Topical Applications and the Mucosa
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Mucosal membranes have unique anatomical and physiological properties -- differing from those of the keratinized epithelium -- which affect drug or chemical absorption. This makes the diagnosis and treatment of diseases of the mucosa a challenge to dermatologists as well as gynecologists, since many conditions are difficult to recognize and well-established principles of skin disease treatment do not apply to the mucosa. This volume is exclusively devoted to the mucosal membrane and delivers a better understanding of this distinctive area. Subsequently to introductory chapters on the morphology and physiology of the mucosa, the topical treatment of impaired mucosal membranes is discussed. A third section covers the wide spectrum of consumer products applied on mucosal surfaces. Finally, the safety of products for mucosal membranes is reviewed.Providing an excellent summary and review of the latest findings and topical applications, this book will be of great value to physicians and clinicians in dermatology or gynecology, pharmacists, scientists and toxicologists who are involved in the development of products for mucosal membranes.



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Date de parution 10 février 2011
Nombre de lectures 0
EAN13 9783805596169
Langue English
Poids de l'ouvrage 1 Mo

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Topical Applications and the Mucosa
Current Problems in Dermatology
Vol. 40
Series Editor
Peter Itin Basel
Gregor Jemec Roskilde
Topical Applications and the Mucosa

Volume Editors
Christian Surber Basel
Peter Elsner Jena
Miranda A. Farage Cincinnati, Ohio
25 figures, 8 in color, and 27 tables, 2011

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Shanghai • Singapore • Tokyo • Sydney
Current Problems in Dermatology
Christian Surber Dermatologische Universitatsklinik Basel Universitatsspital Basel Petersgraben 4 4031 Basel Switzerland
Peter Elsner Department of Dermatology University Hospital Jena Erfurter Str. 35 07743 Jena Germany
Miranda A. Farage The Procter & Gamble Company Feminine Care Innovation Center 6110 Center Hill Rd, Box 136 Cincinnati, OH 45224 USA
Library of Congress Cataloging-in-Publication Data
Topical applications and the mucosa / volume editors, Christian Surber, Peter Elsner, and Miranda A. Farage. p.; cm. (Current problems in dermatology, ISSN 1421-5721; vol. 40) Includes bibliographical references and index. ISBN 978-3-8055-9615-2 (hard cover: alk. paper) ISBN 978-3-8055-9616-9 (e-book) 1. Dermatologic agents. 2. Mucous membrane. 3. Skin absorption. I. Surber, Christian, 1955- II. Elsner, Peter, 1955- III. Farage, Miranda A. IV. Series: Current problems in dermatology; v. 40. 1421-5721 [DNLM: 1. Administration, Topical. 2. Mucous Membrane-drug effects. 3. Genitalia-drug effects. W1 CU804L v.40 2011 / QS 532.5.M8] RM303.T67 2011 616.97’3 dc22

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 2011 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISSN 1421-5721 ISBN 978-3-8055-9615-2 e-ISBN 978-3-8055-9616-9
Surber, C. (Basel); Elsner, P. (Jena); Farage, M.A. (Cincinnati, Ohio)
Section I: Introduction
Anatomical and Physiological Basis of Topical Therapy of the Mucosa
Elsner, P. (Jena)
Morphology and Physiological Changes of Genital Skin and Mucosa
Farage, M.A. (Cincinnati, Ohio); Maibach, H.I. (San Francisco, Calif.)
Section II: Topical Treatment of Impaired Mucosal Membranes
Nasal Drug Delivery in Humans
Bitter, C.; Suter-Zimmermann, K.; Surber, C. (Basel)
Antimicrobial Topical Agents Used in the Vagina
Frey Tirri, B. (Basel)
Topical Therapy for Mucosal Yeast Infections
Summers, P.R. (Salt Lake City, Utah)
Anti-Inflammatory Treatment
Fistarol, S.K.; Itin, P.H. (Basel)
Topical Antineoplastic Agents in the Treatment of Mucocutaneous Diseases
Grossberg, A.L.; Gaspari, A.A. (Baltimore, Md.)
Section III: Consumer Products and Mucosal Membranes
Diaper Area and Disposable Diapers
Erasala, G.N.; Romain, C.; Merlay, I. (Asnières)
Products Used on Female Genital Mucosa
Farage, M.A.; Lennon, L.; Ajayi, F. (Cincinnati, Ohio)
Emollients on the Genital Area
Farage, M.A.; Warren, R. (Cincinnati, Ohio)
Oral Care
Hitz Lindenmüller, I.; Lambrecht, J.T. (Basel)
Section IV: Safety of Products for Mucosal Membranes
Assessing the Dermal Safety of Products Intended for Genital Mucosal Exposure
Farage, M.A. (Cincinnati, Ohio); Scheffler, H. (Schwalbach)
Can the Behind-the-Knee Clinical Test Be Used to Evaluate the Mechanical and Chemical Irritation Potential for Products Intended for Contact with Mucous Membranes?
Farage, M.A.; Miller, K.W. (Cincinnati, Ohio); Ledger, W.J. (New York, N.Y.)
Contact Sensitization in the Anal and Genital Area
Bauer, A.; Oehme, S. (Dresden); Geier, J. (Göttingen)
Perceptions of Sensitive Skin of the Genital Area
Farage, M.A. (Cincinnati, Ohio)
New Irritation Test Method: Behind the Knee and Mucosa
Ledger, W.J. (New York, N.Y.)
Author Index
Subject Index

The diagnosis and treatment of diseases of the mucosa are a challenge for dermatologists and gynecologists, since many conditions are difficult to recognize, and well-established principles of treatment of skin diseases cannot be simply extrapolated to the mucosa. Mucosal membranes have unique anatomical and physiological properties. Drug or chemical absorption is different from that in keratinized epithelium, and research as in other areas (i.e. keratinized skin) is largely missing.
Few books are exclusively devoted to the mucosal membrane. We hope to establish a better understanding of this unique mucosal area and to encourage the needed research. We also hope that this attempt to compile information will be valuable to its intended audience.
This book aims to gather the current knowledge in this field to the benefit of physicians, pharmacists, scientists, clinicians and toxicologists alike. After introductory chapters on the morphology and physiology of the mucosa, the topical treatment of impaired mucosal membranes is discussed. A third section then covers the wide spectrum of consumer products applied to mucosal surfaces. Finally, the safety of products used on mucosae is reviewed.
The editors would like to thank the contributing authors for their enthusiasm and support. We would also like to thank the staff of Karger Publishers for their help with the project.
We are looking forward to receiving critical feedback from our readers for improvements of this text.
Christian Surber, Basel
Peter Elsner, Jena
Miranda A. Farage, Cincinnati
Section I: Introduction
Surber C, Elsner P, Farage MA (eds): Topical Applications and the Mucosa. Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 1–8
Anatomical and Physiological Basis of Topical Therapy of the Mucosa
Peter Elsner
Department of Dermatology and Allergy, University of Jena, Jena, Germany
The mucosa as a nonkeratinized epithelium covering body surfaces has widely differing anatomical and physiological properties depending on the organ system involved (gastrointestinal, respiratory, urinary, genital, ocular). In general, the mucosae close to the skin are more permeable to exogenous substances, more prone to irritant reactivity, and they have a unique microbial ecology which is qualitatively and quantitatively different from that of the adjacent keratinized epithelium. Clinical presentations of exogenous dermatoses in mucosae appear different from those of the skin. These specific properties of mucosae have to be considered in the development and application of topical agents, cosmetics and consumer products.
Copyright 2011 S. Karger AG, Basel
The mucosa is defined as nonkeratinized epithelium covering the surfaces of the gastrointestinal, the respiratory, the urinary and the genital tracts and the eye. In this book, the mucosal surfaces close to the skin are of interest, i.e. the nasal, oral, genital and anal areas. Since it is not possible to cover all of these mucosae in detail, the anal and the genital mucosae are discussed as examples of specialized skin.
Anatomy of the Mucosa of the Anal Canal
The anal canal is a 2.5- to 4-cm-long tubular structure connecting the anal opening with the rectum. While the rectal side of the anal canal is covered with intestinal mucosa, the distal zone is characterized by squamous epithelium. The linea dentata (pectinate line) is located at 2 cm at the transition between the intestinal mucosa and the squamous epithelium. It is a row of alternating anal columns (Morgagni columns) and sinuses marking the limit between the endodermal and the ectodermal parts of the anal canal. While the proximal part of the anal canal is not supplied with somatosensory nerves and therefore not subject to pain, these are present distal of the linea dentata. Anal glands open into the anal sinuses or crypts. When obstructed, anal abscesses or fistulas may develop. The squamous epithelium of the lower anal canal is nonkeratinized. While the anal canal mucosa does not contain skin appendages, there are sebaceous, apocrine and sweat glands in the perianal skin. The outer limit of the anal canal is marked by the anocutaneous line (Hilton’s line). Distal of it, stratified squamous keratinized epithelium is found.
Fig. 1. Topography of the human vulva.

Physiology of the Mucosa of the Anal Canal
The physiological function of the anal canal is to permit and to control defecation (continence). This explains the abundance of sensory nerve endings in the distal zone including receptors for pain (free intraepithelial nerve endings), touch (Meissner’s corpuscles), cold (Krause end bulbs), pressure or tension (corpuscles of Pacini and Golgi-Mazzoni) and friction (genital corpuscles) [ 1 ]. Thus, the sensitive mucosa of the anal canal is able to discriminate between flatus and liquid or solid stool. Very little is known about the barrier properties of the anal canal mucosa.
Anatomy of the Mucosa of the Vulva
The female external genital organs consist of the mons pubis, the labia majora, the labia minora, the clitoris and the glandular structures (fig. 1 ). The size and shape of these structures, their pigmentation and the distribution of hair show considerable variance depending on hormonal status, pelvic architecture, race and age [ 2 ].
Vulvar skin is no biologically uniform entity. On the contrary, there are considerable anatomical and physiological differences between the skin covering mons pubis, labia majora and labia minora, clitoris and perineum (table 1 ). Even within the single structures there are differences between lateral and medial and anterior and posterior locations.
Age-dependent changes in vulvar skin are significant even though this skin is not subject to photoaging [ 3 ]. Lifetime changes in the vulva and vagina have recently been reviewed in detail [ 4 ]. Rete ridges are missing until puberty. In postpubertal women, they gradually develop and increase in depth until menopause when involution begins. The stratum corneum of labium majus skin increases in thickness with age, followed by postmenopausal atrophy [ 5 ]. Vulvar dermis shows elastotic degeneration similar to actinic damage in elderly women. While a stratum corneum is found at the lateral side of the labia minora in 100%, this is only true in two thirds for the medial side [ 5 ]. In specimens from healthy women below 20 years of age, a dermal inflammatory infiltrate is not observed, but it is a regular finding in menstruating women with a maximum around the fourth or fifth decade, followed by gradual involution with age [ 3 ]. Plasma cells in limited numbers are regularly found in genital skin.
In vulvar swabs, parakeratotic cells are regularly observed, most frequently in the third and only very rarely in the eighth decade [ 6 ]. The frequency of parakeratotic cells seems to depend on the hormonal situation, and it is decreased under topical testosterone therapy.
Physiology of Vulvar Skin
Surface pH of Vulvar Skin
Vulvar skin surface pH is more than 1 pH unit higher than forearm pH (5.99 ± 0.45 compared to 5.02 ± 0.50 [ 7 ]). Thus, vulvar skin is like other intertriginous areas that show pH values significantly higher than on nonoccluded skin. Occlusion seems to enhance stratum corneum ion permeability, thus neutralizing the normally acid skin surface. The higher skin surface pH of vulvar skin is an important cause for the high density of microbial colonization.
Table 1. Site-dependent anatomical characteristics of human vulvar skin

Barrier Function of Vulvar Skin
Early work on transepidermal water loss (TEWL) as an indicator of barrier function of vulvar skin revealed the mean TEWL to be 1.45 x 10 3 µg water/cm 2 /h while that of the forearm was 7.7 x 10 2 µg water/cm 2 /h (p < 0.0001) [ 8 ]. Thus, the vulva appears far more permeable to water than the forearm. To eliminate possible eccrine sweat contamination, subjects received subcutaneous injections of atropine in both forearm and vulva test sites. The average mean forearm TEWL was 8.7 x 10 2 µg/cm 2 /h, and the vulvar TEWL was 1.4 x 10 3 µg/cm 2 /h [ 8 ].
Since TEWL may be influenced by anatomical or garment-related occlusion, that of labium majus skin was studied over an extended period (fig. 2 , 3 ) [ 9 ]. It was indeed found that vulvar TEWL decreased following deocclusion. However, the stabilized final value was still significantly higher at the vulva than at the forearm. It should be noted that periodic bursts of markedly increased water loss were noted at vulvar test sites, but none at forearm sites (fig. 2 ). Studies using a topical drying chamber applied to vulvar skin over several days confirmed the increased intrinsic vulvar TEWL [ 7 ]. On the basis of these findings, barrier function of vulvar skin seems to be imperfect compared to other body sites such as the forearm.
This was confirmed by dermatopharmacological data that showed a higher percutaneous penetration of hydrocortisone through vulvar skin compared to forearm skin [ 10 ]. However, the magnitude of difference in percutaneous penetration between vulvar and forearm skin is only three- to fourfold, compared with a more than fortifold higher penetration in scrotal skin.
Irritant Reactivity of Vulvar Skin
Impaired barrier function means a lesser protection from the harmful effects of irritants and thus a higher proclivity to irritant dermatitis. Several studies have sought to determine whether vulvar skin is more or less susceptible to irritation from chemical agents in comparison to the ventral forearm.
In a number of studies, Elsner et al. [ 11-13 ] investigated the effect of sodium lauryl sulfate (SLS), an anionic surfactant widely used in skin-cleansing products, on vulvar compared to forearm skin. Twenty healthy women, 10 before and 10 after menopause, were patch tested with SLS for 24 h. In forearm skin, irritant dermatitis developed in the majority of subjects. In vulvar skin, only 50% of the women developed irritant dermatitis. Postmenopausal women reacted less frequently and more slowly to SLS than premenopausal women in the forearm, whereas no age-related differences were observed in the vulva. The authors concluded that vulvar skin is not more reactive to SLS than forearm skin (fig. 4 ) and that age-related differences in irritant reaction are apparent in the forearm, but not in the vulva [ 11 ]. The reported studies indicate that vulvar irritant reactivity may not be higher than that of the forearm for all irritants, and that data from irritation tests in the arm should not be simply extrapolated to vulvar skin.
If irritant dermatitis does develop in vulvar skin, it tends to heal more quickly than forearm skin upon removal of the irritant. This applies not only to chemically induced trauma, but also to mechanical trauma [ 14 ].
Fig. 2. Long-term monitoring of TEWL of human vulvar skin.

Fig. 3. Long-term monitoring of TEWL of human vulvar skin. The spikes of TEWL increase (arrows) indicate sweating episodes.

Fig. 4. Influence of 5% SLS irritation on forearm and vulvar TEWL in premenopausal women (n = 10) as an indicator of barrier damage [ 13 ]. Whereas a significant TEWL increase occurs in the forearm, this is not the case in the vulva, where a TEWL reduction was observed on days 7 and 10 with 5% SLS. * p < 0.05, ** p < 0.01: significant differences between treated and control sites evaluated by the paired t test.

Microbiology of Vulvar Skin
Skin moisture and pH that are increased on vulvar compared to forearm skin are important factors for microbial growth. Another factor is microbial adherence to keratinocytes. Bibel et al. [ 15 ] found a high adherence of Staphylococcus aureus to the larger, rougher cells of the labium majus matched only by the adherence to fully keratinized nasal epithelial cells. S. aureus adherence both to the labium minus and to vaginal epithelia was low as was the adherence to forearm keratinized cells. Compared to the adherence of S. aureus to labium majus cells, other microorganisms (Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter calcoaceticus and Candida albicans) showed far lower adherence scores. Whereas C. albicans failed to attach to nasal cells and clung poorly to forearm and labium minus cells, there was a significant adherence of the organism to labium majus cells.
Aly et al. [ 16 ] investigated the flora of 18 healthy female volunteers with a mean age of 39 years. Samples from mid-labium majus skin and forearm were collected by the detergent scrub method. Microbial counts were higher on the vulva (2.8 x 10 6 /cm 2 ) than on the forearm (6.4 x 10 2 /cm 2 ). The prevalence data (fig. 5 ) show a higher prevalence of S. aureus, α-hemolytic streptococci, lipophilic and nonlipophilic diphtheroids, lactobacilli, Gram-negative rods and yeasts on vulvar compared to forearm skin, whereas the micrococci were less prevalent in the vulva.
Fig. 5. Prevalence of microorganisms in human forearm and vulvar skin (n = 18). Graph based on data from Aly et al. [ 16 ].

The quantitative results from the same study [ 16 ] are presented in table 2 . Lipophilic diphtheroids, coagulase-negative staphylococci, micrococci, nonlipophilic diphtheroids and lactobacilli composed the dominant flora of the vulva.
Elsner and Maibach [ 17 ] investigated the bacterial population dynamics of labium majus skin during the menstrual cycle. In 20 women, samples were taken on days 2 and 4 of their menstruation and on day 21 of the menstrual cycle. The results confirm the previous work both as far as the approximate density of the aerobic flora and the prevalence and densities of the various organisms are concerned. There was a small, though insignificant, reduction of total organisms during the menstruation from 2.0 x 10 6 on day 2 to 8.9 x 10 5 on day 4. This is more obvious for β-hemolytic streptococci and both Gram-negative and Gram-positive rods. Lower numbers of micrococci and nonlipophilic diphtheroids were found on day 21 than during menstruation, whereas the opposite was true for α-hemolytic streptococci and nonpathogenic Neisseria. The numbers of S. aureus and coagulase-negative staphylococci showed little changes over the menstrual cycle. The numbers of lactobacilli and Gardnerella vaginalis were also relatively constant during the investigation period.
The microbial colonization of human skin is an important variable influencing body odors. While sterile apocrine sweat is odorless, odors are developed by bacterial degradation of the sweat. With the high and relatively stable density of bacteria on vulvar skin, the microbial generation of odors is a physiological, though cosmetically important feature of this area. A fishy odor, especially after alkalinization by sexual intercourse and during menstruation, is an important symptom of bacterial vaginosis, a frequent condition additionally characterized by a thin, homogenous vaginal discharge, vaginal pH of >4.5 and the presence of ‘clue cells’, i.e. vaginal epithelia densely covered by bacteria, in a wet mount [ 18 ]. The fishy odor is attributed to amines produced by the vaginal flora, which is marked by a lack of lactobacilli and an overgrowth of G. vaginalis and anaerobes in patients with bacterial vaginosis.
Table 2. Bacterial counts (organisms/cm 2 ) on vulvar (mid-labium majus) and forearm skin (n = 18)

Anal and vulvar mucosae are forms of specialized skin with unique morphological and functional properties. The vulva tends to be more permeable than other sites and to have specific proclivity to irritant activity, unique microbial ecology and increased blood flow. Regarding unwanted effects of topical products applied to vulvar skin, both the spectrum of irritants and allergens and the clinical presentation of contact urticaria as well as irritant and allergic contact dermatitis may be different from other sites of the human body. One must be aware of these differences of this specialized skin, especially in topical therapy.
1 Duthie HL, Gairns FW: Sensory nerve endings and sensation in the anal region of man. Br J Surg 1960;47:585-595.
2 Hoyme UB, Buehler K: Anatomy and physiology of the vulva, the vagina and the cervix; in Elsner P, Martius J (eds): Vulvovaginitis. New York, Dekker, 1993, pp 275-284.
3 Harper WF, McNicol EM: A histological study of normal vulvar skin from infancy to old age. Br J Dermatol 1977;96:249-253.
4 Farage M, Maibach HI: Lifetime changes in the vulva and vagina. Arch Gynecol Obstet 2006;273:195-202.
5 Jones IS: A histological assessment of normal vulvar skin. Clin Exp Dermatol 1983;8:513-521.
6 Nauth HF, Boon ME: Significance of the morphology of anucleated squames in the cytologic diagnosis of vulvar lesions: a new approach in diagnostic cytology. Acta Cytol 1983;27:230-236.
7 Elsner P, Maibach HI: The effect of prolonged drying on transepidermal water loss, capacitance and pH of human vulvar and forearm skin. Acta Derm Venereol 1990;70:105-109.
8 Britz MB, Maibach HI: Human labia major skin: transepidermal water loss in vivo. Acta Derm Venereol 1979;85 (suppl):23-25.
9 Elsner P, Wilhelm D, Maibach HI: Physiological skin surface water loss dynamics of human vulvar and forearm skin. Acta Derm Venereol 1990;70:141-144.
10 Britz MB, Maibach HI: Human percutaneous penetration of hydrocortisone: the vulva. Arch Derm Res 1980;267:313-316.
11 Elsner P, Wilhelm D, Maibach HI: Effect of low-concentration sodium lauryl sulfate on human vulvar and forearm skin: age-related differences. J Reprod Med 1991;36:77-81.
12 Elsner P, Wilhelm D, Maibach HI: Multiple parameter assessment of vulvar irritant contact dermatitis. Contact Dermatitis 1990;23:20-26.
13 Elsner P, Wilhelm D, Maibach HI: Sodium lauryl sulfate-induced irritant contact dermatitis in vulvar and forearm skin of premenopausal and postmenopausal women. J Am Acad Dermatol 1990;23:648-652.
14 Wilhelm D, Elsner P, Maibach HI: Standardized trauma (tape stripping) in human vulvar and forearm skin: effects on transepidermal water loss, capacitance and pH. Acta Derm Venereol 1991;71:123-126.
15 Bibel DJ, Aly R, Lahti L, Shinefield HR: Microbial adherence to vulvar epithelial cells. J Med Microbiol 1987;23:75-82.
16 Aly R, Britz MB, Maibach HI: Quantitative microbiology of human vulva. Br J Dermatol 1979;101:445-448.
17 Elsner P, Maibach HI: Microbiology of specialized skin: the vulva. Semin Dermatol 1990;9:300-304.
18 Martius J: Bacterial vaginosis; in Elsner P, Martius J (eds): Vulvovaginitis. New York, Dekker, 1993, pp 345-364.
P. Elsner, MD Department of Dermatology, University Hospital Jena Erfurter Strasse 35 DE-07743 Jena (Germany) Tel. +49 3641 937 350, Fax +49 3641 937 418, E-Mail
Section I: Introduction
Surber C, Elsner P, Farage MA (eds): Topical Applications and the Mucosa. Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 9-19
Morphology and Physiological Changes of Genital Skin and Mucosa
Miranda A. Farage a • Howard I. Maibach b
a Feminine Care Clinical Sciences, Procter and Gamble Company, Cincinnati, Ohio, and b Dermatology Department, University of California School of Medicine, San Francisco, Calif., USA
The morphology and physiology of both the vulva and vagina undergo characteristic age-related changes over a lifetime. At birth, these tissues exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina mature under the influence of adrenal and gonadal steroid hormones. During the reproductive years, the vagina responds to ovarian steroid hormone cycling, and both tissues adapt to the needs of pregnancy and delivery. Following menopause, the vulva and vagina atrophy. A rise in the prevalence of incontinence among older women increases the risk of vulvar and perineal dermatitis. This chapter covers the morphology and physiology of the genital area from infancy to old age.
Copyright 2011 S. Karger AG, Basel
The morphology and physiology of the vulva and vagina change over a lifetime. The most salient changes are linked to puberty, the menstrual cycle, pregnancy and menopause. The cutaneous epithelia of the mons pubis, labia and clitoris originate from the embryonic ectoderm and exhibit a keratinized, stratified structure similar to skin at other sites. The mucosa of the vulvar vestibule, which originates from the embryonic endoderm, is nonkeratinized. The vagina, derived from the embryonic mesoderm, is responsive to estrogen cycling. At birth, the vulva and vagina exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina acquire mature characteristics in a sequential fashion in response to adrenal and gonadal maturation. A trend to earlier pubertal onset has been observed in Western developed countries. In women of reproductive age, the vaginal mucosa responds to steroid hormone cycling, exhibiting maximal thickness and intracellular glycogen content at mid-cycle. Vulvar skin thickness remains unchanged but menstrual-cycle-associated changes in ortho-and parakeratosis occur at the cytological level. The vulva and vagina further adapt to the needs of pregnancy and delivery. After menopause, tissue atrophy ensues. Postmenopausal changes in skin barrier function, skin hydration and irritant susceptibility have been observed on exposed skin but not on the vulva. Nevertheless, older women with incontinence are at increased risk for developing incontinence dermatitis. A combination of factors, such as tissue atrophy, slower dissipation of excess skin hydration, shear forces associated with limited mobility and lower tissue regeneration capacity increase the risk of morbidity from incontinence dermatitis in older women. This chapter covers the morphology and physiology of the genital area from infancy to old age and has been reviewed in Farage et al. [ 1 ] and Farage and Maibach [ 2 ]. A summary of these changes can be found in table 1 .
Table 1. Morphological and physiological changes in genital skin and mucosa from infancy to old age (reproduced from Farage et al. [ 1 ] and Farage and Maibach [ 2 ])

Embryonic Derivation and Epithelial Structure
The lower urogenital tract is the only portion of the female anatomy derived from all 3 embryological layers (ectoderm, endoderm and mesoderm) [ 15 ]. Like skin at other anatomical sites, the skin of the mons pubis, the labia, the clitoris and the perineum, derived from the embryonic ectoderm, has a keratinized, stratified squamous structure with sweat glands, sebaceous glands and hair follicles ( fig. 1a ). Cutaneous thickness and degree of keratinization are relatively high on the mons pubis and labia majora, but decrease over the anterior portions of the clitoris and in going from the outer surface to the inner surface of the labia minora [ 16 ]. The mucosa of the vulvar vestibule is the only portion of the female genital tract of endodermal origin [ 17 ]. Its superficial stratum is nonkeratinized, and differentiation of the inner layers is indistinct: loosely packed, polyhedral cells alter in size and organelle density as they migrate upward from the generative basal layer, but do not form clearly demarcated strata as observed in the skin ( fig. 1b ). The vagina, of mesodermal origin, has nonkeratinized squamous epithelium that is responsive to ovarian steroid hormone cycling [ 7 ].
Infancy and Early Childhood
The genitals of the newborn exhibit the effects of residual maternal estrogens. At birth, the labia majora appear plump, and the labia minora are well developed. The vaginal introitus is visible, but the urethral opening less easily discerned. The vaginal mucosa is glycogen rich. It becomes colonized with lactic-acid-producing microbes, such as Lactobacillus species, within the first 24 h of birth [ 6 ]. A physiological, white, mucoid vaginal discharge is present, which may become tinged by slight withdrawal endometrial bleeding as the concentration of residual maternal estrogen falls [ 3 , 18 ].
These estrogenic effects dissipate by the fourth postnatal week. The vaginal epithelium loses its stratification and glycogen content, becoming much thinner. The vaginal pH becomes neutral or alkaline, presumably because of a relative deficiency of acid-producing vaginal microbes [ 5 , 19 , 20 ]. Vulvar skin thickness drops, and the mons pubis and labia majora lose some of the subcutaneous fat present at birth [ 16 , 21 , 22 ]]. Although the full complement of vulvar hair follicles and sebaceous glands is thought to be present from birth, these structures do not mature until the adrenal glands are activated at puberty. The prepubescent labia minora have barely discernible vellus hair follicles that are lost at puberty when the follicles of the labia majora and mons pubis terminally differentiate [ 21 ].
Fig. 1. Vulvar epithelial structure. Adapted with permission from Farage and Maibach [ 2 ]. a Vulvar skin. b Mucosa.

Labial adhesions may occur between the ages of 2 months and 2 years, creating a flat vulvar appearance. This benign condition is due to a lack of estrogen and normalizes without treatment. Should the condition interfere with urinary flow, topical estrogen treatment promotes separation of the labia [ 4 ].
Pubertal changes in the vulva and vagina are induced by adrenal and gonadal maturation. Puberty generally begins between the ages of 8 and 13 years. Physical changes associated with puberty are an accelerated growth rate, the appearance of pubic hair (pubarche), the appearance of axillary hair, breast development (telarche) and the onset of menstruation (menarche). The timing and stages of development of secondary sex characteristics were first defined in the seminal study of 192 girls in a British orphanage by Marshall and Tanner [ 23 ].
Maturation of the adrenal glands and androgen secretion (adrenarche) begin at about the age of 6, approximately 2 years before pituitary-gonadal maturation and the production of ovarian steroid hormones (gonadarche). Because adrenarche and gonadarche proceed independently, the appearance of pubic hair does not provide information about pituitary-ovarian maturation. Pubic hair development, elicited by androgens, proceeds in 5 stages [ 23 ] ( fig. 2 ):
• stage 1: no pubic hair;
• stage 2: sparse hair appears on the labia majora and the mons pubis along the midline;
• stage 3: the thickness and coarseness of the hair increases, with coverage of the lobes of the labia majora and increased lateral growth from the midline of the mons pubis;
• stage 4: hair growth increases such that only the upper lateral corners of the mature triangular configuration are deficient;
• stage 5: adult pattern, attained between the ages of 12 and 17 years, with a characteristic horizontal upper margin on the mons pubis just above the limit of the genitofemoral folds, and hair coverage extending from the labia to the upper aspects of the thighs.
Fig. 2. Tanner stages of pubic hair development. Reproduced from Farage et al. [ 1 ] and Farage and Maibach [ 2 ].

Gonadal maturation usually occurs during the 2 years preceding menarche. During the maturation process, follicular development causes estrogen production to rise. The vaginal epithelium thickens and intracellular glycogen production begins. The cervix and vagina increase in size, the vaginal fornices develop, cervicovaginal secretions are produced, and vaginal fluid becomes acidic.
Vulvar morphology also matures at this time. Fat deposition occurs in the mons pubis and labia majora. The vulvar epithelium increases in thickness [ 16 ], labial skin becomes rugose, the clitoris becomes more prominent, the vestibular glands become active, the introitus increases in diameter, and the urethral orifice is more discernible.
Breast development, influenced by estrogens, is also described by 5 Tanner stages, from no development (stage 1) to the mature adult breast (stage 5) [ 23 ]. Menarche occurs near the end of the Tanner sequence of breast changes, typically sometime between the ages of 11 and 15 years [ 6 ]. The mean age of menarche worldwide lies between 12 and 13 years [ 24 ]. The sequence from first appearance of pubic hair to breast development and menarche takes about 4 years. Normative menstrual cycle length is established by the sixth gynecological year (i.e. the sixth year following menarche), usually at a chronological age of 19 or 20 [ 11 , 12 ].
Idiopathic Precocious Puberty
Historically, puberty had been defined as precocious in girls when secondary sex characteristics (particularly breast development) appeared prior to the age of 8. However, an apparent advance in the age of onset of pubertal changes has been observed in the USA and in girls from developing countries who have migrated to Western Europe for foreign adoption (reviewed in Parent et al. [ 25 ]). Two large studies in the USA found that pubertal signs may appear before the age of 8, especially in African-American compared to Caucasian girls (reviewed in Anderson et al. [ 26 ], Herman-Giddens et al. [ 27 ] and Sun et al. [ 28 ]). Between the 1970s and 1990s, the average age of menarche in the USA fell from 12.75 to 12.54 years [ 26 ].
Controversy surrounds the clinical significance of these findings. Most cases of early pubertal development are idiopathic [ 29 , 30 ] and probably do not represent precocious puberty unless bone maturation and developmental characteristics are so accelerated that diminished adult height is likely [ 29 ]. However, because true endocrine pathology may be overlooked if early pubertal signs are dismissed, a vigilant longitudinal follow-up of girls with early pubertal onset is advised [ 31 ]. Several risk factors, including genetics [ 32 ], low birth weight [ 33 , 34 ], higher body mass index [ 26 , 35-38 ] and exposure to endocrine disruptors [ 39-42 ], have been statistically linked to early onset of pubertal signs. However, the causative biological mechanisms for this phenomenon are still unknown.
Reproductive Years
During the reproductive years, changes in the vulva and vagina are linked to the menstrual cycle and pregnancy. Physiological changes during the menstrual cycle have been recently reviewed in Farage et al. [ 43 ].
Effects of the Menstrual Cycle
Vulvar epithelial thickness is at its highest in the reproductive years. Vulvar skin thickness remains constant over the menstrual cycle, but its surface cells are predominantly orthokeratotic (lacking nuclei) at the beginning and end of the cycle, and increasingly parakeratotic (bearing a degenerated nucleus) at mid-cycle [ 8 ]. These cytological changes are thought to be mediated by estrogen: for example, parakeratosis of vulvar epithelial cells is rare in postmenopausal women but rises dramatically in this group in response to systemic estrogen supplementation [ 8 ].
The vaginal mucosa is sensitive to ovarian steroid hormone cycling. Estrogen stimulation causes the thickness, glycogen content and parakeratosis of the vaginal epithelium to peak at approximately mid-cycle [ 7 ].
Vaginal pH rises during menstruation [ 44 ], and the current understanding of the impact of the menstrual cycle on the microbial ecology of the vagina from infancy to after the menopause has been reviewed by Farage et al. [ 20 ]. Studies using traditional culture techniques suggest that Lactobacillus species predominate in the vaginal flora of healthy women and that their cell densities remain relatively constant over the menstrual cycle [ 9 ]. However, culture techniques typically identify only the most readily cultivated microbial populations, which may represent but a subset of the extant community. Emerging data obtained by analysis of total microbial community DNA indicate that lactic-acid-producing species such as Atopobium, Megasphaera and Leptotrichia, rather than Lactobacillus, are numerically dominant in some women [ 10 ]. Consequently, genera besides Lactobacillus may contribute to the acidity of the vaginal tract, but the impact of the menstrual cycle on these genera is still to be investigated [ 20 ].
Effects of Pregnancy and Delivery
During pregnancy, an increase in total blood volume heightens the coloration of the vulva and vagina. The connective tissue of the vulva, vagina and perineum relaxes, and the muscle fibers of the vaginal wall increase in size in preparation for delivery. Progesterone elevates venous distensibility, which may cause varicose veins in the vulva [ 13 ]. Pregnancy is associated with a 10- to 20-fold increase in the prevalence of vulvovaginal candidiasis [ 14 , 20 ].
During delivery, the perineal and vaginal musculature relaxes and the vaginal rugae flatten to allow expansion of the vaginal tract, accommodating passage of the newborn infant. Injury to the perineum may occur spontaneously or because of episiotomy. After delivery, the vaginal introitus is wider and the fourchette appears more flattened. Over the next 6-12 weeks, the typical morphology and dimensions of the vaginal tract are reestablished.
Menopause and Aging
The loss of follicular activity will lead to menopause which is the permanent cessation of menstruation. A constellation of symptoms emerges during the perimenopause (the transition period to menopause). The most notable is menstrual cycle irregularity, reflecting an increase in the number of anovulatory cycles and cycles with a prolonged follicular phase. Some women experience cramps, bloating or breast tenderness; symptoms of estrogen depletion, such as vasomotor symptoms (’hot flashes’), migraine and vaginal dryness [ 45 , 46 ], may ensue. The perimenopause typically commences after the age of 45 and lasts about 4 years. Menstruation ceases at a median age of 50 years in Western industrialized societies [ 47 ]. Menopause is considered established 1 year after the final menstrual period [ 48 ].
The most apparent changes are the graying of the pubic hair and becoming sparse, the loss of subcutaneous fat in the labia majora and the labia minora, vestibule, and vaginal mucosa atrophy [ 16 , 49 ]. At the cytological level, estrogen-induced parakeratosis of the vulvar stratum corneum is highest in the third decade of life, but rarely seen by the eighth decade [ 50 ].
Postmenopausal atrophic vulvovaginitis is a virtually universal condition [ 46 , 51 ]. Vaginal secretions decrease, reducing lubrication and increasing coital discomfort [ 52 ]. Thinned tissue is more easily irritated and may be more susceptible to infection [ 53 ]. The vaginal pH rises, and the prevalence of colonization by enteric organisms associated with urinary tract infections increases [ 54 , 55 ]. Besides these physiologically induced changes, certain vulvar dermatoses, such as lichen sclerosus, are most prevalent in peri- and postmenopausal women [ 46 , 52 , 56 ].
Vulvar skin differs from exposed skin in the characteristics of skin hydration, friction, permeability and visually discernible irritation (reviewed in Oriba et al. [ 57 ] and Farage et al. [ 58 ]). It is commonly assumed that aged skin is intrinsically less hydrated, less elastic, more permeable and more susceptible to irritation. However, assessments of the vulvar skin of pre- and postmenopausal women, using bioengineering techniques, did not reveal large age-related changes in these characteristics ( table 2 ).
For example, the skin of the labia majora is more hydrated than forearm skin as measured by transepidermal water loss [ 62 ], and its coefficient of friction is higher [ 59 ]. Although small age-related changes in these parameters were measured on the forearm of pre- and postmenopausal women, the impact of the menopause on the water barrier function and friction coefficient of vulvar skin was negligible [ 59 ].
Vulvar skin is more permeable to hydrocortisone than forearm skin, but comparable testosterone penetration rates have been measured at both sites. In postmenopausal women, skin permeability to hydrocortisone drops on the forearm but not on the vulva, and no age-related differences in testosterone penetration were found at either site [ 60 ].
Exposed forearm skin was more susceptible than vulvar skin to the model irritant, aqueous sodium lauryl sulfate (1% w/v). This agent caused more intense erythema on the forearms of premenopausal women, but no visually discernible response on the vulva in either pre- or postmenopausal women [ 61 ].
Although large age-related differences in vulvar skin permeability and intrinsic susceptibility to irritants have not been demonstrated, dermatitis of the vulva, perineum and buttocks is nevertheless a significant problem in older people with incontinence [ 63 ]. Studies of incontinence dermatitis in infants have elucidated a multifactorial etiology. In brief, exposure to urinary moisture under occlusion makes the skin more susceptible to friction damage; urinary ammonia elevates the local pH, which alters skin barrier function [ 46 , 53 , 64-66 ] and activates fecal enzymes; these enzymes further compromise skin integrity and increase skin susceptibility to microbial infection [ 67-71 ].
Table 2. Skin physiological parameters in pre- and postmenopausal women (reproduced from Farage et al. [ 1 ] and Farage and Maibach [ 2 ])

Perineal dermatitis is particularly debilitating to older people with incontinence because urine and feces exert their effects against a background of atrophied tissue, immobility, a potentially weakened immune response, and often compromised physical health and cognition [ 66 , 72-74 ]. Several factors exacerbate the deleterious effects of skin wetness, occlusion and fecal enzyme action in elderly subjects [ 65 ]. Although the baseline skin wetness level does not differ significantly in aged skin, the excess hydration induced by occlusion is significantly greater and dissipated more slowly in older skin than in young [ 75 ]. Although the coefficient of vulvar skin friction is unchanged in older women, reduced mobility subjects atrophied genital tissue to higher shear forces than those encountered by infants. Moreover, atrophied genital tissue may be more susceptible to pH changes and enzymatic action, while immune function and tissue regeneration capacity may also be compromised [ 51 , 52 ]. Lastly, elderly individuals may not receive the same degree of attentiveness as infants, and those with impaired cognition may be unable to alert caregivers to incontinent episodes. These factors underscore the need for vigilant care and proper hygiene to help maintain healthy urogenital skin in older women with incontinence.
In summary, the vulva and vagina undergo characteristic age-related changes over a lifetime. At birth, these tissues exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina mature under the influence of adrenal and gonadal steroid hormones. During the reproductive years, the vagina responds to ovarian steroid hormone cycling, and both tissues adapt to the needs of pregnancy and delivery. Following menopause, the vulva and vagina atrophy. A rise in the prevalence of incontinence among older women increases the risk of vulvar and perineal dermatitis. Vigilant care and proper hygiene in elderly people, especially those with incontinence, are needed to avoid dermatitis and skin deterioration which may be debilitating at this stage of life.
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26 Anderson SE, Dallal GE, Must A: Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart. Pediatrics 2003;111:844-850.
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35 Demerath EW, Towne B, Chumlea WC, Sun SS, Czerwinski SA, Remsberg KE, Siervogel RM: Recent decline in age at menarche: the Fels Longitudinal Study. Am J Hum Biol 2004;16:453-457.
36 Dimartino-Nardi J: Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls. Acta Paediatr Suppl 1999;88:67-72.
37 Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME: Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108:347-353.
38 Wang Y: Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. Pediatrics 2002;110:903-910.
39 Colon I, Caro D, Bourdony CJ, Rosario O: Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect 2000;108:895-900.
40 Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, de Beaufort C, Plomteux G, Bourguignon JP: Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Hum Reprod 2001;16:1020-1026.
41 Larriuz-Serrano MC, Perez-Cardona CM, Ramos-Valencia G, Bourdony CJ: Natural history and incidence of premature thelarche in Puerto Rican girls aged 6 months to 8 years diagnosed between 1990 and 1995. P R Health Sci J 2001;20: 13-18.
42 McKee RH: Phthalate exposure and early thelarche. Environ Health Perspect 2004;112:A541-A543.
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47 Ginsberg J: What determines the age at the menopause? BMJ 1991;302:1288-1289.
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62 Elsner P, Maibach HI: The effect of prolonged drying on transepidermal water loss, capacitance and pH of human vulvar and forearm skin. Acta Derm Venereol 1990;70:105-109.
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Miranda A. Farage, PhD Procter and Gamble Company, Feminine Care Innovation Center 6110 Center Hill Road, Box 136 Cincinnati, OH 45224 (USA) Tel. +1 513 634 5594, Fax +1 866 622 0465, E-Mail
Section II: Topical Treatment of Impaired Mucosal Membranes
Surber C, Elsner P, Farage MA (eds): Topical Applications and the Mucosa. Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 20–35
Nasal Drug Delivery in Humans
Christoph Bitter a • Katja Suter-Zimmermann a • Christian Surber a , b
a Hospital Pharmacy and b Department of Dermatology, University of Basel Hospital, Basel, Switzerland
Intranasal administration is an attractive option for local and systemic delivery of many therapeutic agents. The nasal mucosa is - compared to other mucosae - easily accessible. Intranasal drug administration is noninvasive, essentially painless and particularly suited for children. Application can be performed easily by patients or by physicians in emergency settings. Intranasal drug delivery offers a rapid onset of therapeutic effects (local or systemic). Nasal application circumvents gastrointestinal degradation and hepatic first-pass metabolism of the drug. The drug, the vehicle and the application device form an undividable triad. Its selection is therefore essential for the successful development of effective nasal products. This paper discusses the feasibility and potential of intranasal administration. A series of questions regarding (a) the intended use (therapeutic considerations), (b) the drug, (c) the vehicle and (d) the application device (pharmaceutical considerations) are addressed with a view to their impact on the development of products for nasal application. Current and future trends and perspectives are discussed.
Copyright 2011 S. Karger AG, Basel
Intranasal administration offers a variety of attractive options for local and systemic delivery of diverse therapeutic agents. The nature of the nasal mucosa provides a series of unique attributes, all of which may help to maximize the patient’s safety, convenience and compliance.
The nasal mucosa is - compared to other mucous membranes - easily accessible and provides a practical entrance portal for small and large molecules. Intranasal administration offers a rapid onset of therapeutic effects, no first-pass effect, no gastrointestinal degradation or lung toxicity, noninvasiveness, essentially painless application, and easy and ready use by patients - particularly suited for children - or by physicians in emergency settings. More recently a nasal influenza vaccine spray (Flu Mist ® ) has been successfully introduced. The chances for direct nose-to-brain drug delivery are currently the subject of controversial debates [ 1 , 2 ].
Given these positive attributes, it is obvious to consider intranasal administration when improving the profile of existing drugs including life cycle management or when developing new therapeutics. A quick glance at the market and at current research activities confirms the attractiveness of intranasal drug administration. Table 1 shows selected drugs for intranasal administration with systemic effects.
In order to estimate the feasibility and potential of intranasal administration, a series of questions regarding (a) the intended use (therapeutic considerations), (b) the drug, (c) the vehicle and (d) the application device (pharmaceutical considerations) have to be addressed, e.g.:
Table 1. Selection of compounds for transmucosal nasal drug delivery

(a) Is the drug designated for local or systemic delivery, for single or repetitive administration, is the therapeutic target concentration known?
(b) Are the physicochemical properties of the drug suitable for intranasal administration, can clinically relevant bioavailability be achieved?
(c) Can the vehicle provide prolonged drug stability, ideal characteristics during (ejection) and after application (prolonged residence time on the mucosa) and support drug delivery to local target tissues or to the blood vessels for systemic delivery?
(d) And finally, is the application device easily deployable and does it allow adequate drug/formulation deposition within the nose?
These issues are addressed below with a view to their impact on the development of products for nasal application.
The Nose - Anatomy and Function
The nose is a complex multifunctional organ. The major functions of the nasal cavity comprise cleansing the inhaled air and olfaction. Moreover, it exerts important protective and supportive activities; it filters, heats and humidifies the inhaled air before it reaches the lower parts of the airways. Nasal hairs and mainly the nasal mucosa with its sticky mucus blanket help to prevent xenobiotics like allergens, pathogens or foreign particles from reaching the lungs. It represents a most efficient first line of defense for the body’s airway as it copes with more than 500 liters of air that are filtered hourly into the lung. During this time it is thought that more than 25 million particles are processed by this epithelium [ 34 , 35 ]. Mucociliary activity removing mucus towards the nasopharynx, immunological activities involving a variety of immunocompetent cells and metabolism of endogenous substances are further essential functions of the nasal structures. The nasal cavity connected to other cavities such as the frontal and maxillary sinus and the ear also serves as a resonant body.
Fig. 1. Sagittal section of the nasal cavity.

There are 3 distinct functional areas (fig. 1 ) in the nasal cavity, the vestibular, olfactory and respiratory zones. The vestibular area (approx. 0.6 cm 2 ) serves as a first barrier against airborne particles with low vascularization comprised of stratified squamous and keratinized epithelial cells with nasal hairs. The olfactory area (approx. 15 cm 2 ) enables olfactory perception and is highly vascularized. The respiratory area (approx. 130 cm 2 ) serves with its mucus layer produced by highly specialized cells as an efficient air-cleansing system [ 36 ]. The surface of this zone is enlarged by the division of the cavity by lateral walls into 3 nasal conchae or turbinates and by the magnification of the mucosa by microvilli and cilia. The magnification in terms of square centimeters is unknown. The zone is highly vascularized. The posterior region of the nasal cavity is the nasopharynx. Its upper part consists of ciliated cells, the lower part contains squamous epithelium. The area is also part of the mucosal immune system.
Due to the rich vascularization, the olfactory and in particular the respiratory zone may serve as an efficient absorption surface for topically applied drugs. The olfactory region with its vicinity to the cerebrospinal fluid and direct nervous interface to the brain has attracted research interest for possible nose-to-brain delivery.
Fig. 2. Cell types of the nasal epithelium with covering mucous layer.

The respiratory epithelium as well as other parts of the nasal cavity and airways are lined by superficial epithelium (fig. 2 ) consisting primarily of 2 types of cells: mucus-producing goblet cells (20%) and ciliated cells (80%). The various cell types of the epithelium are joined together by tight junctions. Mucus continuously produced by goblet cells traps inhaled particulate and infectious debris while the propulsive force (about 1,000 strokes/min) generated by ciliated cells transports the mucus towards the nasopharynx and the gastrointestinal tract for elimination. This effective cleansing mechanism is called mucociliary clearance (MCC) [ 37 ]. The MCC time is approximately 20 min but is subject to great inter-subject variability. The MCC is dependent on the function of the cilia and the characteristics of the covering mucus, which can be influenced by acute or chronic illnesses like common cold or allergic rhinitis. Many substances can influence the MCC of the airways, either by stimulation or inhibition. A stimulatory effect of drugs on the MCC is of clinical importance, because these substances can possibly be used to improve pathological conditions of the MCC. Components (drug, ingredient) of nasally administered formulations with a too pronounced MCC-impairing activity may limit their use.
Nasal Delivery
The intranasal administration represents a viable option for local and systemic delivery of many therapeutic agents. Therapeutic and pharmaceutical considerations direct the development of nasal products [ 38 ].
Therapeutic Considerations
Answers to key questions whether the drug is intended for (a) local or systemic delivery or for (b) single or repetitive administration and (c) patient-related issues (e.g. adults, children) define the development strategy for the nasal product. An idea of the clinically effective drug concentration in the target site should exist in order to estimate the feasibility of the nasal application route.
Local Delivery
Prominent examples for locally acting intranasally administered drugs are decongestants for nasal cold symptom relief, antihistamines and corticosteroids for allergic rhinitis. Due to the fact that relatively low doses are effective when administered topically, the intranasal administration of antihistamines and corticosteroids has a weak potential for systemic adverse effects as opposed to systemic therapy. Intranasal administration is therefore a logical delivery choice for the topical (local) treatment of nasal symptoms.
Systemic Delivery
The nasal mucosa provides a practical entrance portal for systemically acting molecules. Intranasal administration offers a rapid onset of therapeutic effects, avoids the first-pass effect or gastrointestinal degradation of drugs, is noninvasive, essentially painless and finally easily administered by patients or by physicians in emergency settings. The intranasal administration provides a true alternative route for systemic drugs presently delivered more conventionally by oral or parenteral routes.
Single versus Repetitive Administration
The disease, the therapeutic goal and the therapeutic agent predefine the dosing regimen. Dosing frequencies of currently marketed intranasally administered products range from weekly dosing to multiple times daily. To avoid multiple parenteral applications, repetitive intranasal administration may be practical for the situation of chronic application with orally insufficient drug bioavailability. The delivery target (local, systemic) as well as the intended dosing schedule govern the development strategy and therefore predefine the drug form (dissolved, ionized etc.), the vehicle form (solid, semisolid, liquid) including the specific ingredients to form the vehicle system (powder, gels, microspheres, solution etc.) and the application device, which determines the drug deposition within the nose.
Patient-Related Issues
The nasal physiology and anatomy have a potential impact on intranasal administration. Temperature, humidity, airflow and the nasal cycle - an alternating congestion and decongestion of the nasal mucosa - may change the absorption area. Any impairment of the physiological and anatomical situation - whether natural (nasal cycle) or pathological (inflammation, nosebleed, alterations as a result from smoking, snuffing, decongestant addiction or nasal drug abuse) - may have a potential impact on intranasal absorption. The extent of this impact is unknown.
Even though the epithelial tissue within the nasal cavity provides an ideal absorption area, the natural permeation barrier and the efficient cleansing mechanism confine the total amount of drug that can be absorbed. Therefore the clinically effective drug concentration at the target site requires a therapeutic agent with sufficient potency.
Pharmaceutical Considerations
Once the therapeutic goal and the therapeutic agent have been defined, the formulation scientist is challenged to incorporate the drug into a vehicle system that provides prolonged drug stability, ideal dispensing characteristics from a tailor-made delivery device during (ejection) and after application (prolonged residence time on the mucosa) which supports drug delivery to a local target site (penetration; e.g. antihistamines such as levocabastine) or to the blood vessels for systemic delivery (permeation; e.g. benzodiazepines such as midazolam).
Thoughtful consideration of all elements in a formulation triad - comprising drug, vehicle form/system and delivery device - is the basis of a successful formulation development (fig. 3 ). Based on the properties of the drug molecule, the vehicle form/system (solid; powder, semisolid; gel, emulsion or liquid; solution) is determined first; second, the device is chosen, and third the ingredients are chosen to create an optimal vehicle. Skillful selection of vehicle form/system and ingredients bypasses natural attributes of the mucus blanket as a protective layer (i.

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