Cosmeceuticals 1st Edition

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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

Basel  ·  Freiburg  ·  Hartford  ·  Oxford  ·  Bangkok  ·  Dubai  ·  Kuala Lumpur  ·  
Melbourne  ·  Mexico City  ·  Moscow  ·  New Delhi  ·  Paris  ·  Shanghai  ·  Tokyo
Jody Comstock Michael H. Gold
Department of Dermatology Gold Skin Care Center
University of Arizona Tennessee Clinical Research Center
Tucson, AZ (USA) Nashville, TN (USA)
[email protected] [email protected]

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
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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.
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ISSN 2235–8609
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ISBN 978–3–318–06689–0
e-ISBN 978–3–318–06690–6
Contents

VII Preface
Comstock, J. (Tucson, AZ); Gold, M.H. (Nashville, TN)

1 Cosmeceuticals and Delivery Mechanisms: Skin Function and Skin Barrier

Almukhtar, R.M.; Fabi, S.G. (San Diego, CA)
11 Evaluating Cosmeceuticals
Draelos, Z.D. (High Point, NC)
20 Cosmeceutical Using Alpha, Beta and Polyhydroxy Acids
Ladenheim, L.A.; Marmur, E.S. (New York, NY)
26 Cosmeceuticals Using Vitamin A and Its Derivatives plus New Delivery Methods
for Them
Kim, A.; Weinkle, S.H. (Tampa, FL)
38 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)
47 Cosmeceuticals Using Growth Factors and Stem Cells
Taub, A.F. (Lincolnshire, IL)
63 Cosmeceuticals Using Peptides, Amino Acids, Glycosaminoglycans and
Other Active Ingredients
Bucay, V.W. (San Antonio, TX)
73 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)
82 Cosmeceuticals for Acne and Rosacea
Turegano, M. (Metairie, LA); Farris, P. (Metairie, LA/New Orleans, LA)
95 Specific Use: Cosmeceuticals for Skin Brightening and Lightening
Burgess, C. (Washington, DC); David, J. (Philadelphia, PA)
104 Specific Use: Cosmeceuticals for Body Skin Texture and Cellulite Treatment
Lindgren, A. (New Orleans, LA); Hui Austin, A.; Welsh, K.M. (San Francisco, CA)
114 Specific Use: Cosmeceuticals for Hair Loss and Hair Care
Holman, J. (Tyler, TX)
121 Specific Use: Cosmeceuticals for the Treatment of Scars, Hypertrophic Scars,
and Keloids
Boen, M.; Alhaddad, M.; Butterwick, K. (San Diego, CA)

V
132 Cosmeceuticals for Sun Protection, Daily Repair, and Protection from
Pollution
Shamban, A. (Santa Monica, CA)
141 Cosmeceuticals following Cosmetic Procedures Including the Use of
Facial Mask
Aristizabal, M. (Bogota); Gold, M.H. (Nashville, TN)
150 Nutraceuticals and Diet for Healthy Skin
Comstock, F. (Tucson, AZ)
157 The Future of Cosmeceuticals
Comstock, J. (Tucson, AZ)

163 Author Index

164 Subject Index

VI Contents
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 companies have taken peptides, proteins, antioxidants,
Arizona in the late 1980s, I had begun to notice an un- nonirritating retinoids, and more to the next level, us-
answered patient demand for the treatment of pigmen- ing more natural ingredients and conducting controlled
tation, redness, large pores, accelerated aging due to studies to thoroughly test them. You will read about the
photodamage, natural aging, and scar tissue that was incredible advances in topical treatment options made
leaving patients with uneven, rough or tired, dull skin. by these companies and more throughout the thought-
The University of Arizona was just completing their ful chapters in this book.
arm of a Retin A study that showed the cosmetic ben- The world of cosmeceuticals is an exciting mix of
efits of retinoids and wrinkle treatment. It was the be- innovative science, strict regulations, and fast-paced
ginning of a transitional time in dermatology. When I consumer business practices. All of this is tempered by
completed my residency, I was fortunate to fall into a our medical oath to do no harm and act in the best in-
small, personalized training in Beverly Hills with Dr. terest of our patients. I am proud to say that the critical
Zein Obagi. While there, I witnessed the potent efficacy role of cosmeceuticals continues to gain respect in the
of medical-grade topical skin care. It specifically was dermatology community, and a faculty position was
able to erase melasma that had been relentlessly and un- created in 2016 for me to teach this important topic to
successfully treated with more traditional means. These dermatology residents at the University of Arizona. I
experiences began a lifelong intrigue with skin care sci- thank Dr. James Sligh for his commitment and vision to
ence that became the foundation of my career. making this happen. New ideas take time.
When I began my private dermatology practice in I was thrilled when Dr. Michael Gold invited me to
1991, I immediately started carrying skin care products be his co-editor of this book. Watching my dermatology
in my clinic, much to the dismay of the local dermatol- colleagues extend their talents to also become cosme-
ogy community. However, my patients were thrilled to ceutical entrepreneurs with devices, products, and busi-
be able to purchase products that cost less than what ness platforms has been a great joy, and we hope this
they had been spending and provided an extension of book helps you on your skin care and science journey.
the care they received in my office. The combination of Dr. Gold is bright, kind, entrepreneurial and incredibly
growing patient demand, patient satisfaction, and passionate about skin care and dermatology. It has been
avoiding the misery of dealing with health insurance nothing but a pleasure working with him.
quickly pushed me to redirect my practice to focus sole- Cosmeceuticals have created an explosion of oppor-
ly on the evolving subspecialty of cosmetic dermatology tunity to optimize healthy and beautiful skin. I am
at a time when that was unheard of. I have never looked grateful to be a cosmetic dermatologist with an array of
back. Cosmeceuticals afford every person a safe, at- treatment and business tools in my practice. The joy of
home means of improving skin tone and texture, as well facilitating my patients to achieve their best and health-
as maximizing global improvement and healing after iest skin is only superseded by their appreciation. The
medical aesthetic procedures. best thing about cosmeceuticals is that there is always
Over the years I have been able to advise excellent more to come!
skin care leaders, including Skin Medica, Colorescience,
Physician’s Choice of Arizona, Skinceuticals, Sente, Conflict of Interest Statement
Obagi, and ZO Skin Health. In 2014, I was named the Dr. Comstock has worked as a consultant, advisor, or in-
Cosmetic Medical Director for Skinbetter Science, an structor for: Skinbetter Science, Allergan, Gladerma, Re-
exciting and science-laden skin care line led by my vance, Evolus, and Endo.
friend, colleague, and mentor Jonah Shacknai. These Jody Comstock, Tucson, AZ

VII
The world we call cosmeceuticals has grown at an as- old, I figured that if a little worked, a lot worked even
tounding rate over the past several years. We have more better. So instead of a little, I put a lot of this solution on
and more cosmeceuticals being developed, which have my skin every night. By night three, I realized I was not
helped many of our patients achieve healthier and more going to be having a fun next few days. What I found
rejuvenated skin. out was that Dr. Kligman had given me a 5% tretinoin
A cosmeceutical is defined as a skin care product solution and then I proceeded to have a medium depth
with bioactive ingredients, which have a desired effect chemical peel over the next week. I stayed home from
on the skin. They have no actual claims of changing the school, was miserable, and in quite some discomfort.
structure and function of the skin in the eyes of the US When all was said and done, my acne was gone, and
FDA, but those cosmeceuticals that dermatologists and now some 45 years later, I rarely get an acne lesion. To
cosmetic physicians use and recommend to patients this day, Dr. Kligman was the inspiration for me to be-
and clients definitely play a major role in skin care. come a dermatologist, and with my later mentor, Dr.
Many companies make skin care products that they Henry Roenigk, this dream became a reality. It was also
call cosmeceuticals. Many have very nice science be- amusing to see Dr. Kligman at some of the dermatology
hind them. It is the purpose of this book to show the conferences. When I lectured, he always seemed to quiz
reader how these cosmeceuticals work for a variety of me to make sure that I was continuing with my studies,
skin care concerns, and in concert with our most com- even while practicing dermatology. I was very fortu-
monly used cosmetic procedures. nate.
The term cosmeceutical was coined by Dr. Albert I was also very lucky to have an incredible editor
Kligman in the 1990s using the terms cosmetic and partner for this project. Dr. Jody Comstock is a rock star
pharmaceutical, to show that they acted like a cosmetic and someone that has been a true professional, and
but had attributes of pharmaceuticals. Again, no claims through this process a good friend. I thank her for her
are made by the companies that make these products. dedication and her commitment to this project. It has
Those in dermatology are lucky to have mentors and been a pleasure working with her.
teachers that spark our interest and command our curi-
osity. I am fortunate that Dr. Kligman became my der- Conflict of Interest Statement
matologist when I was 16 years old. I suffered from a Dr. Gold declares that he has been a consultant and/or per-
very bad case of cystic acne vulgaris. Dr. Kligman pre- formed clinical research for: Defenage, Stratacel, Alastin,
scribed me a solution to use on my skin and told me to Revision, and Topix.
use a little bit every night. Well, being a smart 16 year Michael H. Gold, Nashville, TN

VIII Gold/Comstock

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp VII–VIII (DOI: 10.1159/000491839)
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 The stratum corneum (SC) provides a strong bar-

Cosmeceuticals represent one of the fastest growing seg- rier to drug delivery. This is especially problem-
ments of personal care products. Advances in the field of atic for relatively large molecules with a molecu-
skin biology and pharmacology have facilitated the devel- lar mass larger than 500 Da [1]. Overcoming the
opment of novel active compounds. The increase in the skin barrier in a safe and effective way is the goal
number of active ingredients delivered topically through of transcutaneous delivery systems [2]. Topical
the skin has led to a heightened importance of under- drug delivery heavily depends on the ability of ac-
standing the mechanisms of delivery of those active in- tive ingredients to permeate the skin in sufficient
gredients. Ideal delivery of actives aims at a high delivery quantities to achieve their desired therapeutic ef-
capacity, formulation stability, and minimal side effects. fects. Transcutaneous delivery of medications
There are two pathways for the delivery of cosmeceuti- and active ingredients has gained an unprece-
cals: transepidermal and a transappendageal pathways. dented popularity in the past decade due to de-
Delivery systems can be divided into active systems and mand for targeted and localized delivery with
passive systems. Active systems use physical enhance- minimal side effects [3].
ment methods, like sonophoresis, ionophoresis, micro-
needling, micro-dermabrasion, and ablative, nonablative,
and fractional laser delivery methods. Passive systems uti- Pathways for Skin Penetration
lize chemical delivery methods including chemical pene-
tration enhancers, emulsions, vesicular lipid-based sys- Pathways for transcutaneous drug delivery in-
tems, and lipid particulate carrier systems. Here we review clude transepidermal (intercellular and intracel-
the mechanisms of delivery of active ingredients through lular) and transappendageal (hair follicles, sweat
the skin and the systems by which they are delivered ducts, and sebaceous glands) pathways [4]
through the epidermis. © 2021 S. Karger AG, Basel (Fig. 1).
 Transappendageal route
Intracellular route Intracellular route

a
Fig. 1. Transcellular or intracellular
movement entails the use of an
aqueous pore through the degrada-
tion of corneodesmosomes. Trans-
b
appendageal transportation con- Sebaceous Intracellular lipid
sists of movement through follicular Corneocytes gland matrix
and glandular structures. Intercellu-
lar movement involves the lipid la-
mellae of the intercellular spaces c
where most solute substances per-
Hair follicle Sweat duct
meate across intercellular lipid ave-
nues. a Epidermis (SC). b Dermis.
c Subcutaneous layer.

Transepidermal Pathway Delivery Systems

The transepidermal pathway consists of intercel-
lular and intracellular pathways. Intercellular The first major approach to overcome the skin
pathways involve solute diffusion through the in- barrier is the use of chemical delivery systems
tercellular lipid domains (Fig. 1) [4]. Multiple such as chemical penetration enhancers (CPEs),
studies report that intercellular lipids, and not the emulsions, vesicular lipid-based systems, and lip-
corneocyte proteins, are the main epidermal per- id particulate carrier systems. A second approach
meability barrier. The intracellular (transcellular) is to use physical enhancement methods in which
pathway involves permeation through the cor- an external driving force is used to permeate the
neocytes followed by the intercellular lipids [5]. active ingredient(s). Such methods include sono-
The permeation through corneocytes entails cre- phoresis (ultrasound), electroporation, magneto-
ation of an aqueous pore through degradation of phoresis, micro-needles, thermal ablation, micro-
corneodesmosomes. This route is therefore be- dermabrasion, and iontophoresis [2, 4, 8–11].
lieved to prefer hydrophilic compounds for deliv- Furthermore, ablative, nonablative, and fraction-
ery. Occlusion, ultrasound waves, and ionopho- al lasers have shown efficacy as means to increase
resis can increase this form of permeation [6]. the cutaneous permeation of cosmeceuticals [4].
Both of the aforementioned approaches, chemi-
Transappendageal Pathway cal and physical, have shown successful delivery
In the transappendageal pathway, penetration of for a variety of cosmeceuticals. This article will
actives occurs through the opening of the hair fol- focus on the chemical delivery systems.
licles 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]. Chemical Delivery Systems
Follicular unit numbers, opening diameter, and
follicular volume are important considerations in Chemical Penetration Enhancers
defining the extent of delivery through this path- Skin provides an easily accessible route for drug
way. delivery without first-pass metabolism. To achieve

2 Almukhtar/Fabi

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)
transcutaneous drug delivery, it is often required wide attention in recent years and emerged as a
to overcome the low permeability of the SC. One simple and effective noninvasive strategy for
common strategy is to employ penetration en- macro-molecule delivery into the skin [17]. Al-
hancers which act to increase drug passage across though CPPs have demonstrated their potential
the SC and to decrease the barrier resistance. in enhancing skin delivery, they are still evolving
CPEs act by multiple postulated mechanisms; as a new class of skin penetration enhancers.
solubilizing the intercellular lipid matrix, dis- CPPs are relatively short (up to 30 amino acids in
rupting the protein component of the intracellu- length), water soluble, cationic, and/or amphipa-
lar keratin domains, and increasing drug parti- thic peptides that are capable of carrying large
tioning into the tissue by acting as a solvent for macromolecules across cellular membranes [17].
the permeant within the membrane [12]. As a re- CPPs have been increasingly used to mediate the
sult, CPEs can cause skin irritation and safety delivery of molecular cargoes such as small mol-
concerns related to the health of the skin barrier. ecules, small interfering RNA nucleotides, drug-
Many different classes of compounds have been loaded nanoparticles, proteins, and peptides
proposed as CPE, including fatty acids (e.g., do- without using any receptors and without causing
decanoic acid, stearic acid, oleic acid), surfactants any significant membrane damage [18]. These
(e.g., sodium dodecyl sulfate), azone (e.g., lauro- peptides are capable of internalizing electrostati-
capram), osmolytes (e.g., urea and glycols, in- cally or covalently bound biologically active car-
cluding propylene glycol), and monoterpenes goes with high efficiency and minimal toxicity
(e.g., thymol, carvacrol, and geraniol) [13, 14]. [19].
These compound classes are different with re-
spect to their chemical and physical properties, Emulsion
and therefore expected to influence the SC mo- Emulsions are mixtures of liquids that do not
lecular properties in different ways. Fatty acids, normally blend (water and oil): oil-in-water
surfactant, and monoterpenes mainly affect SC (O/W), in which oil droplets are dispersed in wa-
lipids while osmolytes affect both SC lipid and ter, or water-in-oil (W/O), in which water drop-
protein components [15]. The irritation response lets are dispersed in oil [20]. The former is more
of CPEs correlates with their ability to denaturize commonly used in topical formulations. Emul-
SC proteins [15]. Furthermore, molecular effects sions are milky with coarse dispersion and a
of added compounds on SC depend on SC hydra- droplet size in the range of micrometers. They are
tion. The addition of water leads to increased mo- thermodynamically but not kinetically stable and
lecular mobility of both protein and lipid compo- thus will eventually phase-separate. Micro-emul-
nents of the SC. Increasing fluidity is expected to sions and nano-emulsions are formulations of
lead to higher permeability for both polar and water and oil, similar to emulsions, but with the
nonpolar compounds [16]. The main part of both addition of surfactants.
the lipid and the keratin components are solid. In Micro-emulsions are dispersions with a drop-
hydrated conditions, minor fractions of the SC let size between 10 and 100 nm [21]. They are
lipid and protein components become fluid. Fur- clear or translucent and thermodynamically sta-
thermore, the fluidity in these components can ble. The advantages of micro-emulsions include:
also be altered by the addition of compounds like the ease and low cost of preparation, the possibil-
urea or glycerol which are constituents of the nat- ity of incorporating both hydrophilic and lipo-
ural moisturizing factor. philic drugs at the same time, the increased drug
Cell-penetrating peptides (CPPs), also known loading, and the penetration-enhancing ability.
as protein transduction domains, have garnered The absorption is improved by the use of penetra-

Delivery Mechanisms: Skin Function and Barrier 3

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)
 4
Table 1. Vesicular lipid-based delivery system

Vesicular system Composition Advantages Disadvantages

Liposomes Vesicles formed by biodegradable Lipids are biocompatible and biodegradable High cost of lipids
lipids (phospholipid and Suitable for both hydrophobic and hydrophilic Poor chemical (e.g., oxidative degradation)
cholesterol) surrounding an drug loading and physical stability (e.g., aggregation and
aqueous core fusion)
Poor permeation to viable epidermis and
dermis
Poor physicochemical characteristics (higher
particle size, higher rigidity, and low
encapsulation efficiency)
Ultra-deformable Similar to the vesicular structure Lipids are biocompatible and biodegradable High cost of lipids
liposomes of conventional liposomes but Higher elasticity and smaller vesicle size when Hydrophobic drug loading can compromise
functionally they are sufficiently compared to conventional liposomes the elasticity of vesicles
deformed due to the presence of High membrane hydrophilicity and elasticity Limited skin permeation under occlusive
edge-activator decreases aggregation and fusion properties conditions
under osmotic stress
Higher skin permeation potential compared to
liposomes
Ethosomes Similar to conventional liposomes Lipids are biocompatible and biodegradable High cost of lipids
in vesicular structure but Suitable for both hydrophobic and hydrophilic Lack of long-term structural and chemical
functionally they are sufficiently drug loading stability data during storage
deformed due to the presence of Higher elasticity, smaller vesicle size, and higher Challenge in optimizing lipid and ethanol
ethanol entrapment efficiency than conventional physicochemical properties without
liposomes compromising the stability of ethosomes
Possibility of skin irritation and toxicity due
to high ethanol content

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)
Almukhtar/Fabi
tion 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 in-
creases their desirability and use in many cosme-
ceuticals, including moisturizers, sunscreen prep- Aqueous
medium
arations, tanning products, antiaging products,
antiperspirants, deodorants, hair care and color-
ing products, and perfumes. A common concern
related to micro-emulsion use for topical delivery
is their potential side effects, mainly skin irrita-
tion potential and comedogenic effects. These
Fig. 2. Structure of a liposome.
side effects are generally associated with exposure
time and the composition and concentration of
components, especially of surfactants, and com-
ponents of the oil phase. [29]. Vesicular-based systems consist of three
Nano-emulsions are emulsions with droplets main carriers: liposomes, transfersomes (ultra-
smaller than 100 nm, comparable to the size of deformable liposomes), and ethosomes [30] (Ta-
micro-emulsions despite what the name implies ble 1).
[22]. Nano-emulsions present the advantage of
being formed with smaller amounts of surfac- Liposomes
tants, and thus lower skin irritation potential The first generation of vesicular-based systems
[23]. The preparation of stable nano-emulsions are liposomes, which were first described by Me-
generally requires expensive, high-energy input zei and Gulasekharam [31] in 1980. A liposome is
methods. Nano-emulsions are kinetically, not formed by a lipid bilayer surrounding an aqueous
thermodynamically, stable [24]. Their instability solution (Fig. 2) and can range in size between
leads to a more favorable use of other nano-sized 200 and 800 nm [29, 32]. Drug delivery using
delivery systems like nanosomes or solid lipid these carriers is mainly limited by their rigidity
nanoparticles (SLNs), which will be discussed lat- and size, which can impede SC penetration. Lipo-
er. Nano-emulsions are used for transcutaneous somes more than 600 nm in size do not penetrate
delivery of multiple agents, including gamma to- deeply and remain in the SC. Their advantages lie
copherol, caffeine, and plasmid DNA [25–27]. in the wide variety of drugs that can be incorpo-
rated as well as their biocompatibility with natu-
Vesicular Lipid-Based Systems ral phospholipids. Examples of drugs delivered
Over the past few years, vesicular-based systems throughout the skin using liposomes are curcum-
have been increasingly used as a compelling in and retinoic acid [33–35]. Furthermore, lipo-
means of transcutaneous delivery of various ther- somes have been utilized to deliver siRNA through
apeutic agents. A vesicular-based system consists the skin and impact protein expression at basal
of a concentric lamellar structure with an aqueous keratinocytes [36].
core surrounded by a phospholipid bilayer [28].
These systems provide multiple opportunities for Transfersomes
the entrapment of hydrophilic, lipophilic, and The need for smaller, more elastic carriers led to
amphiphilic drugs. Mechanisms of drug trans- the development of the second generation of ve-
port involve improving drug solubility, drug par- sicular-based lipid carriers, transferosomes, also
titioning into the skin, and fluidizing SC lipids termed ultra-deformable liposomes [37]. In 1992,

Delivery Mechanisms: Skin Function and Barrier 5

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)
Cevc and Blume [38] introduced the transfer- nonocclusive conditions. The addition of ethanol
somes, which resemble liposomes in morphology in ethosomes may contribute to their superior de-
but are more lipophilic, smaller than 300 nm, and livery properties, which can lead to the systemic
are at least one order of magnitude more elastic absorption of drugs encapsulated within etho-
than liposomes. Furthermore, when compared to somes [41]. The potential of ethosomes for irrita-
liposomes, transfersomes contain one or more tion and systemic absorption in addition to their
edge-activator substance(s), surfactants being the long-term safety needs further exploration. Etho-
most commonly used edge-activators. Edge-acti- somal delivery systems dramatically enhance skin
vators typically used for ultra-deformable lipo- permeation of minoxidil and have been used in
some preparation include sodium cholate, sodi- the delivery of hyaluronic acid [42–44].
um deoxycholate, Span 60, Span 65, Span 80,
Tween 20, Tween 60, Tween 80, and dipotassium Other Emerging Lipid-Based Vesicles
glycyrrhizinate [37]. There are 2 major proposed Niosomes are nonionic unilamellar or multila-
mechanisms of skin delivery via ultra-deformable mellar vesicles in which the active ingredient is
liposomes [37, 39]. The first mechanism proposes encapsulated. They have improved the stability
that the deformable nature of the intact vesicles and availability of active ingredients as well as
contributes to their entry into the SC. The second skin penetration compared to liposomes. Exam-
mechanism proposes that vesicles act as penetra- ples of drugs delivered using niosomes are min-
tion enhancers, whereby vesicles modify the in- oxidil and ellagic acid [44]. The synergistic effects
tercellular lipids of the SC. Because their trans- of two antioxidants, α-tocopherol and curcumin,
port across the skin is driven by a hydration gra- were demonstrated using a niosomal delivery sys-
dient, occlusive application can compromise the tem [45].
action of the deformable vesicles by eliminating Ultrasomes are liposomes encapsulating a
the gradient force. One disadvantage of these ves- UV-endonuclease enzyme [46]. They help repair
icles corresponds to the difficulty in loading hy- UV-induced DNA damage and inhibit the ex-
drophobic drugs into the vesicles without com- pression of pro-inflammatory cytokines. Similar-
promising their deformability and elastic proper- ly, photosomes help repair DNA damage by en-
ties [39]. capsulating a light-activated enzyme (photolyase)
in a liposomal structure and are thus included in
Ethosomes certain sunscreen products.
Godin and Touitou [40] developed the third gen-
eration of liposomes, called ethosomes. An etho- Lipid Particulate Carrier Systems
some is composed of an aqueous core, phospho- Lipid particulate carrier systems have attracted
lipid bilayer, and ethanol (20–45%). The incorpo- researchers and gained popularity over other de-
ration of high ethanol concentration, which livery systems in recent years because of the avail-
differentiates ethosomes from other vesicular- ability of nontoxic and bio-compatible lipid in-
based carriers, confers a negative charge to the li- gredients [47]. Lipid particulate systems typically
posomes which causes the vesicular size to de- include micro-capsules, micro-sponges, and lipid
crease to the nanometer range, thus enhancing nanoparticles, such as SLNs and nanostructured
their skin permeation capacity. They also have lipid carriers (NLCs) [47].
higher elasticity, typically 10–30 times higher
than conventional liposomes [40, 41]. Unlike Micro-Capsules
transfersomes, ethosomes are able to improve the The use of micro-capsules in cosmeceutical prod-
skin delivery of drugs both under occlusive and ucts has gained more interest in recent years due

6 Almukhtar/Fabi

Comstock J, Gold MH (eds): Cosmeceuticals. Aesthet Dermatol. Basel, Karger, 2021, vol 5, pp 1–10 (DOI: 10.1159/000491840)