Cosmeceuticals

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

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. Almukhtara Sabrina G. Fabia, 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