Cosmeceuticals
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Cosmeceuticals Aesthetic Dermatology Vol. 5 Series Editor D.J. Goldberg New York, NY   Cosmeceuticals Volume Editors J. Comstock Tucson, AZ M.H. Gold Nashville, TN 19 figures, 15 in color, and 17 tables, 2021 _______________________ Jody Comstock Department of Dermatology University of Arizona Tucson, AZ (USA) jcommd@gmail.com _______________________ Michael H. Gold Gold Skin Care Center Tennessee Clinical Research Center Nashville, TN (USA) drgold@goldskincare.com Library of Congress Cataloging-in-Publication Data Names: Comstock, J. (Jody), editor. | Gold, Michael H., editor. Title: Cosmeceuticals / volume editors, J. Comstock, M.H. Gold. Other titles: Cosmeceuticals (Comstock) | Aesthetic dermatology (Series), 2235-8609 ; v. 5. Description: Basel ; Hartford : Karger, [2021] | Series: Aesthetic dermatology, 2235-8609 ; vol. 5 | Includes bibliographical references and indexes. | Summary: “The purpose of this book is to show how cosmeceuticals (defined as a skin care product with bioactive ingredients, which have a desired effect on the skin) work for a variety of skin care concerns, and in concert with cosmetic procedures commonly used by dermatologists and cosmetic physicians”-- Provided by publisher. Identifiers: LCCN 2020046787 (print) | LCCN 2020046788 (ebook) | ISBN 9783318066890 (hardcover : alk.

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Cosmeceuticals
Aesthetic Dermatology
Vol. 5
Series Editor
D.J. Goldberg New York, NY
 
Cosmeceuticals
Volume Editors
J. Comstock Tucson, AZ
M.H. Gold Nashville, TN
19 figures, 15 in color, and 17 tables, 2021
_______________________ Jody Comstock Department of Dermatology University of Arizona Tucson, AZ (USA) jcommd@gmail.com
_______________________ Michael H. Gold Gold Skin Care Center Tennessee Clinical Research Center Nashville, TN (USA) drgold@goldskincare.com
Library of Congress Cataloging-in-Publication Data
Names: Comstock, J. (Jody), editor. | Gold, Michael H., editor.
Title: Cosmeceuticals / volume editors, J. Comstock, M.H. Gold.
Other titles: Cosmeceuticals (Comstock) | Aesthetic dermatology (Series), 2235-8609 ; v. 5.
Description: Basel ; Hartford : Karger, [2021] | Series: Aesthetic dermatology, 2235-8609 ; vol. 5 | Includes bibliographical references and indexes. | Summary: “The purpose of this book is to show how cosmeceuticals (defined as a skin care product with bioactive ingredients, which have a desired effect on the skin) work for a variety of skin care concerns, and in concert with cosmetic procedures commonly used by dermatologists and cosmetic physicians”-- Provided by publisher.
Identifiers: LCCN 2020046787 (print) | LCCN 2020046788 (ebook) | ISBN 9783318066890 (hardcover : alk. paper) | ISBN 9783318066906 (ebook)
Subjects: MESH: Cosmeceuticals--pharmacology | Cosmeceuticals--therapeutic use
Classification: LCC RL87 (print) | LCC RL87 (ebook) | NLM QV 60 | DDC 613/.488--dc23
LC record available at https://lccn.loc.gov/2020046787
LC ebook record available at https://lccn.loc.gov/2020046788
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents ® .
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2021 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed on acid-free and non-aging paper (ISO 9706)
ISSN 2235–8609
e-ISSN 2235–8595
ISBN 978–3–318–06689–0
e-ISBN 978–3–318–06690–6
 
Contents
Preface
Comstock, J. (Tucson, AZ); Gold, M.H. (Nashville, TN)
Cosmeceuticals and Delivery Mechanisms: Skin Function and Skin Barrier
Almukhtar, R.M.; Fabi, S.G. (San Diego, CA)
Evaluating Cosmeceuticals
Draelos, Z.D. (High Point, NC)
Cosmeceutical Using Alpha, Beta and Polyhydroxy Acids
Ladenheim, L.A.; Marmur, E.S. (New York, NY)
Cosmeceuticals Using Vitamin A and Its Derivatives plus New Delivery Methods for Them
Kim, A.; Weinkle, S.H. (Tampa, FL)
Cosmeceuticals Using Vitamin C and Other Antioxidants
Barnes, L.E.; Mazur, C.; (Virginia Beach, VA); McDaniel, D.H. (Virginia Beach, VA/Hampton, VA/Norfolk, VA)
Cosmeceuticals Using Growth Factors and Stem Cells
Taub, A.F. (Lincolnshire, IL)
Cosmeceuticals Using Peptides, Amino Acids, Glycosaminoglycans and Other Active Ingredients
Bucay, V.W. (San Antonio, TX)
Specific Use: Cosmeceuticals for Daily Skin Maintenance Optimizing Tone, Texture, and Tightening
Ehrman Tedaldi, R. (Wellesley, MA); Braun Levin, L.; Glick, J.B. (New York, NY)
Cosmeceuticals for Acne and Rosacea
Turegano, M. (Metairie, LA); Farris, P. (Metairie, LA/New Orleans, LA)
Specific Use: Cosmeceuticals for Skin Brightening and Lightening
Burgess, C. (Washington, DC); David, J. (Philadelphia, PA)
Specific Use: Cosmeceuticals for Body Skin Texture and Cellulite Treatment
Lindgren, A. (New Orleans, LA); Hui Austin, A.; Welsh, K.M. (San Francisco, CA)
Specific Use: Cosmeceuticals for Hair Loss and Hair Care
Holman, J. (Tyler, TX)
Specific Use: Cosmeceuticals for the Treatment of Scars, Hypertrophic Scars, and Keloids
Boen, M.; Alhaddad, M.; Butterwick, K. (San Diego, CA)
Cosmeceuticals for Sun Protection, Daily Repair, and Protection from Pollution
Shamban, A. (Santa Monica, CA)
Cosmeceuticals following Cosmetic Procedures Including the Use of Facial Mask
Aristizabal, M. (Bogota); Gold, M.H. (Nashville, TN)
Nutraceuticals and Diet for Healthy Skin
Comstock, F. (Tucson, AZ)
The Future of Cosmeceuticals
Comstock, J. (Tucson, AZ)
Author Index
Subject Index
 
Published online: January 19, 2021
Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp VII–VIII (DOI: 10.1159/000491839)
Preface
During my dermatology residency at the University of Arizona in the late 1980s, I had begun to notice an unanswered patient demand for the treatment of pigmentation, redness, large pores, accelerated aging due to photodamage, natural aging, and scar tissue that was leaving patients with uneven, rough or tired, dull skin. The University of Arizona was just completing their arm of a Retin A study that showed the cosmetic benefits of retinoids and wrinkle treatment. It was the beginning of a transitional time in dermatology. When I completed my residency, I was fortunate to fall into a small, personalized training in Beverly Hills with Dr. Zein Obagi. While there, I witnessed the potent efficacy of medical-grade topical skin care. It specifically was able to erase melasma that had been relentlessly and unsuccessfully treated with more traditional means. These experiences began a lifelong intrigue with skin care science that became the foundation of my career.
When I began my private dermatology practice in 1991, I immediately started carrying skin care products in my clinic, much to the dismay of the local dermatology community. However, my patients were thrilled to be able to purchase products that cost less than what they had been spending and provided an extension of the care they received in my office. The combination of growing patient demand, patient satisfaction, and avoiding the misery of dealing with health insurance quickly pushed me to redirect my practice to focus solely on the evolving subspecialty of cosmetic dermatology at a time when that was unheard of. I have never looked back. Cosmeceuticals afford every person a safe, at-home means of improving skin tone and texture, as well as maximizing global improvement and healing after medical aesthetic procedures.
Over the years I have been able to advise excellent skin care leaders, including Skin Medica, Colorescience, Physician’s Choice of Arizona, Skinceuticals, Sente, Obagi, and ZO Skin Health. In 2014, I was named the Cosmetic Medical Director for Skinbetter Science, an exciting and science-laden skin care line led by my friend, colleague, and mentor Jonah Shacknai. These companies have taken peptides, proteins, antioxidants, nonirritating retinoids, and more to the next level, using more natural ingredients and conducting controlled studies to thoroughly test them. You will read about the incredible advances in topical treatment options made by these companies and more throughout the thoughtful chapters in this book.
The world of cosmeceuticals is an exciting mix of innovative science, strict regulations, and fast-paced consumer business practices. All of this is tempered by our medical oath to do no harm and act in the best interest of our patients. I am proud to say that the critical role of cosmeceuticals continues to gain respect in the dermatology community, and a faculty position was created in 2016 for me to teach this important topic to dermatology residents at the University of Arizona. I thank Dr. James Sligh for his commitment and vision to making this happen. New ideas take time.
I was thrilled when Dr. Michael Gold invited me to be his co-editor of this book. Watching my dermatology colleagues extend their talents to also become cosmeceutical entrepreneurs with devices, products, and business platforms has been a great joy, and we hope this book helps you on your skin care and science journey. Dr. Gold is bright, kind, entrepreneurial and incredibly passionate about skin care and dermatology. It has been nothing but a pleasure working with him.
Cosmeceuticals have created an explosion of opportunity to optimize healthy and beautiful skin. I am grateful to be a cosmetic dermatologist with an array of treatment and business tools in my practice. The joy of facilitating my patients to achieve their best and healthiest skin is only superseded by their appreciation. The best thing about cosmeceuticals is that there is always more to come!
Conflict of Interest Statement
Dr. Comstock has worked as a consultant, advisor, or instructor for: Skinbetter Science, Allergan, Gladerma, Revance, Evolus, and Endo.
Jody Comstock , Tucson, AZ
The world we call cosmeceuticals has grown at an astounding rate over the past several years. We have more and more cosmeceuticals being developed, which have helped many of our patients achieve healthier and more rejuvenated skin.
A cosmeceutical is defined as a skin care product with bioactive ingredients, which have a desired effect on the skin. They have no actual claims of changing the structure and function of the skin in the eyes of the US FDA, but those cosmeceuticals that dermatologists and cosmetic physicians use and recommend to patients and clients definitely play a major role in skin care.
Many companies make skin care products that they call cosmeceuticals. Many have very nice science behind them. It is the purpose of this book to show the reader how these cosmeceuticals work for a variety of skin care concerns, and in concert with our most commonly used cosmetic procedures.
The term cosmeceutical was coined by Dr. Albert Kligman in the 1990s using the terms cosmetic and pharmaceutical, to show that they acted like a cosmetic but had attributes of pharmaceuticals. Again, no claims are made by the companies that make these products.
Those in dermatology are lucky to have mentors and teachers that spark our interest and command our curiosity. I am fortunate that Dr. Kligman became my dermatologist when I was 16 years old. I suffered from a very bad case of cystic acne vulgaris. Dr. Kligman prescribed me a solution to use on my skin and told me to use a little bit every night. Well, being a smart 16 year old, I figured that if a little worked, a lot worked even better. So instead of a little, I put a lot of this solution on my skin every night. By night three, I realized I was not going to be having a fun next few days. What I found out was that Dr. Kligman had given me a 5% tretinoin solution and then I proceeded to have a medium depth chemical peel over the next week. I stayed home from school, was miserable, and in quite some discomfort. When all was said and done, my acne was gone, and now some 45 years later, I rarely get an acne lesion. To this day, Dr. Kligman was the inspiration for me to become a dermatologist, and with my later mentor, Dr. Henry Roenigk, this dream became a reality. It was also amusing to see Dr. Kligman at some of the dermatology conferences. When I lectured, he always seemed to quiz me to make sure that I was continuing with my studies, even while practicing dermatology. I was very fortunate.
I was also very lucky to have an incredible editor partner for this project. Dr. Jody Comstock is a rock star and someone that has been a true professional, and through this process a good friend. I thank her for her dedication and her commitment to this project. It has been a pleasure working with her.
Conflict of Interest Statement
Dr. Gold declares that he has been a consultant and/or performed clinical research for: Defenage, Stratacel, Alastin, Revision, and Topix.
Michael H. Gold , Nashville, TN
 
Published online: January 19, 2021
Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)
______________________
Cosmeceuticals and Delivery Mechanisms: Skin Function and Skin Barrier
Rawaa M. Almukhtar a Sabrina G. Fabi a , b
a Cosmetic Laser Dermatology, Goldman, Butterwick, Groff, Fabi and Boen, San Diego, CA, USA; b Department of Dermatology, University of California, San Diego, CA, USA
______________________
Abstract
Cosmeceuticals represent one of the fastest growing segments of personal care products. Advances in the field of skin biology and pharmacology have facilitated the development of novel active compounds. The increase in the number of active ingredients delivered topically through the skin has led to a heightened importance of understanding the mechanisms of delivery of those active ingredients. Ideal delivery of actives aims at a high delivery capacity, formulation stability, and minimal side effects. There are two pathways for the delivery of cosmeceuticals: transepidermal and a transappendageal pathways. Delivery systems can be divided into active systems and passive systems. Active systems use physical enhancement methods, like sonophoresis, ionophoresis, micro-needling, micro-dermabrasion, and ablative, nonablative, and fractional laser delivery methods. Passive systems utilize chemical delivery methods including chemical penetration enhancers, emulsions, vesicular lipid-based systems, and lipid particulate carrier systems. Here we review the mechanisms of delivery of active ingredients through the skin and the systems by which they are delivered through the epidermis.
© 2021 S. Karger AG, Basel
The stratum corneum (SC) provides a strong barrier to drug delivery. This is especially problematic for relatively large molecules with a molecular mass larger than 500 Da [ 1 ]. Overcoming the skin barrier in a safe and effective way is the goal of transcutaneous delivery systems [ 2 ]. Topical drug delivery heavily depends on the ability of active ingredients to permeate the skin in sufficient quantities to achieve their desired therapeutic effects. Transcutaneous delivery of medications and active ingredients has gained an unprecedented popularity in the past decade due to demand for targeted and localized delivery with minimal side effects [ 3 ].
Pathways for Skin Penetration
Pathways for transcutaneous drug delivery include transepidermal (intercellular and intracellular) and transappendageal (hair follicles, sweat ducts, and sebaceous glands) pathways [ 4 ] ( Fig. 1 ).


Fig. 1. Transcellular or intracellular movement entails the use of an aqueous pore through the degradation of corneodesmosomes. Transappendageal transportation consists of movement through follicular and glandular structures. Intercellular movement involves the lipid lamellae of the intercellular spaces where most solute substances permeate across intercellular lipid avenues. a Epidermis (SC). b Dermis. c Subcutaneous layer.
Transepidermal Pathway
The transepidermal pathway consists of intercellular and intracellular pathways. Intercellular pathways involve solute diffusion through the intercellular lipid domains ( Fig. 1 ) [ 4 ]. Multiple studies report that intercellular lipids, and not the corneocyte proteins, are the main epidermal permeability barrier. The intracellular (transcellular) pathway involves permeation through the corneocytes followed by the intercellular lipids [ 5 ]. The permeation through corneocytes entails creation of an aqueous pore through degradation of corneodesmosomes. This route is therefore believed to prefer hydrophilic compounds for delivery. Occlusion, ultrasound waves, and ionophoresis can increase this form of permeation [ 6 ].
Transappendageal Pathway
In the transappendageal pathway, penetration of actives occurs through the opening of the hair follicles and the sweat glands [ 7 ]. Hair follicles play a major role in this pathway due to the follicular depth which extends deep into the dermis [ 8 ]. Follicular unit numbers, opening diameter, and follicular volume are important considerations in defining the extent of delivery through this pathway.
Delivery Systems
The first major approach to overcome the skin barrier is the use of chemical delivery systems such as chemical penetration enhancers (CPEs), emulsions, vesicular lipid-based systems, and lipid particulate carrier systems. A second approach is to use physical enhancement methods in which an external driving force is used to permeate the active ingredient(s). Such methods include sonophoresis (ultrasound), electroporation, magnetophoresis, micro-needles, thermal ablation, micro-dermabrasion, and iontophoresis [ 2 , 4 , 8 – 11 ]. Furthermore, ablative, nonablative, and fractional lasers have shown efficacy as means to increase the cutaneous permeation of cosmeceuticals [ 4 ]. Both of the aforementioned approaches, chemical and physical, have shown successful delivery for a variety of cosmeceuticals. This article will focus on the chemical delivery systems.
Chemical Delivery Systems
Chemical Penetration Enhancers
Skin provides an easily accessible route for drug delivery without first-pass metabolism. To achieve transcutaneous drug delivery, it is often required to overcome the low permeability of the SC. One common strategy is to employ penetration enhancers which act to increase drug passage across the SC and to decrease the barrier resistance.
CPEs act by multiple postulated mechanisms; solubilizing the intercellular lipid matrix, disrupting the protein component of the intracellular keratin domains, and increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane [ 12 ]. As a result, CPEs can cause skin irritation and safety concerns related to the health of the skin barrier. Many different classes of compounds have been proposed as CPE, including fatty acids (e.g., dodecanoic acid, stearic acid, oleic acid), surfactants (e.g., sodium dodecyl sulfate), azone (e.g., laurocapram), osmolytes (e.g., urea and glycols, including propylene glycol), and monoterpenes (e.g., thymol, carvacrol, and geraniol) [ 13 , 14 ]. These compound classes are different with respect to their chemical and physical properties, and therefore expected to influence the SC molecular properties in different ways. Fatty acids, surfactant, and monoterpenes mainly affect SC lipids while osmolytes affect both SC lipid and protein components [ 15 ]. The irritation response of CPEs correlates with their ability to denaturize SC proteins [ 15 ]. Furthermore, molecular effects of added compounds on SC depend on SC hydration. The addition of water leads to increased molecular mobility of both protein and lipid components of the SC. Increasing fluidity is expected to lead to higher permeability for both polar and nonpolar compounds [ 16 ]. The main part of both the lipid and the keratin components are solid. In hydrated conditions, minor fractions of the SC lipid and protein components become fluid. Furthermore, the fluidity in these components can also be altered by the addition of compounds like urea or glycerol which are constituents of the natural moisturizing factor.
Cell-penetrating peptides (CPPs), also known as protein transduction domains, have garnered wide attention in recent years and emerged as a simple and effective noninvasive strategy for macro-molecule delivery into the skin [ 17 ]. Although CPPs have demonstrated their potential in enhancing skin delivery, they are still evolving as a new class of skin penetration enhancers. CPPs are relatively short (up to 30 amino acids in length), water soluble, cationic, and/or amphipathic peptides that are capable of carrying large macromolecules across cellular membranes [ 17 ]. CPPs have been increasingly used to mediate the delivery of molecular cargoes such as small molecules, small interfering RNA nucleotides, drug-loaded nanoparticles, proteins, and peptides without using any receptors and without causing any significant membrane damage [ 18 ]. These peptides are capable of internalizing electrostatically or covalently bound biologically active cargoes with high efficiency and minimal toxicity [ 19 ].
Emulsion
Emulsions are mixtures of liquids that do not normally blend (water and oil): oil-in-water (O/W), in which oil droplets are dispersed in water, or water-in-oil (W/O), in which water droplets are dispersed in oil [ 20 ]. The former is more commonly used in topical formulations. Emulsions are milky with coarse dispersion and a droplet size in the range of micrometers. They are thermodynamically but not kinetically stable and thus will eventually phase-separate. Micro-emulsions and nano-emulsions are formulations of water and oil, similar to emulsions, but with the addition of surfactants.
Micro-emulsions are dispersions with a droplet size between 10 and 100 nm [ 21 ]. They are clear or translucent and thermodynamically stable. The advantages of micro-emulsions include: the ease and low cost of preparation, the possibility of incorporating both hydrophilic and lipophilic drugs at the same time, the increased drug loading, and the penetration-enhancing ability. The absorption is improved by the use of penetration enhancers in the micro-emulsion’s oil phase, such as oleic acid, or by the use of surfactants. Their clear appearance and ease of application increases their desirability and use in many cosmeceuticals, including moisturizers, sunscreen preparations, tanning products, antiaging products, antiperspirants, deodorants, hair care and coloring products, and perfumes. A common concern related to micro-emulsion use for topical delivery is their potential side effects, mainly skin irritation potential and comedogenic effects. These side effects are generally associated with exposure time and the composition and concentration of components, especially of surfactants, and components of the oil phase.

Table 1. Vesicular lipid-based delivery system

Nano-emulsions are emulsions with droplets smaller than 100 nm, comparable to the size of micro-emulsions despite what the name implies [ 22 ]. Nano-emulsions present the advantage of being formed with smaller amounts of surfactants, and thus lower skin irritation potential [ 23 ]. The preparation of stable nano-emulsions generally requires expensive, high-energy input methods. Nano-emulsions are kinetically, not thermodynamically, stable [ 24 ]. Their instability leads to a more favorable use of other nano-sized delivery systems like nanosomes or solid lipid nanoparticles (SLNs), which will be discussed later. Nano-emulsions are used for transcutaneous delivery of multiple agents, including gamma tocopherol, caffeine, and plasmid DNA [ 25 – 27 ].
Vesicular Lipid-Based Systems
Over the past few years, vesicular-based systems have been increasingly used as a compelling means of transcutaneous delivery of various therapeutic agents. A vesicular-based system consists of a concentric lamellar structure with an aqueous core surrounded by a phospholipid bilayer [ 28 ]. These systems provide multiple opportunities for the entrapment of hydrophilic, lipophilic, and amphiphilic drugs. Mechanisms of drug transport involve improving drug solubility, drug partitioning into the skin, and fluidizing SC lipids [ 29 ]. Vesicular-based systems consist of three main carriers: liposomes, transfersomes (ultra-deformable liposomes), and ethosomes [ 30 ] ( Table 1 ).


Fig. 2. Structure of a liposome.
Liposomes
The first generation of vesicular-based systems are liposomes, which were first described by Mezei and Gulasekharam [ 31 ] in 1980. A liposome is formed by a lipid bilayer surrounding an aqueous solution ( Fig. 2 ) and can range in size between 200 and 800 nm [ 29 , 32 ]. Drug delivery using these carriers is mainly limited by their rigidity and size, which can impede SC penetration. Liposomes more than 600 nm in size do not penetrate deeply and remain in the SC. Their advantages lie in the wide variety of drugs that can be incorporated as well as their biocompatibility with natural phospholipids. Examples of drugs delivered throughout the skin using liposomes are curcumin and retinoic acid [ 33 – 35 ]. Furthermore, liposomes have been utilized to deliver siRNA through the skin and impact protein expression at basal keratinocytes [ 36 ].
Transfersomes
The need for smaller, more elastic carriers led to the development of the second generation of vesicular-based lipid carriers, transferosomes, also termed ultra-deformable liposomes [ 37 ]. In 1992, Cevc and Blume [ 38 ] introduced the transfersomes, which resemble liposomes in morphology but are more lipophilic, smaller than 300 nm, and are at least one order of magnitude more elastic than liposomes. Furthermore, when compared to liposomes, transfersomes contain one or more edge-activator substance(s), surfactants being the most commonly used edge-activators. Edge-activators typically used for ultra-deformable liposome preparation include sodium cholate, sodium deoxycholate, Span 60, Span 65, Span 80, Tween 20, Tween 60, Tween 80, and dipotassium glycyrrhizinate [ 37 ]. There are 2 major proposed mechanisms of skin delivery via ultra-deformable liposomes [ 37 , 39 ]. The first mechanism proposes that the deformable nature of the intact vesicles contributes to their entry into the SC. The second mechanism proposes that vesicles act as penetration enhancers, whereby vesicles modify the intercellular lipids of the SC. Because their transport across the skin is driven by a hydration gradient, occlusive application can compromise the action of the deformable vesicles by eliminating the gradient force. One disadvantage of these vesicles corresponds to the difficulty in loading hydrophobic drugs into the vesicles without compromising their deformability and elastic properties [ 39 ].
Ethosomes
Godin and Touitou [ 40 ] developed the third generation of liposomes, called ethosomes. An ethosome is composed of an aqueous core, phospholipid bilayer, and ethanol (20–45%). The incorporation of high ethanol concentration, which differentiates ethosomes from other vesicular-based carriers, confers a negative charge to the liposomes which causes the vesicular size to decrease to the nanometer range, thus enhancing their skin permeation capacity. They also have higher elasticity, typically 10–30 times higher than conventional liposomes [ 40 , 41 ]. Unlike transfersomes, ethosomes are able to improve the skin delivery of drugs both under occlusive and nonocclusive conditions. The addition of ethanol in ethosomes may contribute to their superior delivery properties, which can lead to the systemic absorption of drugs encapsulated within ethosomes [ 41 ]. The potential of ethosomes for irritation and systemic absorption in addition to their long-term safety needs further exploration. Ethosomal delivery systems dramatically enhance skin permeation of minoxidil and have been used in the delivery of hyaluronic acid [ 42 – 44 ].
Other Emerging Lipid-Based Vesicles
Niosomes are nonionic unilamellar or multilamellar vesicles in which the active ingredient is encapsulated. They have improved the stability and availability of active ingredients as well as skin penetration compared to liposomes. Examples of drugs delivered using niosomes are minoxidil and ellagic acid [ 44 ]. The synergistic effects of two antioxidants, α-tocopherol and curcumin, were demonstrated using a niosomal delivery system [ 45 ].
Ultrasomes are liposomes encapsulating a UV-endonuclease enzyme [ 46 ]. They help repair UV-induced DNA damage and inhibit the expression of pro-inflammatory cytokines. Similarly, photosomes help repair DNA damage by encapsulating a light-activated enzyme (photolyase) in a liposomal structure and are thus included in certain sunscreen products.
Lipid Particulate Carrier Systems
Lipid particulate carrier systems have attracted researchers and gained popularity over other delivery systems in recent years because of the availability of nontoxic and bio-compatible lipid ingredients [ 47 ]. Lipid particulate systems typically include micro-capsules, micro-sponges, and lipid nanoparticles, such as SLNs and nanostructured lipid carriers (NLCs) [ 47 ].
Micro-Capsules
The use of micro-capsules in cosmeceutical products has gained more interest in recent years due to the need to combine various active ingredients within one product [ 48 ]. Micro-capsulation is used to avoid incompatibility of actives, reduce ingredient odor, and to protect actives prone to oxidation by atmospheric moisture. Micro-capsules are used in the controlled delivery of multiple active ingredients, including sun filters (e.g., octyl salicylate), antioxidants (e.g., tocopherols), oils (e.g., mineral oils), fragrances, cleansing products (e.g., isopropyl palmitate), vitamins (e.g., vitamin A and D), and topical retinoids [ 46 , 48 ].

Table 2. Comparison between SLNs and NLCs

Micro-Sponges
Micro-sponges utilize micro-entrapment technology wherein the shell surrounding the active ingredient has a porous structure rather than a continuous shell structure as in a microcapsule [ 49 ]. The porous shell results in sustained release of the active ingredient(s) over longer periods of time. The spheres can be programmed to release active ingredient(s) with the use of different triggers such as applied pressure or the introduction of water [ 49 ]. Entrapment systems can control the release of actives onto the epidermis, thus reducing irritation while maintaining efficacy. An example of increased efficacy and reduced irritation with use of micro-sponges is that observed with benzoyl peroxide entrapped in a micro-sponge system [ 50 ]. Micro-sponges reduce unpleasant characteristics of the main ingredient, as has been observed with zinc pyrithione and selenium sulfide [ 51 ].
Lipid Nanoparticles
Lipid nanoparticles are colloidal particles ranging in size from 10 to 1,000 nm. Currently, there are two generations of lipid nanoparticles: SLNs and NLCs. SLNs can be considered as the first generation of lipid nanoparticles, whereas NLCs are regarded as the second generation, overcoming the shortcomings of SLNs [ 47 , 52 , 53 ] ( Table 2 ).
Solid Lipid Nanoparticles
SLNs are colloidal drug delivery systems composed of physiological and biodegradable lipids. Structurally, they are spherical in shape with a lipid content between 1 and 30% [ 54 ]. SLNs have gained popularity and superiority to other delivery systems due to their controlled release of actives, higher drug entrapment efficiency for lipophilic drugs, enhanced drug stability, as well as protection of labile substances from chemical degradation, photo degradation, hydrolysis, and oxidation [ 55 ]. Moreover, their nano-size ensures enhanced contact with and penetration of the epidermis. SLNs possess UV protection and occlusive properties preventing transepidermal water loss. All of these unique properties make SLNs attractive carriers for skin delivery of cosmeceutical ingredients. Examples of actives delivered via SLNs include hydroquinone, adapalene, and curcuminoids [ 56 – 59 ].
Nanostructured Lipid Carriers
NLCs are second-generation lipid nanoparticles [ 60 ]. They are modified forms of SLNs in which the lipid phase is comprised of both liquid lipids and solid lipids. NLCs were developed to overcome some of the challenges with SLNs, such as particle agglomeration, drug leakage, risk of gelation, high water content, and poor drug loading. The addition of liquid lipids to the structure of NLCs led them to have a higher drug-entrapment potential, higher skin-permeation potential, and lower occlusive capacity when compared to SLNs [ 61 ]. The mechanism of skin permeation of NLCs is similar to SLNs. Since NLCs have a higher drug loading capacity, a higher concentration gradient can be achieved as compared to SLNs. The use of NLCs in physical sunscreen has been found to have synergistic UV protection properties. All these attributes make NLCs excellent carriers for topical drug delivery to improve skin hydration, controlled drug release, drug permeation, and drug stability [ 62 ]. NLCs have been successfully utilized in the topical delivery of photolabile antioxidants like alpha-lipoic acid and topical retinoids [ 62 – 65 ].
Conflict of Interest Statement
Sabrina G. Fabi is an investigator and consultant for Allergan, Merz, Galderma, and Revance. Dr. Rawaa Almukhtar has nothing to declare.
Funding Sources
No funding was provided for the development of this article.
Author Contributions
R.M.A. contributed to the conception and design of this book chapter, contributed to the analysis and interpretation of scientific material, and prepared the manuscript draft. S.G.F. contributed to the conception and design of the chapter, contributed to the analysis and interpretation of scientific material, and provided intellectual input and critical revision of the manuscript draft.
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Rawaa M. Almukhtar Cosmetic Laser Dermatology 9339 Genesee Ave, Suite 300 San Diego, CA 92121 (USA) ralmukhtar@clderm.com
 
Published online: January 19, 2021
Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 11–19 (DOI: 10.1159/000491841)
______________________
Evaluating Cosmeceuticals
Zoe Diana Draelos
Dermatology Consulting Services, PLLC, High Point, NC, USA
______________________
Abstract
Cosmeceuticals must be evaluated based on a variety of criteria. First, it is important to consider the location for product application. More moisturization is required around the eyes, for example, than around the nose. Second, the formulation can be adjusted to account for differential facial sebum production. Third, the value of the formulation can be assessed via noninvasive assessments, such as corneometry and transepidermal water loss. Photography may also be helpful in assessing facial appearance changes that are cumulative with use over time.
© 2021 S. Karger AG, Basel
The proper evaluation of cosmeceuticals is important to ensure optimal efficacy. It is sometimes hard to determine efficacy, since cosmeceuticals are basically cosmetics, which by definition are intended to adorn, scent, and color the skin. Since efficacy was never part of the role of cosmetics in skin care, no established guidelines exist for evaluating cosmeceuticals. Definite United States Food and Drug Administration (FDA) guidelines are in place for new drug approval, but the FDA at present has no jurisdiction over cosmetics, which are unregulated. There has been some conversation at the FDA about the regulation of new cosmetic ingredients utilizing the same approach presently in place for investigational new drug applications.
This chapter will focus on the evaluation of cosmeceuticals; however, the opinions expressed are those of the author. A cosmeceutical is basically a moisturizer with an added “hero” ingredient designed to discriminate the formulation from a traditional moisturizer, but lacking in clinical efficacy to the point where the product might be perceived by regulatory bodies as a drug. Most cosmeceuticals are applied to the face, which is the part of the body where photoaging is first observed. Thus, this chapter will focus on facial cosmeceuticals examining the needs of the face, moisturizer formulation, noninvasive testing, and clinical evaluation to establish efficacy.
Facial Cosmeceutical Needs
Cosmeceuticals must be designed to meet the unique anatomy and physiology of the face. The face begins at the anterior hairline, stops at the ears, and is bounded by the lateral jaw line and chin. It is the most complex and challenging area of the body for the formulator, containing all of the glandular structures of the body, including hair, characterized by dry transitional skin found around the eyes, nose, and mouth. Facial skin is the thinnest on the body, except for that around the eyelids, making it the most susceptible to irritation and allergy, a challenge for the cosmeceutical formulator. The face is also characterized by numerous follicular structures in the form of pigmented terminal hairs in the eyebrows, eyelashes, and male beard combined with white fine downy vellus hairs over the rest of the face. These follicular structures are the transition between the skin on the surface of the face and the ostia, which create interesting facial topography consisting of mountains around each follicular structure with intervening valleys constituting the facial dermatoglyphics.
The skin lining of the pore connecting the surface to the depth of the follicle is an important transitional area. It is the site of irritation resulting in a follicular irritant contact dermatitis causing the “breakouts” associated with cosmetics. The elimination of all irritants from cosmeceutical formulations is important to prevent this acneiform eruption. In the longer term, it is important that perifollicular irritation and occlusion does not occur, otherwise inflammatory papules and/or comedones may result. Cosmeceuticals should be tested to be sure they are noncomedogenic and nonacnegenic.
Cosmeceuticals must also improve the condition of the skin by optimizing the barrier. This is actually the major benefit of cosmeceuticals. An intact barrier is smooth and soft and able to reflect light and create the appearance of luminous skin, which is considered younger, more attractive skin. Cosmeceuticals contain a variety of ingredients, including emollients and polymers, to create this enhanced light reflection; however, this is truly an appearance benefit that will be lost when the cosmeceutical is removed from the skin surface. Cosmeceuticals can also improve the skin barrier functionally. Enhanced organization of the intercellular lipids, composed of sphingolipids, free sterols, and free fatty acids [ 1 ], and corneocytes will optimize skin behavior and appearance simultaneously [ 2 ]. Thus, the moisturizer vehicle of cosmeceuticals is a very important part of perceived efficacy.
Cosmeceutical Moisturizer Formulation
Many believe the active ingredient of a cosmeceutical formulation accounts for the majority of the efficacy. This is not correct. The moisturizer vehicle probably accounts for at least 75% of the product efficacy. Not only can the moisturizer create a smooth soft film over the skin surface, it can also reduce transepidermal water loss (TEWL), which reduces the fine lines of dehydration, especially noticeable around the lateral eyes. This is accomplished through the application of occlusive and humectant substances.
Occlusive substances place an oily film on the skin surface that is more or less impermeable to water. Highly occlusive substances, such as petrolatum, mineral oil, paraffin, lanolin, and carnauba wax, significantly reduce water loss, but are sticky and provide poor compatibility with colored cosmetics [ 3 ]. Aesthetics are a very important part of cosmeceuticals. For this reason, most cosmeceutical formulations include less occlusive but also less greasy substances, such as silicone derivatives (dimethicone, dimethiconol) and polymers (acrylates). Many of the botanically based formulations will include jojoba, hemp, borage, or evening primrose oils.
Occlusive agents must be combined with humectants to not only stop water from leaving the skin, but also to rehydrate the skin by attracting water. Humectants have been used in cosmetics for many years to increase shelf life by preventing product evaporation and subsequent thickening due to variations in temperature and humidity. Humectants act like sponges in the skin to hold water with the natural major skin humectant being hyaluronic acid, which is also used as a humectant in cosmeceutical preparations. Other common humectants include glycerin, sodium lactate, urea, propylene glycol, sorbitol, pyrrolidone carboxylic acid, gelatin, vitamins, and some proteins [ 4 , 5 ].
Finally, emolliency is an important concept in cosmeceutical efficacy. Emollients smooth down desquamating corneocytes to make the skin surface appear smooth and feel soft, which are very important consumer-perceived cosmeceutical benefits [ 6 ]. In addition, some emollients are also occlusive moisturizers. Important to consumer satisfaction with a moisturizing product since smooth skin is expected following application, even though emolliency may not necessarily correlate with decreased TEWL. Emollients function by filling the spaces between the desquamating skin scale with oil droplets, but their effect is only temporary. Commonly used emollients include propylene glycol, isopropyl isostearate, octyl stearate, and isopropyl myristate [ 7 ].
Most cosmeceutical moisturizers consist of water, lipids, emulsifiers, preservatives, fragrance, color, and specialty additives. Most cosmeceuticals are 60–80% water with the water functioning as a diluent, rapidly evaporating after application. Emulsifiers are generally detergents in concentrations of 0.5% or less, keeping the lipids emulsified in the water to form one continuous phase. This then means the specialty additives become the differentiating factor between various cosmeceutical moisturizer products. In summary, a cosmeceutical moisturizer formulation must increase the water content of the skin (moisturization) and make the skin feel smooth and soft (emolliency).
Noninvasive Testing of Cosmeceutical Moisturizer Efficacy
Most cosmeceuticals are evaluated prior to marketing to be sure they meet formulation efficacy goals. Since invasive biopsy analyses are not appropriate, given that drug-like effects could be demonstrated, cosmeceuticals are tested with noninvasive methods. These noninvasive methods include regression analysis, profilometry, squametry, in vivo image analysis, corneometry, and evaporimetry [ 8 ].
Regression analysis is an important method to determine if a moisturizer can produce benefits even after application has been discontinued. A good cosmeceutical moisturizer will maintain some benefits 48 h after the product was applied. Most regression studies will have the subjects apply the facial cosmeceutical for 2–4 weeks followed by discontinuation. The skin will be evaluated at the end of the study period; subjects will discontinue application, return to the research center 48 h after the last application, and undergo evaluation [ 9 ]. This method is particularly valuable since the efficacy of all moisturizers is excellent immediately following application, but true effectiveness can only be assessed based on the longevity of benefits [ 10 ].
The minimization of fine lines and wrinkles is a commonly purported cosmeceutical benefit. One noninvasive method used to document wrinkle reduction is profilometry, which involves the analysis of silicone replicas of the skin surface with scanning laser imaging. The unpolymerized silicone, which is the same as dental impression material, is mixed with the catalyst. The silicone is placed over the skin surface to create a negative replica of the skin texture. Analysis of these replicas before and after application of the cosmeceutical can determine the ability of the product to minimize wrinkles and support wrinkle reduction claims [ 11 ].
Many cosmeceutical moisturizers claim to smooth the skin surface or uncover younger skin through exfoliation. Exfoliation removes nonliving corneocytes from the skin surface, which is a cosmetic effect, by using ingredients that digest the intercellular bonds. Ingredients capable of inducing exfoliation include glycolic, lactic, malic, and salicylic acids. While the appearance of exfoliated skin can be seen and felt, squametry is a noninvasive technique that can be used to demonstrate enhanced exfoliation. With this technique, a sticky round tape, known as a D-squame, is pressed against the skin surface with a constant pressure plunger for a count of 10. The D-squame is then removed with forceps and placed on a black backing card. The opacity of the tape, which increases as more skin scale is removed, is compared against a photonumeric reference card to provide an ordinal rating for the amount of skin scale that was removed. Limited skin scale indicates the cosmeceutical induced little exfoliation, while more skin scale indicates a greater exfoliant benefit [ 12 ]. The D-squame technique is a valuable noninvasive efficacy assessment for exfoliation.
Visible cosmeceutical efficacy can be assessed with the human eye, but more subtle effects can be observed with in vivo image analysis utilizing a video microscope [ 13 ]. Care must be taken to standardize lighting and camera angles to insure accurate comparison images. The use of a video microscope may be of limited value in assessing cosmeceutical efficacy, however. If the human eye cannot see improvement and only the video microscope images can detect benefit, will the consumer continue using the cosmeceutical without visible results? This is always a challenge when evaluating cosmeceutical efficacy.
As mentioned earlier, skin water content is important to skin appearance optimization. A major cosmeceutical benefit is to decrease the amount of water leaving the skin and increase the amount of water in the skin. These two benefits can be measured through noninvasive equipment. The amount of water leaving the skin, known as TEWL, can be measured through evaporimetry [ 14 , 15 ]. This technique uses a probe containing two humidity meters at a known distance apart placed above a collecting chamber of known diameter. The probe is placed in contact with the skin for 1 min and the amount of humidity measured is collected until a steady state is reached. This allows determination of the amount of water lost by the skin over a certain area in a fixed period of time. Lower TEWL could be a major benefit of a facial cosmeceutical moisturizer. In addition, the amount of water in the skin can also be assessed with a technique known as corneometry [ 16 ]. Corneometry puts a lower level electrical current into the skin, which is conducted by water between the sending probe and receiving probe. The amount of electricity conducted by the skin is directly proportional to the amount of water in the skin. A higher number is indicative of superior moisturization.
Photography and Cosmeceutical Evaluation
Before and after photographs are commonly used in scientific and consumer publications to document the benefit of a cosmeceutical. Photographs are quite effective because the observer can make a personal judgment as to whether the formulation performed well. Photographs can be used for visual evaluation, as demonstrated in Figure 1 , showing the before and after images of a cosmeceutical designed for facial redness reduction.
Photographs can also be computer enhanced for more detailed image analysis. Figure 2 shows the use of line enhancement to assess the linear length of fine lines/wrinkles before and after use of a cosmeceutical eye moisturizer. The line enhancement was done manually on this computer image, thus there is an element of human judgment involved. Also note that photography can distort cosmeceutical benefits. In Figure 2 a before treatment, more fine lines/wrinkles have been highlighted than after treatment in Figure 2 b; however, the eye appears to be more relaxed in Figure 2 b, perhaps contributing to the improvement. Eye positioning is very important when assessing before and after images documenting the benefit of an eye cosmeceutical.
Figure 3 presents before and after images of a product designed to minimize the appearance of pores. The pores have been highlighted using a computer algorithm for pattern recognition. More pores have been highlighted in the before ( Fig. 3 a) than the after ( Fig. 3 b) image. Will the consumer be able to perceive the pore reduction? This is the challenge when using computer assessment to evaluate cosmeceutical efficacy.


Fig. 1. Before ( a ) and after ( b ) images post-application of a cosmeceutical designed to minimize facial redness.


Fig. 2. Before ( a ) and after ( b ) facial images to assess the efficacy of a cosmeceutical designed to minimize fine lines/wrinkles utilizing digital image analysis.
Developing a Plan for Cosmeceutical Evaluation
No cosmeceutical can deliver all skin benefits; thus it is important to determine the goals of the formulation. The conceptualization of the cosmeceutical should address the needs of aging skin ( Table 1 ). Sometimes it is better to elucidate the desired benefits of the cosmeceutical first and then fit the formulation to claims rather than the claims to the formulation. However, realistic benefits are important, or the consumer will purchase the cosmeceutical once, but not again. This is the biggest reason for cosmeceutical failure in the marketplace. It is also the biggest reason why cosmeceutical formulations enter and exit the market with great rapidity, promising that the new formulation works better, faster, and with more dramatic results.


Fig. 3. Before ( a ) and after ( b ) facial images to assess the efficacy of a cosmeceutical designed to minimize pores utilizing digital image analysis.

Table 1. Needs of aging skin

If the cosmeceutical is designed to address lines and wrinkles of the face, the formulator should target which lines and wrinkles will be improved and then fit available ingredients to the goal. It is also possible that some wrinkles of the face cannot be addressed with a topical product, in which case more minor lines should be selected for minimization. Skin color and dyspigmentation problems may be addressed alone or in combination with wrinkles and folds. Cosmetic retinoids, such as retinol, can improve all of these facial aging issues, but care must be taken not to drive the concentration too high so as to induce irritation. Skin irritation can be tolerated in prescription retinoid use under the direction of a dermatologist, but irritation must be avoided at all cost in cosmetic formulation. Similarly, brown skin dyspigmentation can be treated with skin lightening cosmeceuticals containing hydroquinone.
Cosmeceutical Ingredient Challenges
No evaluation of cosmeceuticals is complete without a brief discussion of ingredient challenges. Cosmeceutical formulation involves the careful selection of ingredients to produce a safe, elegant, efficacious product suitable for patient purchase [ 17 ]. Many considerations go into a final formulation including moisture barrier effects, pH, lubricating action, soothing effects, osmotic effects, emolliency, and percutaneous absorption [ 18 ]. Some of the more controversial ingredients that go into cosmeceuticals include preservatives, herbal additives, and biologic additives.
Preservatives
Preservatives are perhaps the most controversial of all cosmeceutical ingredients. All currently available preservatives are made synthetically as no totally natural preservative blend has been created to date. No cosmeceutical can be sold commercially without refrigeration devoid of preservatives. However, preservatives have been blamed for everything from breast cancer to obesity to environmental damage. Without preservatives, the occlusive and emollient lipids in cosmeceutical formulations would rapidly oxidize, rendering the cream rancid, or bacterial contamination would render the water-soluble ingredients unsafe. Preservatives are the second most common allergenic group of substances found in cosmeceuticals behind fragrances [ 19 ]. However, the number of cases of irritant and allergic contact dermatitis are indeed small compared with the two necessary functions preservatives perform in cosmetics: spoilage prevention prior to purchase and prevention of contamination after purchase [ 20 , 21 ]. Paraben esters are the most popular preservatives used in cosmetics as their sensitization and irritation potential is low when applied to healthy skin [ 22 ]. They are usually found in concentrations of 0.5% or less in the USA. Some of the “natural” cosmeceuticals use essential oils and fragrances with antimicrobial capabilities, such as oil of clove, cinnamon, eucalyptus, rose, lavender, lemon, thyme, rosemary, and sandalwood [ 23 ].
Herbal Additives
Herbal additives possess tremendous consumer appeal due to their “natural” derivation, even though herbicide and heavy metal contamination is a problem. Botanical ingredients must be carefully sourced for purity or formulation problems will ensue [ 24 ]. The addition of herbals makes the distinction between a standard mass-produced body moisturizer and a boutique cosmeceutical moisturizer. Plant additives are purchased from large manufacturers and typically added to the cosmeceutical at the end of processing either as a liquid or powder. The plant material may color and scent the final product, but also add skin benefits [ 25 ].
Herbal additives may take several forms, including: hydroglycolic extracts, essential oils, and whole plant extracts [ 26 ]. Hydroglycolic extracts, such as aloe vera, are used in concentrations of 3–10% and are a combination of propylene glycol and water, yielding water-soluble constituents, but not oil-soluble aromatic fragrances [ 27 ]. Essential oils, such as avocado oil, sesame oil, and tea tree oil, are used in concentrations of 2–5% [ 28 ]. Whole plant extracts, also known as aromaphytes, are used at 5–20% concentration and manufactured by double extraction containing all the constituents of the plant. In cosmeceuticals, herbal additives are sometimes added for their antioxidant capabilities, but efficacy must be assessed based on the quality, concentration, and composition of the herbal ingredient.
Biologic Additives
Biological additives are also found in cosmeceuticals and are derived from the extracts and hydrolysates of glands and tissues of animals of different species. Biologics can be obtained as aqueous, hydroglyceric, hydroalcoholic, hydroglycolic, and oily extracts of animal-derived products. Commonly used cosmeceutical biological additives include collagen, elastin, hyaluronic acid, keratin, placenta, blood derivatives, and stem cells.
Collagen, a large molecule composed of three twisted alpha helical peptide chains, is a biological additive used in some cosmeceutical moisturizers. Collagen is usually obtained from shredded calf skin that is carefully handled to eliminate denaturation.
Elastin, a structural component of the dermis responsible for the ability of the skin to regain its original configuration following stretching and other deformation, is obtained from bovine neck ligaments. Elastin, usually added as a hydrolysate, is a clear yellow liquid. While the addition of collagen and elastin to a cosmeceutical moisturizer might be presumed to thicken skin and increase elasticity, these ingredients actually function as humectants to improve the water-holding capacity of the skin [ 29 ]. Part of evaluating cosmeceutical efficacy is to determine the true value of a biologic additive.
Conclusion
This chapter has presented some of the important considerations regarding cosmeceutical efficacy. The cosmeceutical concept has great consumer appeal because the idea of putting a cream on an aging face to make it look young again is enticing. While Ponce de Leon was actually pursuing a cosmeceutical concept when looking for the fountain of youth, he was never successful in his quest. Most consumers will not be successful in their quest either. Nevertheless, great advancements have been made in cosmeceutical formulations and understanding how to evaluate their efficacy is important.
Conflict of Interest Statement
The author has no financial, commercial, or other relationships to declare as a possible conflict of interest.
Funding Sources
The author received no funding for this work.
Author Contributions
Z.D.D. was the sole contributor to the authorship of this article.
References
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Zoe Diana Draelos Dermatology Consulting Services, PLLC 2444 North Main Street, High Point, NC 27262 (USA) zdraelos@northstate.net
 
Published online: January 19, 2021
Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 20–25 (DOI: 10.1159/000491842)
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Cosmeceuticals Using Alpha, Beta, and Polyhydroxy Acids
Lena A. Ladenheim Ellen S. Marmur
Marmur Medical, New York, NY, USA
______________________
Abstract
Alpha, beta, and polyhydroxy acids have been utilized and well documented through research and literature for decades. They are extremely useful in both medical and cosmetic applications, working to treat a wide variety of skin issues while functioning to preserve youthful skin characteristics. The hydroxy acids (HAs) are similar in structure to each other, each bringing forth their unique mechanisms of action and applications. In chemical peels, HAs are used on their own in addition to solutions where two or more are combined to produce the desired results. In other cosmeceuticals they are useful for superficial exfoliation and moisturization, and when used in combination with injectables like neuromodulators or dermal fillers, their results are enhanced and beautifully displayed. When used with topical prescriptions they can provide properties to make the patient feel more comfortable, like adding moisture to lessen a burning sensation. More information is emerging about the benefits of each HA now more than ever, which bodes well for the future in terms of being able to prescribe and recommend the most precise treatment options for patients, and in turn, advancing and improving results.
© 2021 S. Karger AG, Basel
Hydroxy acids (HAs) are no strangers to the world of cosmeceuticals, as they have been widely used for decades for a variety of reasons on the skin. Alpha HA (AHA), a naturally occurring compound found in many fruits, is a carboxylic acid with one hydroxyl group attached to the alpha position of the carboxyl group [ 1 ]. Through the mechanism of gentle cleavage, the bonds between keratinocytes break, inducing fresh collagen to form. AHAs are well known for their efficacy in treating fine lines and wrinkles, seborrheic or actinic keratoses, verrucae vulgares, psoriasis, acne, xerosis, ichthyosis, and hyperpigmentation [ 1 ]. A few well-known examples of AHAs include glycolic acid, lactic acid, and mandelic acid [ 2 ].
Much like the AHAs, beta HAs (BHAs) are similarly structured but instead of the hydroxyl group attachment to the alpha position of the carboxyl group, attachment is to the beta position of the carboxyl group. BHAs utilize the same mechanism of action as AHAs, but it is valuable to note that while AHAs are water soluble and penetrate to the dermis, BHAs are lipid-soluble and penetrate only to the epidermis and pilosebaceous unit [ 3 ], meaning the latter are more effective when treating oily skin types due to their capability of penetrating through sebaceous follicles [ 4 ]. The most notable BHA is salicylic acid, in addition to its related entities including sodium salicylate and willow bark extract [ 2 ].
A third group of HAs are polyhydroxy acids (PHAs), which are differentiated by their unique carboxylic acid molecular structure which is comprised of 2 + hydroxyl groups. The hydroxyl groups are attached to either the carbon atoms or an alicyclic chain. It should be noted that at least one of the hydroxyl groups must be attached at the alpha position of the carboxyl group [ 5 ]. PHAs have been purported to be less irritating to the skin than AHAs and BHAs in cosmeceuticals due to their larger molecular size, in addition to their surface-level penetration capability versus a deeper level that AHAs and BHAs are able to reach [ 3 ]. PHAs are humectants which allow for greater moisturization efficacy when compared to AHAs and BHAs, and they also contain antioxidant/chelation characteristics [ 5 ]. Polyhydroxy bionic acids are another group related to PHAs and HAs, with the differentiating feature of having an extra sugar molecule which is attached to the PHA. They act through analogous mechanisms of action by gently exfoliating the stratum corneum and, consequently, smoothing the skin [ 5 ]. Gluconolactone is one of the more prominent examples from the PHA family, commonly found in many skincare products and cosmeceuticals. Gluconolactone effectively reinforces the skin barrier while maintaining the HA’s anti-aging property of exfoliation to improve the skin’s texture and quality [ 2 ].
History
The recorded use of AHAs, BHAs, and PHAs dates back in its earliest form to ancient Egypt, when sour milk was utilized to smooth the skin with the active agent of lactic acid [ 6 ]. In the 1800s, chemical elements including phenol, lime, and croton oil were used to lighten freckles and treat melasma under the aegis of stratum corneum exfoliation; only mere decades later, sulfur and resorcinol were used for skin rejuvenation. In the middle of the twentieth century, Jessner’s peel solution was created and pioneered by the German dermatologist Max Jessner when salicylic acid, resorcinol, and lactic acid were combined [ 7 ].
Later, the well-documented acid known as trichloroacetic acid (TCA) came into the picture. To this day, it is one of the most widely used chemical peeling agents to treat wrinkles, acne, pigmentation, texture, and actinic damage by reaching a medium-depth of the skin and stimulating fibroblast type I collagen production [ 6 ]. Fast-forward to modern-day dermatology, we are now armed with the knowledge of the numerous peeling agents’ depth of reach as well as the extensive and ever-evolving database of lasers which allow for skin resurfacing results that are more accurate than ever.
Myths
The unique intersection of skincare, medicine, pharma, science, and economics collide to create the universe of cosmeceuticals. As with any field of study, there are a handful of myths and misconceptions which should be addressed. In “Cosmeceuticals: Myths and Misconceptions” [ 8 ], seven myths were discussed and debunked, including one claiming that cosmeceuticals are, in fact, regulated as drugs. According to the author, Amy Newburger [ 8 ], this is absolutely false due to the FDA reviewing product claims purely based on their intended use. If a product is intended for pharmacological use, it must undergo numerous safety studies, including interactions with other drugs, animal testing, toxicology testing, pharmacology testing, and pharmacokinetic testing, all of which are compared with other relevant studies and data. Additionally, if a product claims that it may cure, prevent, mollify, or treat a disease process, it must be regulated as if it is a drug versus solely a cosmeceutical [ 9 ].
As previously established, HAs work by gently exfoliating dead keratinocytes from the skin, ergo leaving the skin smoother, more supple, and more radiant [ 1 ]. When layering HAs with retinols, there is a misconception that the pH level in AHAs, BHAs, or PHAs disrupt retinol from working to its full potential [ 10 ]. However, this is a false claim because the HAs actually allow for better penetration of the retinols due to their exfoliative nature [ 1 ].
Proven: Combination Peels
Over the past few decades, an abundance of information regarding cosmeceuticals utilizing AHAs, BHAs, and PHAs has emerged. Many studies have determined the family of HAs to be efficacious in the treatment of a copious amount of skin ailments and issues, as well as being heralded as some of the most classic anti-aging ingredients [ 1 ]. HAs treat hyperkeratotic conditions by regulating the attachment of corneocytes to the stratum corneum. This produces a highly specific result of epidermal shedding compared to nonspecific results from other keratolytic products [ 11 ] like coal tar or tazarotene. In conjunction with the exfoliative properties that HAs possess, their anti-aging capabilities stem from the collagen stimulation that occurs when keratinocytes compensate for their own loss following exfoliation due to the acid’s effects, also known as dermal matrix remodeling [ 11 ]. This leads to the impressive effects on fine lines and wrinkles that HAs deliver, whether they are used topically in a cream, gel, serum, or in a peel. They have been found to act on hyperpigmentation through the promotion of desquamation that takes place when the HAs interact with the skin, as well as PHAs exhibiting antioxidant traits [ 11 ]. Gluconolactone, as previously stated, is one of the most well-known PHAs and has demonstrated free radical inhibition of a solar elastosis due to photoaging activity in a study that was conducted when compared to other antioxidants (i.e., vitamin C and vitamin E). The results of the study yielded revealing information about gluconolactone, summing up the concept that it is comparable to the more notable antioxidants, and that it should be regarded as one in its own right [ 11 ].
Combination peels have been around for years because their results are exceptional. The famous Jessner’s peel solution contains 14% resorcinol, 14% lactic acid, 14% salicylic acid, and they are all mixed into a base of ethyl alcohol [ 12 ]. Used chiefly for sun-exposed conditions like actinic keratosis, hyperpigmentation, rhytides, and solar lentigines, it can also treat acne. Jessner’s peels are our first-choice peel for the treatment of melasma in all skin types I–VI. Its depth is superficial, it is self-neutralizing, it is typically difficult to overpeel using Jessner’s, and any complications are rare [ 12 ]. The Jessner’s mechanism of action derives from the keratolytic property in the resorcinol and salicylic acid, as well as the epidermolytic property in the lactic acid. Corneocyte cohesion is broken in the stratum corneum due to the resorcinol and salicylic acid, thus causing edema in the epidermis at both the intercellular as well as the intracellular levels. Clinically, the end point hallmarks are erythema and frosting. Possible complications include activating a dormant Herpes outbreak, experiencing delayed healing or lengthened redness, scarring, PIH or post-hypopigmentation, and contact dermatitis [ 12 ]. Contraindications for Jessner’s include having an active HSV outbreak, having been on isotretinoin within the previous 6 months, and pregnancy [ 12 ].
TCA is a corrosive agent used frequently in the dermatological field, and typically stored in an opaque glass bottle so as to prevent photodamage to the solution. Utilizing higher concentration percentages of TCA and/or applying more coats will lead to a deeper depth of the peel’s penetration. TCA used alone reaches a medium depth of the dermis and TCA 30% is our choice peel for dermal melasma in patients who first tolerated the Jessner’s peel well and who are not prone to PIH. TCA is frequently used in combination with other solutions and/or acids. For example, combining TCA 35% with Jessner’s solution will produce the Monheit combination, which is a medium-depth peel. This amalgamation is very popular for actinic keratosis as well as other symptoms derived from photoaging [ 13 ]. It has been found to be as effective as 5-fluorouracil topical chemotherapy with fewer side effects [ 13 ]. This particular combination is extremely beneficial for the TCA’s penetration capability, because the foundation layer of the Jessner’s peel allows for keratolysis and epidermolysis. In turn, the TCA is more readily available to the stratum corneum [ 13 ].
Combining TCA 35% and glycolic acid 70% forms the Coleman combination, which allows for medium-depth penetration [ 13 ]. The peel is self-neutralizing and is commonly used for reversing actinic damage, reducing rhytides and pigmentation, and improving scarring [ 14 ]. When TCA 35% is combined with solid CO 2 , the Brody combination is created [ 13 ]. According to Brody and Coleman, the medium depth peel occurs when TCA 35% is preceded by solid CO 2 to allow for further penetration of the TCA to a greater depth of penetration. This process takes place through the papillary dermis. Jessner’s plus unbuffered 70% glycolic acid can be used to do the same as solid CO 2 but with less depth histologically. Solid CO 2 is much warmer than liquid nitrogen and therefore is not capable of scarring the dermis by only freezing it under customary circumstances. Additionally, freezing with solid CO 2 can cause edema without collagen destruction. The ensuing edema will stretch the distance between cells, and will allow the active acids to penetrate to the papillary dermis. As a result, it will provide better clinical results, while avoiding the loss of pigmentation or scarring when performed with the proper technique and on the proper skin type [ 15 ].
In general, medium-depth peels with TCA provide better results than those from superficial peels alone. TCA has a lengthy shelf life and the desquamation from TCA peels does not cause systemic toxicity. These authors often follow the TCA peels with a sweep of liquid nitrogen (rolled cotton on a cotton swab dipped in LN 2 and swept over the frosted skin to cool the skin and remove some dead keratinocytes). The results of these peels are predictable and safe, and have been shown to reduce future occurrences of basal or squamous cell carcinomas [ 13 ].
One of the most common agents utilized for deep-level peels is phenol, which is a carbolic acid compound obtained from coal tar and is absorbed very quickly. Phenol is indicated for moderate to deep wrinkles, acne scars, actinic keratoses and cheilitis, verrucae, xanthelasma [ 16 ], and even nonsurgical closures of earlobe clefts [ 17 ]. When phenol is blended with croton oil to form the phenol-croton oil peel, it reaches deep-level penetration to the dermis and the need for covering pigment changes may last as long as 6 months post-procedure [ 18 ]. Phenol peels are completely contraindicated in people with cardiac disease as the toxicity from the peeling has been found in some cases to cause undesired cardiac side effects [ 18 ]. It is preferable that windows and exhaust fans are used throughout the procedure [ 18 ].
Combination Peels with Other Cosmeceutical Ingredients and Topical Prescriptions
Using cosmeceutical ingredients like vitamin C to improve procedural outcomes and boost radiance following an HA/combination peel, or using vitamin K to reduce the chances of ecchymoses have proven themselves successful in the medical field [ 11 ]. It is always crucial to identify the recommended amount of time to resume using specific cosmeceuticals, i.e., vitamin A, vitamin C, vitamin E, niacinamide, growth factor serums, and peptides, among others [ 19 ].
When combining HAs with topical prescriptions, the results can be marvelous under the direction and care of a trained physician. For instance, salicylic acid is very commonly utilized in conjunction with topical prescriptions [ 20 ] like benzoyl peroxide (BP). When looking at data from using BP alone, BP with topical antibiotics, or topical antibiotics on their own, the results are far inferior when compared to BP with salicylic acid [ 20 ]. The superficial peel healing time may be accelerated by a topical prescription of desonide cream [ 21 ], which is a mild corticosteroid used for pruritis, erythema, and/or inflammation. On the contrary, the results throughout the recovery period from a superficial peel may be enhanced by pretreating the skin with a topical prescription of tretinoin 0.025–0.1%, or an AHA of 8–10% which should be applied at night for 2–4 weeks prior to the procedure and discontinued 3–5 days before the procedure [ 22 ].
Latest Advances in Cosmeceuticals Using Hydroxy Acids
The deep-level penetration combination peel known as the phenol-croton oil peel may have augmented results when used together with neurotoxin therapy. Pretreating the facial muscles 2–3 weeks before the peel has been proven to aid the healing time by relaxing the muscles and, in turn, alleviating discomfort and pain associated with the post-peel period [ 18 ]. It is not recommended to treat the patient with neurotoxins on the day of the phenol peel because the first 24-h period of edema may cause undesired spreading of the toxins [ 18 ]. Dermal fillers may also be used in conjunction with peels to reinforce and enhance the volumizing and plumping effects that peels may cause on patients [ 18 ].
In recent years, research has been conducted on 30% salicylic acid in a polyethylene glycol (PEG)-based solution and results have demonstrated high efficacy when treating skin texture and acne [ 23 ]. The mixture allows for the salicylic acid to be released in trace quantities onto the epidermis because PEG has a strong intermolecular bond with salicylic acid [ 23 ], which is the reason for a low rate of systemic toxicity from the combination, in addition to a low incidence of burning during the procedure [ 23 ].
Additionally, lactic acid (an AHA) and lactobionic acid have been shown to be extremely hydrating and moisturizing ingredients while maintaining their exfoliative nature [ 24 ]. As a humectant, studies have shown that it is effective at decreasing transepidermal water loss while inhibiting matrix metalloproteinase enzymes which are principally produced as a result of sun exposure [ 24 ]. Hence, lactic acid and lactobionic acid are hydrating, exfoliating, and have antioxidant properties – such workhorses! The future is looking bright for lactic acid and lactobionic acid regarding all of the possible formats through which these powerful ingredients may be utilized.

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