4, daily for 5 days. The degree of desquamation, their effect on cell proliferation, and their impact upon total collagen levels were determined 24 h later. The results showed that collagen levels were increased in all concentrations, with a dose dependent response relative to the increased levels of GA. The new study also confirmed its skin rejuvenation properties.23
3.1.3 Mandelic acid (MdcA)
MdcA is another alpha hydroxy acid that has been shown to be effective in treatment of skin disorders. Notably, MdcA has been previously shown to be effective in the treatment of acne and hyperpigmentation.24 A separate study undertook to objectively research the viscoelastic changes to the skin following treatment with topical MdcA.25 Twenty-four patients were topically administered MdcA twice daily for 4 weeks. Results on the lower eyelid skin were measured using the Cutometer MPA 580. The elasticity of lower eyelid skin increased 25.4% (p = 0.003). Skin firmness increased 23.8% (p = 0.029).25 This study confirms that besides the therapeutic use of MdcA for acne and hyperpigmentation, MdcA can be effective in increasing skin elasticity.
3.1.4 LA and ferulic acid (FA) peel
Older studies confirmed the use of a LA peel as a successful treatment for melasma.26 Newer research often aims to refine therapeutic concentrations and newer applications, and combine therapies for better efficacy. This 2021 study compares the efficacy of a chemical peel of FA and LA for the treatment of photoaging.27 A randomized group of 30 patients were treated with ferulic peel 12% (hydroalcohol base), and 30 patients with a combination peel of LA 30% with FA peel 12%. The results showed a significantly greater improvement in patients treated with a combined LA and FA peel as compared to patients treated with the ferulic peel alone. This study demonstrates that the combination of FA/LA peel is more effective than that of LA alone in the treatment of photoaging and, that AHAs remain relevant to successful dermatological therapy.27
3.1.5 Malic acid
The HA dl-Malic acid (dl-MA) has historically been used in cosmetic formulations as a pH-adjuster exfoliator or as a preservative.28 A 2019 study determined to research its effect on atopic dermatitis as induced by 2,4-dinitrochlorobenzene. Immune cell thickness and infiltration into the dermis and epidermis. serum levels of cytokines, and mitogen-activated protein kinase and nuclear factor-kappa B in tissue were measured in AD mice treated with dl-MA. Inflammatory mediators in a human keratinocyte cell line were also assessed. The results suggested that dl-MA significantly improves the skin condition of mice with AD.28, 29 This study was able to demonstrate a newer application for MA as a treatment for AD.
Another study of caffeoyl malic acid (CMA) for the treatment of AD.30 Tumor Necrosis Factor-a (TNF-α) is actively involved in inflammation processes and Interleukin-4 (IL-4) is a key cytokine in the development of the allergic inflammation. This study investigates CMA via network analysis-deep learning-molecular simulation to identify key therapeutic targets and screening of potential multi-target drugs for the treatment AD. From the traditional Chinese medicine database in Taiwan, and computer algorithms, they identified that the CMA molecule was able to inhibit the key therapeutic targets of TNFa and IL-4. The study findings suggest that CMA is a potential dual TNF-α/IL-4 inhibitor for the treatment of AD.30
A study evaluated whether some combination therapies would show increased efficacy over monotherapies with the same HAs.31 The study evaluated the effectiveness of a topical combination of alpha- and beta-HAs, antibacterial molecules and Herculean thermal water as applied to acne-prone skin over a 28-day period. The use of RCM technology was able to assess microscopic changes occurring inside infundibula and the inter-infundibular epidermis. The study included 40 subjects. The study design was to determine if changes to the skin could be measured using the RCM technology soon after the start of treatment. At the end of the study on day 28, the number of follicles colonized by Cutibacterium acnes was significantly reduced (p = 0.003).31 This new combination protocol which included AHA and BHA was demonstrated to be effective to treat acne prone skin. The authors also demonstrated the advantage of the newer RCM technology in the study of HAs.
3.1.6 New concerns for consumer safety
In 1997 the first social media platform was launched. Since then, the public has increasingly turned to social media for advice on health and wellness. An article considered the effect of social media on the dissemination of information. The authors assessed 900 Instagram posts on the subject of acne. The authors found that the majority of the content was generated by influencers, followed by retailers and non-dermatologist providers. Dermatologists were responsible for only 17 posts. This study also found that only 11% of posts referenced a treatment with grade A evidence based on AAD guidelines.32 It is a new trend that direct advice from dermatologists is now losing ground to influencers and other social media sources. Also, skin care products are now being obtained to a much greater extent from online sales. These products often come from unregulated sources, and chemical levels are not always at safe levels, or labeled correctly.33 Self-prescribed and incorrectly labeled products could be harmful to consumers.
3.2 BHAs
3.2.1 Old Established Uses
SA has been widely used in cosmetic and therapeutic formulations keratolytic agent to treat skin conditions, such as keratoses, acne, and photoaging.7 SA is applied in various concentrations, pHs, and formulations depending on the type and severity of condition. A 2002 study has shown that SA is also photoprotective.34 A C-8 derivative of SA known as β-lipohydroxy acid (βLHA), was developed in the late 1980s, and was shown to be an exfoliant and a successful treatment of photoaged skin and acne.35 In 2010, PHAs and PHBAs were reported to represent the next generation of αHAs for use in cosmetic and dermatologic skin care.7 Studies at the time showed that PHAs and PHBAs provide clinically proven antiaging and skin-smoothing effects that are comparable to αHAs, while offering several therapeutic advantages. βLHA also has antibacterial effects, which has been utilized in the treatment of acne.36 These therapeutic uses of SA and its derivatives continue to be relevant in the treatment of applicable skin conditions. Newer studies build on these attributes to innovate and improve on therapeutic protocols.
What's New
3.2.2 SA
The most common form of BHA used in skin care formulations is SA and it is still a subject of continuing research. SA has been utilized at different concentrations for a variety of applications. Lower dosages of 1 to 6% daily of topical creams and gels have been recommended for conditions such as acne. For adult psoriasis or seborrheic dermatitis, a higher concentration of up to 10% ointment as needed. SA peels of 30% at a lower frequency were described as well tolerated in the treatment of mild to moderate acne.37 These applications were found to be effective, with few side effects other than mild skin irritation More recent research continues to compare other potential effective treatments. A 2021 study compared the clinical efficacy and safety of 25% trichloroacetic acid (TCA) and 30% SA peels in the treatment of mild and moderate acne vulgaris.38 Patients were randomized to receive either the TCA or SA peels at 2-week intervals for 12 weeks. Photographs were taken at 2-week intervals and improvement was assessed. The study found that the mean comedone and pustule counts at the end of therapy were significantly lower than the baseline values in both groups. In terms of safety and tolerability, the 30% SA peel was determined to be better than the 25% TCA peel, as a greater number of patients in the 25% TCA peel group developed adverse effects such as burning and stinging. Thus, SA peels remain comparable to newer options such as TCA.
Newer research into SA includes different modes of application and endeavors to decrease the time interval for improvement. Dense comedones are often difficult to treat in patients with acne vulgaris. One study attempted to increase the efficacy of treatment in less time. In a split face trial, 30 patients with even comedone distribution were assigned to 30% supramolecular SA (SSA) combined with CO2 laser or CO2 laser monotherapy every 2 weeks for six treatments.39 At the end of the study, the mean reduction rate of the combined-SSA side was 85.76%, and that of the CO2 laser-treated side was 62.32% (p < 0.001). The treatment that included the SSA was significantly better than laser alone. transepidermal water loss (TEWL) and Hydration Index were also measured with no significant differences.
Formulations of SA including other active ingredients are also being studied. One 2023 study sought to improve the efficacy of SA in the treatment of Cutibacterium acnes.40 This study modified a SA-based ionic pair with l-carnitine (the authors named IP-BHA). The study attempted to reduce the irritation and low efficacy of the current pH neutral SA preparations. They also studied the combination of IP-BHP effect with and without magnolol, a bioactive organic lignan derived from a species of magnolia. Although IP-BHA and magnolol achieved excellent erythema alleviation effects when applied individually, the simultaneously applied group showed a better improvement effect. The erythema recovery rates were 81.9% on Day 12 with statistical significance. The Minimum Inhibitory Concentration of IP-BHA at pH 5.5 was found to be equivalent to that of original SA, however, the combined application of IP-BHA and magnolol was demonstrated to be much more effective in antibacterial activity. The study was a randomized, double-blind, placebo-controlled clinical evaluation on 20 volunteers aged 20−35 years. with rigorous evaluation of factors such as: MMP-1 and VEGF inflammatory-related factors, sebum secretion regulation through inhibition of lipogenesis, (evaluated in testosterone-induced lipogenesis assays using SZ95 cells), and absorption spectroscopic analyses of IP-BHA. This study showed that IP-BHA and magnolol both target the main mechanisms of acne, and it is expected that they could be this study showed that IP-BHA and magnolol could be used in combination to target the mechanisms of acne. The authors conclude that future research could be done to develop a hypoallergenic and effective antiacne product containing IP-BHA and magnolol.40 This recent research demonstrates that SA can be more effective when combined with other products.
3.3 Polyhydroxy acid
3.3.1 Old established uses
The range of applications for HAs in cosmetics and dermatology has evolved across the past few decades. Previous uses for AHAs were initially identified during the early 1970s, discovering AHAs contribution in promoting antiaging, effects, refining skin texture, and offering exfoliative properties.14 A new derivative category of AHAs, known as PHAs, are considered the new generation of AHAs. PHAs are known to offer comparable effects as AHAs without the skin sensitivity reactions observed with AHA usage; they are suitable in treatment of skin conditions associated with hypersensitivity, such as atopic dermatitis and rosacea, making them also applicable for post-cosmetic usage. To further evaluate the distinction between AHAs and PHAs, a 12-week clinical trial conducted in 2004, directly compared the two HAs by assessing the antiaging effects and skin tolerability of products containing gluconolactone, a commonly used PHA in skin care, and those containing glycolic acid. The results of the clinical study revealed that both the gluconolactone and glycolic acid regimens demonstrated significant antiaging benefits. Skin resilience was measured through pinch recoil and various other skin parameters were measured through silicone replicas and clinical grading. Through self-assessment and skin tolerability evaluations, the PHA regimen was overall tolerated better compared to the AHA regimen. Participants in the AHA treatment group reported higher incidence of stinging and burning with application of glycolic acid in both week 6 and week 12. Sensitivity level was also rated more severe in the AHA regimen. Advancement of research into the properties and mechanisms of PHAs has allowed an expansion of their novel applications.14
What's New
3.3.2 Gluconolactone
Presently, PHAs have evolved to offer a broader range of dermatological applications including treating various dermatoses. PHAs penetration into the stratum corneum is less forceful compared to AHAs, due to their larger molecular size. 41PHAs are gradually absorbed into the skin without increasing skin irritation thus are less likely to disrupt the skin's barrier function.41 In a recent study conducted in 2023, the research focused on the antioxidant and moisturizing functions of gluconolactone when used as a chemical peel, particularly due to this PHA providing a protective effect on elastin fibers exposed to UV-driven degenerative effects.41 They investigated the functionality of 10% and 30% gluconolactone chemical peel effects upon sebum shifts, pH and TEWL.41 The results of this study revealed that even at 10% level, gluconolactone was successful in reducing sebum production, pH and TEWL within the 16 volunteer participants involved in this study.
3.3.3 LA
LA, another common PHA used in skin care products, can serve as an effective skin barrier, and can decrease pH of the skin surface without irritation as revealed in a 2019 study.42 The study conducted represents a novel approach in treatment of inflammatory dermatoses; it investigates whether the application of an emulsion containing 10% LA can lower the pH of the skin surface without triggering an inflammatory response. The results of the study revealed that after application of the LA emulsion there was reduction in the pH of the skin surface without compromising the skin barrier or causing an adverse reaction.42 The combination of PHAs and exfoliation has become popular in the realm of skin care treatments. Another study assessed the efficacy of a LA peel at 20% alone and when used in conjunction with aluminum oxide crystal microdermabrasion.13 This was a split face method, in which 20% of LA (lactobionic acid) was used on the left side of the face, and aluminum oxide crystal microdermabrasion that was followed by 20% LA was applied to the right side of the face, involving 20 female participants.13 These participants received a total of 6 treatments at weekly intervals. The study assessed skin hydration, elasticity, and TEWL at 1, 3, and 6 weeks. The results indicated an improvement in skin elasticity and hydration on the side where the combined procedure was performed. There was also a decrease in the TEWL in both treatments, signifying an improvement in moisture retention and skin barrier integrity.13 This ongoing research is important to verify efficacy, and to be able to minimize the concentrations of chemical use on skin where possible. These new studies confirm that PHAs are both effective and safe, however there appears to be a limited amount of new published research into these formulations.
4 CONCLUSION
HAs have been used for decades in cosmetic and therapeutic formulations to treat a variety of skin conditions. The most often used classes of these compounds are AHAs, BHAs and PHAs. These products were used in varying concentrations to treat conditions including photoaging, acne, ichthyosis, rosacea, psoriasis, and psoriasis. HAs are currently found in an increasing number and variety of cosmetic products available for sale from both prescription, retail and on-line sources with clinical implications. New research includes combining HAs and adding other chemicals to enhance the efficacy of the HA alone. Continuing research is necessary to validate claims about the efficacy and safety of less regulated cosmetic products, and to continue to improve the knowledge of the mechanism and effects of HAs. The articles reviewed here represent new research on the safety and therapeutic relevance of HAs. This table is summarized in Table 1. All studies showed statistically significant results, however, they were completed with a small sample size over a short experimental period. Also, some of the studies were conducted in vitro and these results cannot be reliably extrapolated to clinical application. Further research should be completed in these areas. Overall, the articles included in this review demonstrate the continuing therapeutic relevance and developments in application of HAs in skin care.
| Type of hydroxy acid | Derived from43 | Old uses43 | New applications/findings |
|---|---|---|---|
| AHAs (water soluble) | |||
| Glycolic Acid | Sugar cane | Accelerates collagen synthesis, recovery of photodamage, increase epidermal thickness, increased hyaluronic acid, improve acne and acne scars in peels or daily in lotion and creams epidermal type melasma |
Low concentration (0.1 mM): photoprotective High concentration (5 mM): phototoxic12 Increased collagen from 8 to 25% relative to concentration23 |
| Lactic Acid | Milk | Decreased melasma, Stimulates collagen synthesis hydration |
Photoaging improvement 30% concentration with better results with addition of 10% ferulic27 |
| Mandelic Acid | Almonds | Acne, acne scars Antimicrobial Increased collagen production |
Firmness and elasticity, early response to treatment25 |
| Tartaric Acid | Grapes | Acne, exfoliation | Not reviewed |
| Malic Acid | Apples and pears | Hydration, exfoliation, photoaging, preservative Increased collagen production |
Improved atopic dermatitis in mice28 With caffeoyl: inhibits TNF-α/IL-4 treatment of AD30 |
| Citric Acid | Citrus fruits | Hydration, exfoliation, aging | Not reviewed |
| Ferulic Acid | Exfoliates decreased melasma, anti-inflammatory |
Photoaging improvement 10% concentration with better results with addition of 30% lactic27 | |
| BHAs (lipid soluble) | |||
| Salicylic Acid | Willow bark | SA (and derivative βLHAs antimicrobial, acne, exfoliate-inflammatory, antifungal, and anti-comedogenic properties. Photoprotective |
Acne: 1 to 6% daily37 Psoriasis: 30% less frequent AD: 30% less frequent Acne: 30% peel less frequent SSA with CO2 laser improved IP-BHA and magnolol target acne39 |
| PHAs | |||
| Lactobionic Acid Galactose | Milk | Antiaging and skin-smoothing effects humectant and moisturizer antioxidant chelation effects |
Lactobionic acid with aluminum oxide crystal microdermabrasion shows increased elasticity and moisturizing13 |
| Gluconolactone | Milk | Photoaging reduction and skin-smoothing effects humectant and moisturizer antioxidant chelation effects |
Increased skin hydration in both 10% and 30% protocols44 |
- Abbreviations: AD, atopic dermatitis; IL-4, interleukin 4; IP-BHA, salicylic acid with l-carnitine; SA, salicylic acid; SSA, supramolecular salicylic acid; TNFa, tumor necrosis factor alpha.
ACKNOWLEDGMENTS
N/A.
CONFLICT OF INTEREST STATEMENT
R. K. S. serves as a scientific advisor for LearnHealth, Arbonne, and Codex Labs and as a consultant to Burt's Bees, Novozymes, Nutrafol, Abbvie, Sanofi, Fotona, Incyte, Leo, UCB, Novartis, Biogena, Pfizer, Bristol Myers Squibb, Lilly, Sun and Regeneron Pharmaceutical.
Open Research
DATA AVAILABILITY STATEMENT
There is no primary data that is available and all data supporting the findings are within the referenced manuscripts.
