Nanocarrier systems and iontophoresis: complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

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Thesis

Reference

Nanocarrier systems and iontophoresis: complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

KANDEKAR, Somnath

Abstract

A localized drug delivery provides several advantages over systemic drug delivery for treatment of dermatological diseases. Effective pharmacotherapy depends on being able to attain the right therapeutic concentrations of a drug in the target compartment within the right time-frame. This depends on the drug's physicochemical properties, potency, pharmacokinetics, and type of formulation or delivery technique used. Development and optimization of novel formulations and delivery technique could be a good option for enhancement of drug delivery into the target compartment. This thesis work involves investigation of the targeted delivery of (i) poorly water-soluble drugs (adapalene and vismodegib) using nanocarrier systems and (ii) a hydrophilic drug (capecitabine) by using iontophoresis. Topical cutaneous delivery of therapeutic agents to treat dermatological conditions would be able to increase local drug concentrations at the disease site while reducing systemic exposure and thereby offering the potential to improve upon existing therapies.

KANDEKAR, Somnath. Nanocarrier systems and iontophoresis: complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs. Thèse de doctorat : Univ. Genève, 2018, no. Sc. 5292

DOI : 10.13097/archive-ouverte/unige:114118 URN : urn:nbn:ch:unige-1141183

Available at:

http://archive-ouverte.unige.ch/unige:114118

Disclaimer: layout of this document may differ from the published version.

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UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES Section de Sciences Pharmaceutiques Professeur Yogeshvar N. Kalia Laboratoire de Biochimie Pharmaceutique Professeur Leonardo Scapozza

Nanocarrier systems and iontophoresis:

Complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

THÈSE

présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention sciences pharmaceutiques

par

Somnath G. Kandekar de

Ahmednagar (Inde)

Thèse N° 5292

Genève

Atelier de reproduction Repromail 2018

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“You can't cross the sea merely by standing and staring at the water.”

Rabindranath Tagore

“It always seems impossible until it's done.”

Nelson Mandela

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Dedicated to my beloved family

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Résumé

Une administration localisée de médicaments présente plusieurs avantages par rapport à une administration systémique pour le traitement de maladies dermatologiques. Une pharmacothérapie efficace dépend de la capacité à atteindre les concentrations thérapeutiques d’un médicament dans le compartiment cible dans un délai imparti. Cela dépend des propriétés physicochimiques du médicament, de son activité, des paramètres pharmacocinétiques et du type de formulation ou de technique d'administration utilisée.

Le développement et l'optimisation de nouvelles formulations et des techniques d'administration pourraient être une option intéressante afin d’améliorer l'administration de médicaments dans le compartiment cible.

Le but de ce travail de thèse était d'étudier l’administration ciblée (i) de médicaments faiblement solubles dans l'eau en utilisant des systèmes de nanovecteurs et (ii) d'un médicament hydrophile en utilisant l’iontophorèse. L’administration cutanée d'agents thérapeutiques destinés à traiter des affections dermatologiques serait en mesure d'augmenter les concentrations locales du médicament au site de la maladie tout en réduisant l'exposition systémique et en offrant ainsi le potentiel d'amélioration des traitements existants.

Le chapitre I traite des défis et des opportunités liés à l’administration de médicaments par voie cutanée. La structure et la fonction de la peau humaine et les affections dermatologiques courantes sont examinées, suivies du potentiel de marché des produits dermatologiques. Les défis posés par l’administration topique de médicaments sont présentés, suivis d’une brève discussion sur les techniques d’administration passive et active qui peuvent être utilisées pour améliorer l’administration cutanée. Un accent particulier est mis sur l'application de micelles polymériques, de microémulsions et

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d'iontophorèse pour une administration cutanée ciblée. L’importance de la biodisponibilité et des méthodes utilisées pour étudier la biodistribution du médicament présent dans la peau et dans la structure folliculaire sont abordées dans la dernière partie.

Le chapitre II concerne la mise au point de systèmes d'administration de médicaments ciblant sélectivement l'unité pilosébacée (UPS), ce qui pourrait permettre d'améliorer la prise en charge clinique des maladies d'origine folliculaire. Les objectifs de cette étude étaient (i) de préparer des micelles polymérique à l'aide d'un copolymère dibloc D-α- tocopherol poly(éthylène glycol) succinate incorporant de l'adapalène (ADA), un rétinoïde indiqué pour l’acné vulgaire, et (ii) d'étudier la faisabilité d'administrer l’ADA préférentiellement dans l’UPS dans des conditions de dose finie - permettant ainsi de mieux mimer les conditions réelles d’utilisation par les patients. L'incorporation de l'ADA dans les micelles sphériques (dn <20 nm) augmentait la solubilité dans l'eau d'environ 50 000 fois (de <4 ng/mL à 0.2 mg/mL). Les formulations optimisées de micelles en solution et en gel (0,02% d'ADA) étaient stables après un stockage de 4 semaines à 4 °C. Des expériences avec des doses finies effectuées sur des peaux porcines et humaines ont révélé que l'efficacité d'administration d'ADA à partir des formulations de micelles en solution et en gel était équivalente et était >2 à 10 fois supérieure à celle de Differin^® gel et de Differin^® crème (produits contenant de l'ADA à 0.1% (w/w)). Des études d’administration folliculaire sur de la peau humaine, utilisant une technique de biopsie au poinçon pour extraire l’UPS intacte, ont montré que la solution micellaire et le gel permettaient effectivement une administration préférentielle de l’ADA à l’UPS (respectivement 4.5 et 3.3 fois plus élevée que les biopsies cutanées sans UPS). La microscopie confocale à balayage laser a confirmé visuellement que l'ADA était uniformément distribué dans les follicules pileux. En conclusion, les résultats ont démontré que les micelles polymériques permettaient une administration sélective et

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ciblée du médicament dans l’UPS dans des conditions de dose finie et qu’elles pourraient donc améliorer le traitement des maladies folliculaires et réduire les effets secondaires hors-site.

Le chapitre III décrit le développement d'une formulation de micelles polymériques de vismodegib (VSD) - un inhibiteur de la voie Hedgehog utilisé dans le traitement du carcinome basocellulaire (CBC) - en utilisant le copolymère dibloc de méthoxy- poly(éthylène glycol) et de poly acide lactide substitué de chaînes dihexyl (MPEG-dihex- PLA) biodégradable et biocompatible et une étude de son potentiel à cibler sélectivement la libération de VSD dans l'épiderme viable et le derme supérieur. La solution micellaire optimale (Zav 20-30 nm) augmentait la solubilité aqueuse de VSD de plus de 8 000 fois.

Des études préliminaires ont montré que le contenu en médicament était stable pendant 4 semaines à 4 °C. L'application d'une solution micellaire (0.086%) sur la peau porcine et humaine pendant 12 h dans des conditions de dose infinie a entraîné une déposition de VSD statistiquement équivalente (0.88 ± 0.20 et 0.62 ± 0.11 g/cm², respectivement).

L'application d'un gel micellaire (à nouveau à 0.086%) sur la peau humaine dans les mêmes conditions a entraîné une déposition de VSD de 0.67 ± 0,14 g/cm², ce qui était statistiquement équivalent à la solution micellaire. La biodistribution cutanée de la peau humaine suite à l’application de micelles en solution et en gel à des doses infinies a montré que les concentrations de VSD obtenues dans le compartiment cible (l'épiderme basal à une profondeur de 120 à 200 m) étaient environ 3 800 fois supérieures à la CI50

pour l’inhibition in vitro de la voie de signalisation Hedgehog. Encore plus frappant, l'application du gel micellaire dans des conditions de dose finie a abouti à une concentration environ 2 300 fois plus élevée que la CI50. En conclusion, les formulations micellaires ont été en mesure d’administrer des quantités supra-thérapeutiques de VSD

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dans l'épiderme basal et le derme supérieur sans perméation transdermique, offrant ainsi potentiellement une option thérapeutique topique ciblée attrayante pour le traitement du CBC superficiel avec un risque minimum d'exposition systémique.

Le chapitre IV porte sur la mise au point de formulations de microémulsions pour l’administration ciblée de vismodegib (VSD) par voie cutanée. Des formulations de microémulsions ont été développées en utilisant Capryol 90 comme phase huileuse, Kolliphor^® EL/Kolliphor^® RH40 comme tensioactifs, le Transcutol P comme co- tensioactif et de l'eau. À mesure que la concentration du mélange tensioactif :co- tensioactif (SM) augmentait, la teneur en VSD (mg/mL) dans les différentes formulations de microémulsions augmentait. Les microémulsions optimales (0.78% de VSD) utilisant deux tensioactifs différents, à savoir Kolliphor^® EL (ME7) et Kolliphor^® RH40 (ME8), ont été préparées avec succès et avaient une composition de 20:55:25 (huile:SM:eau) avec des teneurs en VSD de 7.82 ± 0.30 et de 7.76 ± 0.55 mg/mL, respectivement. La solubilité aqueuse de VSD a augmenté d'environ 78 000 fois. Les microémulsions ont été caractérisées par la taille des globules par diffusion dynamique de la lumière; pour les microémulsions optimales (0.78% de VSD), la taille se situait dans la gamme de 50 à 80 nm. L’application des formulations de ME7 et ME8 à doses infinies sur peau humaine pendant 12 h a entraîné la déposition de 1.36 ± 0.40 et de 1.44 ± 0.21 g/cm² de VSD, avec une perméation minimale dans le compartiment récepteur. Après 12 h d'application sur la peau humaine dans des conditions de dose finies, les formulations de ME7 et ME8 ont conduit à la déposition de 0.65 ± 0.29 et 0.63 ± 0.04 g/cm² de VSD. Les études de biodistribution sous les conditions de dose finie ont montré que la concentration de VSD atteinte dans la région correspondant à l’épiderme basal (120-200 m) était >2 100 fois supérieure à la concentration requise de VSD pour l’inhibition in vitro de la voie de

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signalisation de Hedgehog, pour les deux formulations. Dans la région correspondant aux couches plus profondes du derme (200 à 400 µm), la concentration était >1 200 fois plus élevée. Les résultats suggèrent que la formulation de microémulsions pourrait être une stratégie prometteuse pour l’administration locale de VSD par voie cutanée dans le traitement du carcinome basocellulaire.

Dans le chapitre V, l'administration topique ciblée de capécitabine (CAP) a été étudiée à l'aide d'une iontophorèse anodale pour le traitement localisé du cancer de la peau.

L’administration iontophorétique de CAP dans la peau porcine a été étudiée en fonction de la densité de courant (0.125, 0.25, 0.5 mA/cm²), de la concentration (5, 10, 20 mM) et du temps. L'augmentation de la densité de courant de 0.125 à 0.25 et 0.5 mA/cm² a entraîné la déposition de 15.28 ± 2.34, 31.76 ± 4.36 et 32.94 ± 5.10 g/cm² de CAP, respectivement après 3 h. L'augmentation de la concentration de CAP dans les solutions aqueuses de 5 à 10 et 20 mM a entraîné la déposition de 13.97 ± 2.77, de 32.94 ± 5.10 et de 37.79 ± 4.42 g/cm2, respectivement, au bout de 3 h. L'utilisation d'hydrogel CAP (10 mM) et de la meilleure condition iontophorétique (c'est-à-dire un courant de 0.5 mA/cm² et un temps d'application de 3 h) en utilisant de la peau porcine et humaine a permis l’administration d’une quantité de CAP statistiquement identique (24.6 ± 8.34 vs. 20.28 ± 5.25 g/cm²). Les dépositions de CAP dans la peau humaine ont augmenté de >4 fois après l'iontophorèse par rapport à l'administration passive de l’hydrogel de CAP. Comme le CAP après métabolisation se convertirait en 5-FU, l’administration passive de 5-FU (crème Efudex^®) a été comparée à l’administration iontophorétique de l’hydrogel de CAP en tenant compte du nombre de nmol/mL administrés. L’administration ionophorétique de CAP à partir d'un hydrogel était >5 fois supérieure à celle passive de 5-FU (c'est-à-dire 564.6 ± 146.4 vs. 112.8 ± 24.4 nmol/ml). En outre, des études de biodistribution cutanée

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ont démontré que la concentration de CAP était plus de 100 fois plus élevée dans l'épiderme que la concentration thérapeutique requise, tandis que le 5-FU se déposait principalement dans les couches superficielles de la peau. Bien que la CAP soit neutre, l'iontophorèse a considérablement amélioré son administration, suggérant qu'une administration locale ciblée de médicaments/prodrogues chimiothérapeutiques neutres dans la peau pourrait constituer une stratégie intéressante pour le traitement du cancer de la peau sans mélanome bénin par iontophorèse.

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Summary

A localized drug delivery provides several advantages over systemic drug delivery for treatment of dermatological diseases. Effective pharmacotherapy depends on being able to attain the right therapeutic concentrations of a drug in the target compartment within the right time-frame. This depends on the drug’s physicochemical properties, potency, pharmacokinetics, and type of formulation or delivery technique used. Development and optimization of novel formulations and delivery technique could be a good option for enhancement of drug delivery into the target compartment.

The aim of this thesis work was to investigate the targeted delivery of (i) poorly water- soluble drugs using nanocarrier systems and (ii) a hydrophilic drug by using iontophoresis. Topical cutaneous delivery of therapeutic agents to treat dermatological conditions would be able to increase local drug concentrations at the disease site while reducing systemic exposure and thereby offering the potential to improve upon existing therapies.

Chapter I discusses challenges and opportunities in dermal drug delivery. The structure and function of the human skin and common dermatological conditions are discussed followed by the market potential of dermatological products. Challenges in the topical drug delivery are presented followed by a brief discussion of passive and active delivery techniques which can be used to enhance dermal delivery. A special focus is given on the application of polymeric micelles, microemulsions, and iontophoresis for targeted dermal delivery. The importance of bioavailability and methods used to study the biodistribution of drug present in the skin and follicular structure are discussed in the last section.

Chapter II involves the development of drug delivery systems that target the pilosebaceous unit (PSU) selectively which could lead to improvement in the clinical

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management of diseases that originate in the hair follicle. The aims of this study were (i) to prepare polymeric micelles using D-α-tocopheryl polyethylene glycol succinate diblock copolymer that incorporated adapalene (ADA), a retinoid indicated for Acne vulgaris, and (ii) to investigate the feasibility of delivering ADA preferentially to the PSU under finite dose conditions – thereby better approximating actual conditions of use by patients. Incorporation of ADA into spherical micelles (dn <20 nm) increased aqueous solubility by ∼50 000-fold (from <4 ng/mL to 0.2 mg/mL). Optimized micelle solution and gel formulations (0.02% ADA) were stable after storage for 4 weeks at 4 °C. Finite dose experiments using full-thickness porcine and human skin revealed that ADA delivery efficiency from micelle solution and gel formulations was equivalent and was

>2- and 10-fold higher than that from Differin^® gel and Differin^® cream (products containing ADA at 0.1% (w/w)). Follicular delivery studies in human skin, using a punch biopsy technique to extract the intact PSU, demonstrated that the micelle solution and gel formulations did indeed enable preferential delivery of ADA to the PSU (4.5- and 3.3- fold higher, respectively, than that to PSU-free skin biopsies). Confocal laser scanning microscopy provided visual corroboration that ADA was uniformly distributed in the hair follicles. In conclusion, the results confirmed that polymeric micelle nanocarriers enabled selective, targeted drug delivery to the PSU under finite dose conditions and so might improve therapy of follicular diseases and decrease off-site side-effects.

Chapter III describes the development of a polymeric micelle formulation of vismodegib (VSD) ̶ a hedgehog pathway inhibitor used in the treatment of basal cell carcinoma (BCC) − using the biocompatible/biodegradable methoxypoly(ethylene glycol)-dihexyl substituted polylactide (MPEG-dihex-PLA) diblock copolymer and an investigation of its potential to selectively target delivery of VSD to the viable epidermis and upper dermis.

The optimal micelle solution (Zav 20-30 nm) increased aqueous solubility of VSD by

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>8 000-fold. Preliminary studies showed that the drug content was stable over 4 weeks at 4 °C. Application of a micelle solution (0.086%) to porcine and human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.88 ± 0.20 and 0.62 ± 0.11 g/cm², respectively). Application of a micelle-gel (again at 0.086%) to human skin under the same conditions resulted in VSD deposition of 0.67 ± 0.14 g/cm², which was statistically equivalent to the micelle solution. Cutaneous biodistribution in human skin using micelle solution and micelle-gel under infinite dose conditions showed that the VSD concentrations obtained in the target compartment (i.e.

basal epidermis at depth 120-200 m) were ˃3800-fold greater than the IC50 for hedgehog signaling pathway inhibition in vitro. Even more striking, application of the micelle-gel under finite dose condition resulted in a concentration that was ˃2300-fold higher than the IC₅₀. In conclusion, micelle based formulations were able to deliver supra-therapeutic amounts of VSD to the basal epidermis and upper dermis without transdermal permeation, thus potentially offering an attractive targeted topical therapeutic option for superficial BCC treatment with minimum the risk of systemic exposure.

Chapter IV involves the development of microemulsion formulations for the targeted dermal delivery of vismodegib (VSD). Microemulsion formulations were developed using Capryol 90 as the oil phase, Kolliphor^® EL/Kolliphor^® RH40 as surfactants, Transcutol P as cosurfactant and water. As the concentration of surfactant:cosurfactant mixture (SM) increased the VSD content (mg/mL) in the different microemulsion formulations increased. The optimal drug-loaded microemulsions (0.78%) using two different surfactants i.e. Kolliphor^® EL (i.e. ME7) and Kolliphor^® RH40 (i.e. ME8) were successfully prepared having a composition of 20:55:25 (oil:SM:water) with VSD contents of 7.82 ± 0.30 and 7.76 ± 0.55 mg/mL, respectively. This enhanced aqueous

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solubility of VSD by 78 000-fold. The microemulsions were characterized for globule size by dynamic light scattering; for the optimal microemulsions (0.78% VSD) size were in the range of 50-80 nm. After 12 h exposure of human skin to ME7 and ME8 formulations using infinite dose resulted in the deposition of 1.36 ± 0.40 and1.44 ± 0.21

g/cm² of VSD, with minimal permeation into the receptor compartment. After 12 h application of ME7 and ME8 formulations to human skin under finite dose conditions resulted in delivery of 0.65 ± 0.29 and 0.63 ± 0.04 g/cm² of VSD. The biodistribution studies under finite dosing indicated that the concentration of VSD achieved in the region corresponding to the basal epidermis (120-200 m) was >2100-fold higher than the required concentration of VSD for hedgehog signaling pathway inhibition in vitro for both the formulations, in the region corresponding to deeper dermis layers (200-400 m) the concentration was >1200-fold higher. The results suggested that microemulsion formulation could be a promising strategy for the local dermal delivery of VSD in the treatment of basal cell carcinoma.

In chapter V targeted topical delivery of capecitabine (CAP) was studied using anodal iontophoresis for localized treatment of skin cancer. In vitro iontophoretic delivery of CAP into porcine skin was studied as a function of current density (0.125, 0.25, 0.5 mA/cm²), concentration (5, 10, 20 mM), and time. Increasing the current density from 0.125 to 0.25 and 0.5 mA/cm² resulted in the deposition of 15.28 ± 2.34, 31.76 ± 4.36 and 32.94 ± 5.10 g/cm² of CAP, respectively after 3 h. Increasing the CAP concentration in aqueous solution from 5 to 10 and 20 mM resulted in deposition of 13.97 ± 2.77, 32.94 ± 5.10 and 37.79 ± 4.42 g/cm², respectively after 3 h. Iontophoresis of CAP from a hydrogel (10 mM CAP) for 3 h at 0.5 mA/cm² resulted in statistically equivalent delivery across porcine and human skin (24.6 ± 8.34 vs. 20.28 ± 5.25 g /cm²). CAP deposition

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was enhanced by >4-fold in human skin after iontophoresis compared to passive delivery from the CAP hydrogel. As CAP is metabolized to 5-FU, passive delivery of 5-FU (Efudex^® cream) was also compared to CAP hydrogel iontophoresis by determining the cutaneous concentrations (nmol/mL) of the two species. Iontophoretic delivery of CAP from the hydrogel was >5-fold greater compared to passive delivery of 5-FU (i.e. 564.6 ± 146.4 vs. 112.8 ± 24.4 nmol/mL). Furthermore, dermal biodistribution studies indicated that the CAP concentration was more than 100-fold higher in the epidermis than the required therapeutic concentration while 5-FU was deposited mainly in the superficial layers of the skin. Although CAP is neutral, iontophoresis significantly enhanced its delivery, suggesting that targeted local delivery of neutral chemotherapeutic drugs/prodrugs to the skin could be an attractive strategy for treatment of non-melanoma skin cancer using iontophoresis.

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Chapter I

Market potential, challenges and opportunities in dermal drug

delivery

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Chapter I: Market potential, challenges and opportunities in dermal drug delivery

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Market potential, challenges and opportunities in dermal drug delivery

Somnath G. Kandekar, Yogeshvar N. Kalia

School of Pharmaceutical Sciences,

University of Geneva & University of Lausanne, 1 rue Michel Servet,

1211 Geneva 4, Switzerland

Manuscript under preparation

Abstract

A localized drug delivery provides several advantages over systemic drug delivery for treatment of dermatological diseases. Effective pharmacotherapy depends on being able to attain the right therapeutic concentrations of a drug in the target compartment within the right time-frame. This depends on the drug’s physicochemical properties, potency, pharmacokinetics, and type of formulation or delivery technique used. Development and optimization of novel formulations and delivery technique could be a good option for enhancement of drug delivery into the target compartment.

This chapter discusses the structure and function of the human skin and common dermatological conditions followed by the market potential of dermatological products.

Challenges in the topical drug delivery are presented followed by a brief discussion of passive and active delivery techniques which can be used to enhance dermal delivery. A special focus is given on the application of polymeric micelles, microemulsions, and iontophoresis for targeted dermal delivery. The importance of bioavailability and methods

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used to study the biodistribution of drug present in the skin and follicular structure are discussed in the last section.

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1. Anatomy of the human skin

The skin is the largest organ of the human body with a surface area of 1.8−2.0 m² representing the outmost barrier between the body and the surrounding environment.

Human skin is composed of four main layers: the stratum corneum, the viable epidermis, dermis, and subcutaneous tissues. Stratum corneum (or horny layer) is the outermost layer of epidermis with thickness 10-20 μm formed from 10-15 layers of keratinocytes [1]. It serves as the primary barrier of the skin, regulating water and heat loss from the body and preventing ingress of potentially harmful substances and microorganisms from the skin surface. The unique composition of the stratum corneum intercellular lipids and their structural arrangement in multiple lamellar layers within a continuous lipid domain is critical to the barrier function of the stratum corneum [1-3].

The viable epidermis is formed from stratum lucidum, stratum germivatum, stratum spinosum, and stratum basale. In addition stratum basal contains melanocytes, Langerhans cells, and Markel cells [4]. The dermis is about 2-5 mm in thickness and consists of collagen fibrils that provide support and connective tissue that provides elasticity and flexibility which are embedded in the mucopolysaccharide matrix. Due to the hydrophilic nature of dermis, it provides little barrier to the permeation of hydrophilic molecules; however, it hinders the permeation of very lipophilic molecules into the deeper tissues. The appendageal structures like hair follicles, sebaceous glands, and sweat glands originate in the dermis; in addition, it contains blood and lymph vessels and nerve endings [5].There are number of physiological factors like age, anatomical site, ethnicity, and normal vs. diseased skin that affect the skin barrier function and hence skin permeability[6-8]. Due to changing lifestyle and environmental factors incidences of dermatological disease are increasing [9, 10] which is discussed in the next section.

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2. Dermatological disorders

Skin is associated with a number of dermatological conditions ranging from non- cancerous to cancerous diseases that are caused by infection, inflammation, and autoimmune disorders [11-13]. The most common skin disorders are psoriasis, acne, ichthyosis, non-melanoma skin cancer (NMSC), eczema, rosacea, alopecia areata, melasma, vitiligo (pigmentation disorder), warts, herpes simplex infections, urticaria, and fungal infections leading to change in the barrier function of the skin [13]. Physicians treating skin diseases have an opinion that “patients hardly ever die from a skin disease, but it can be truly bothersome”; however, these diseases are an important cause of health loss on a global level. Altogether skin conditions combined were the fourth leading cause of non-fatal disease burden at the global level [14]. In this section, the dermatological condition Acne vulgaris (acne) and non-melanoma skin cancer (NMSCs) are discussed briefly.

Acne is a highly predominant dermatological condition of the pilosebaceous unit (PSU).

It affects over 80% of the adult population mostly on the face, chest, and back. Acne has a complex pathogenesis with altered follicular keratinization, increased sebum production, inflammation, and infection of Propionibacterium acnes in the PSU [15]. The early stage of acne typically features comedones, where the abnormal desquamation of follicular epithelium occurs and the follicular duct infundibulum becomes partially or completely clogged with excessively secreted sebum and desquamated cells. As a result, the drainage of sebum to the surface of the skin is obstructed; P. acnes growth is thus promoted inside the PSU and may lead to rupture of the entire PSU and formation of inflamed pustules and cysts [15-18]. Chapter two focuses on selective drug delivery to PSU for acne treatment.

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Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represent the most frequently occurring NMSC arising from the viable epidermis. BCC originates from the cells composing the basale layer of the epidermis, occurs more frequently than SCC; it is also a less aggressive form of NMSC [19, 20]. SCC originates in the squamous cell of the epidermis and as tumor progression occurs, it spreads in the upper layers and further in the deeper layers of the skin. If NMSC remains untreated it could undergo metastasis and spread into the other body organs. Immunosuppression, sun exposure and, certain genetic diseases are the highly acknowledged risk factors in NMSC [20]. Chapter three to five focus on the targeted cutaneous delivery of chemotherapeutic agents that could provide an option for the treatment of NMSC.

As the numbers of skin diseases are high and with advances in pharmaceutical science new products and therapy options are getting available to patients as a result market of dermatological products is growing [21] and it is discussed in the next section.

3. Market potential and trend in dermatological product development

Skin diseases were the 4^th leading cause of nonfatal burden expressed as years lost due to disability in 2010 [13]. Globally each year, nearly 60.5 billion topical skin medication units are sold. The global dermatological products market is expected to grow at a moderate 5-year compound annual growth rate (CAGR) of 3.6% and reach $20.4 billion in 2020 from $17.1 billion in 2015. The United States stands as the largest dermatology market (valued at $7.5 billion in 2015; 44% of market share) and its dominance will continue in next years while the BRIC (Brazil, Russia, India, China) countries are expected to experience the fastest growth rate at a CAGR of 6%, taking 23% of market share by 2020 [22].

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Innovation in dermatology occurs at a slower rate than in other therapeutic areas. A study demonstrates that the number of new chemical entities (NCE) developed in recent years for dermatologic diseases are remarkably small. Moreover, US FDA approved fewer new topical drugs in recent years (2010–2014) than in period 2000–2009 (4.8 approvals/year versus 8.8 approvals/year). The most common indications are for acne, tinea infections, psoriasis, and atopic dermatitis. Most approvals were for dosage changes, new combinations, and new formulations while only one-eighth of the total approvals (2000–

2014) were for new chemical entities (NCEs) [23]. There are four major factors that contribute to the development of few NCEs for skin disease: the economic potential of new dermatologic drugs, the risk-to-benefit ratio, and few surrogate endpoints during clinical trials and inadequate basic knowledge of the pathophysiologic mechanisms of skin diseases. A major reason that few companies undertake the development of NCEs solely or even partly for dermatologic diseases is that the economic return from dermatologic drugs (especially topical products) is relatively small compared with markets for drugs for other diseases, such as cardiovascular diseases [24]. Many dermatological drugs went off-patent in last few years, thus increasing the number of generic formulations in the market. However, generic formulations need to be bioequivalent to that of brand-name formulation. There are several factors that affect the bioavailability of topical drugs. Thus, the nature of dermatological formulations warrants caution when substituting brand-name formulations with the generic equivalents.

The improved safety profile and patient compliance with topical delivery for local skin conditions compared with traditional oral and parenteral administration are appealing features for drug developers. Due to this renewed interest in dermatology has been observed; major pharmaceutical companies have re-entered this sector mainly by broadening the indications of existing products into dermatology. Patent cliffs, the

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increasing burden of chronic skin conditions, the need to improve patient compliance, and innovations in topical drug product development are the main driving forces for the growth of dermatology market [22]. Developing novel topical products with improved efficacy and safety based on existing drug substances represents an important strategy for topical drug product development and this was considered as one of the important parameters during research work performed in this doctoral research thesis.

4. Dermal drug delivery challenges

Compounds have been applied to the skin for thousands of years to treat local conditions and enhance beauty. The outermost layer of the skin, the stratum corneum is the main barrier to permeation of externally applied chemicals [21]. For most skin diseases, the target site lies in the viable epidermis or upper dermis. Some applications may necessitate targeting the skin surface (e.g., sunscreens, cosmetics products) or hair follicles (e.g., hair growth boosters, antiacne, and antiperspirants products). However, developing an appropriate topical formulation is a complex and challenging process as several factors need to be considered, e.g. intended use and the site of action, physicochemical properties of the active and the selection of excipients. The topical delivery of any active is much affected by the type of formulation/vehicle used than any other route of administration [25]. The rate at which a drug diffuses across the stratum corneum determines its overall rate of dermal penetration and permeation. Delivery efficiency and therapeutic effect mainly depend on drug diffusion affinity and interaction between the formulation excipients and membrane components. Furthermore, the success of a topical drug is dependent on its ability to reach the correct target in sufficient quantity to be therapeutically effective. Therefore, formulations and active should be better designed and modified for crossing the stratum corneum as it acts as a barrier for topical drug

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delivery and its low permeability limits the delivery of drugs via the topical route [26]. To overcome this various efforts has been made that includes (i) development of novel formulation/vehicle systems (passive delivery) [25, 27, 28] and (ii) physical enhancement techniques that use an energy to achieve the desired therapeutic level of drug into the skin (active delivery) [29, 30].

4.1. Passive dermal drug delivery

Large number of drug (from small drug molecules to biological macromolecules) is used to treat the local dermatological ailment by topical route of administration. Although they have different molecular structures and physicochemical properties, depending on their properties formulation strategies could be designed. For small drug molecules based on their properties and disease condition, conventional formulations like cream, gel, ointment etc. or novel formulations like liposomes, polymeric nanocarriers, microemulsions could be developed for passive delivery. The rate and extent of drug delivery should be reasonable to achieve local therapeutic concentrations in a reasonable timeframe to provide sustained pharmacological action and also avoid systemic exposure of the drug [26, 31].

4.1.1. Conventional formulations for dermal drug delivery

Conventional topical formulations include the use of ointments, creams, gels, lotion, liniment, powder etc. Active from such preparations first needs to diffuse from the vehicle to the skin surface and then partitions into the stratum corneum, diffuses through the stratum corneum, partitions into the viable epidermis and diffuses through the viable epidermis. High concentration of active is generally required by these vehicles to achieve therapeutic effect due to a low efficiency of the delivery system. Two parameters are imperative for the drugs to be effective: they have to reach the site of action at a significant amount and have to stay at the site in an effective concentration for a certain

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time [31]. Moreover, sometimes the application of formulation results in lack of patient compliance due to problems such as greasiness and stickiness, the unpleasant odor associated with the formulations and it may also result in toxic reactions such as irritation, allergic reactions. The delivery from these systems is often unspecific and the skin penetration can be very low with high variation. To increase the penetration of active into and across the skin layers, penetration enhancers have been used which increase transport rate through the epidermal barrier, however; it also increases unwanted effects like enhanced drug level in the blood, irritation or even toxic side effects after application [32]. So, conventional topical formulations have some limitations and are compromised with regard to efficacy and safety of the therapy and patient compliance. To overcome these problems, novel drug delivery systems are being developed that could improve the efficacy and safety of the therapy and enhance patient compliance.

4.1.2. Nanocarriers for dermal drug delivery

There is increasing interest in nanocarrier enabled delivery of therapeutic molecules, diagnostic, prophylactic or cosmetic substances into the skin, which could overcome the skin barrier to reach targets tissues in the skin i.e. the stratum corneum, epidermis or deeper tissues in a very precise and controlled manner. Based on properties of a carrier system like their narrow size distribution, surface morphology, and charge it can proficiently control the release of an active to the target site in the skin after interaction and could provide the localized effect by creating depot in the skin [33], Figure 1 shows potential drug delivery mechanisms of different nano-sized systems. The encapsulation of active moiety in nanocarriers is an interesting strategy in targeted topical delivery; as such systems could enable sustained release, resulting in an extended activity or enhanced uptake and could reduce the adverse effects associated with a drug. Moreover,

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encapsulated active substances are shielded from external factors and their degradation could be avoided [34].

In last decades lot of efforts have been made to develop novel formulation for improved delivery, efficacy, safety and stability profile, resulting into development of various drug delivery systems which includes but not limited to liposomes, niosomes, polymeric micelles, high deformation vesicles, microemulsions, transfersomes, ethosomes, solid lipid nanoparticles etc. [25, 35-37]. In this thesis, chapter two presents the development of adapalene polymeric micelle-based formulations to target the hair follicles i.e. the site of acne origin. Chapter three and four focuses on the development of polymeric micelle and microemulsion formulations for selective delivery of vismodegib (a poorly water-soluble drug used in the treatment of basal cell carcinoma) into the viable epidermis. In this section, polymeric micelles and microemulsions are discussed briefly.

Figure 1. Potential drug delivery mechanisms of nano-sized delivery systems. Adapted with permission from [37].

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Polymeric micelles

Polymeric micelles are colloidal particles of amphiphilic copolymers that self-assemble above the critical micelle concentration (CMC) to form a specific core-shell structure. In the case of polymeric micelles (PM), the amphiphilic copolymer contains blocks with different lipophilic and hydrophilic properties [38]. Polymeric micelles are characterized by the nature of their copolymer constituents and composition. Polymers used for micelle formulation are mostly block copolymers that can be subdivided into different classes: (1) diblock copolymers, (2) triblock copolymers, (3) graft copolymers, and (4) star-block copolymers are most common structures [39]. The ability of the PM to solubilize lipophilic compounds directly depends on the nature and the size of the hydrophobic chain of the copolymer. The copolymer structures can influence the intermolecular interactions between the drug and the polymer and the size could affect the amount of drug that can be incorporated. Conversely, the drug itself can impact the characteristics of the micelles [40]. Commonly used methods for the micelle preparation are direct dissolution, dialysis, oil-in-water emulsion, and solvent evaporation method. Drug present in micelle formulation is mainly characterized for drug content (mg/mL), drug loading, and incorporation efficiency. For the size characterization dynamic light scattering (DLS) and for morphology transmission electron microscopy (TEM), scanning electron microscopy (SEM), or atomic force microscopy is used [41].

PM could be useful as a reservoir for lipophilic drugs to deliver them into the skin in a controlled manner is becoming an important strategy for the treatment of different dermatological ailments [39]. Lapteva et al developed nanometer-sized tacrolimus (TAC) PM using biodegradable and biocompatible methoxy poly(ethylene glycol)-dihexyl substituted polylactide (MPEG-dihex-PLA) diblock copolymer for investigation of their potential for delivery of TAC into the skin. Biodistribution studies of TAC polymeric

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micelles in the human skin indicated that the increase in cutaneous drug deposition could be due to deposition of PM into the hair follicle. Compared to that of Protopic (0.1% w/w;

TAC ointment PM has shown the superior delivery profile in the human skin [42].

Topical delivery of cyclosporine (CsA) was also done successfully by MPEG-dihex-PLA micelles [43]. In another study, azole antifungals (fluconazole, clotrimazole and econazole nitrate) were delivered into the skin by MPEG-hexPLA polymeric micelles successfully [44].

Topical delivery of PM comprising retinoic acid (RA) using MPEG-dihexPLA was also studied to evaluate their ability to deliver RA to the pilosebaceous unit (PSU) for the treatment of acne. Micelle formulation development followed by ex vivo delivery studies showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A^® Micro (0.04%), a marketed gel formulation containing RA loaded microspheres. PM formulation also displayed selectivity for delivery to the PSU compared to noncolloidal RA formulation [45]. In another study, benzoyl peroxide (BPO) delivery using PM of Pluronic^®F127 into hair follicles was studied, the results indicated that PM offers a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment [46]. The better cutaneous bioavailability of PM could be due to the small size of micelles that might provide the larger contact surface with the skin or by the formation of a depot in the appendage structures and on the skin surface (including furrows) [44, 45]. In addition, it is also hypothesized that the micelle can disassemble and release the drug upon contact with the stratum corneum because of its interaction as micelles possess hydrophilic shell leading to polarity changes [47].

Several therapeutic agents used in topical application suffer from poor cutaneous bioavailability when delivered using conventional formulations. Research papers

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presenting the use of PM to enhance dermal drug delivery are not many till date;

however, it shows that micelles are efficient drug delivery systems for local dermal delivery and to target the appendageal structures. Thus, these carriers may enable targeted topical drug delivery and could help in better management of local dermatological conditions and disease associated with hair follicles. In this thesis, adapalene and vismodegib polymeric micelles were developed using biodegradable and biocompatible copolymers D-α-tocopherol polyethylene glycol succinate and MPEG-dihexPLA, respectively. Developed micelle and micelle gel formulations were tested in vitro to estimate delivery potential using porcine and human skin models and dermal bioavailability in different skin layers and in hair follicles was studied.

Microemulsion

Microemulsion (ME) is a monophasic, transparent, thermodynamically stable colloidal dispersion system composed of an aqueous phase, oil phase, surfactant and cosurfactant mixed in a suitable ratio. Physical properties like thermodynamic stability, high solubilization capacity for both lipophilic and hydrophilic compounds makes them extremely effective drug delivery systems for dermal and transdermal applications, in addition, ease of preparation and aesthetic feel after application makes them attractive drug delivery system [48-50]. Unlike coarse emulsions micronized with external energy, microemulsions are based on low interfacial tension which is achieved by adding a cosurfactant leading to the spontaneous formation of thermodynamically stable microemulsions [51]. The droplet size in the dispersed phase remains mostly small in diameter (in nm range) making microemulsions transparent liquids. In addition to nano size of globules, certain ingredient acts as permeation enhancer ultimately helps drug molecules to cross the biological barrier.

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Bhatia et al developed and investigated the microemulsion formulation of adapalene for transfollicular delivery. Based on in vitro delivery and confocal laser scanning microscopy studies it was concluded that hair follicles provide the path for transfollicular permeation of adapalene microemulsion [52]. Microemulsion with gel-like properties for the cutaneous delivery of imiquimod was developed by Telò et al using a 1/1 TPGS (D-α- tocopheryl polyethylene glycol 1000 succinate)/Transcutol mixture as a surfactant system and oleic acid as an oil phase. Delivery studies confirmed that microemulsion mesostructure affects the drug distribution between the epidermis and dermis [53].

Microemulsions are also investigated for transdermal delivery of ropivacaine, testosterone and for several other molecules [49, 54, 55]. In this thesis microemulsion formulations of vismodegib were developed and finally, two best formulations were tested in vitro on human skin model.

4.2. Physical techniques (energy driven) for dermal drug delivery

Passive drug delivery is a suitable option for treatment of local dermatological conditions in most of the cases as explained above; however, when applied it need to be on the skin surface for certain time to give enough time for a drug to diffuse and partition from the formulation into the skin layers. In certain cases, it causes the skin irritation, redness and other skin reactions as active remains in contact with stratum corneum for a long time [56, 57]. This can be minimized by different strategies like developing prodrugs or delivering drug molecules actively into the skin within a short period of time. The active methods involve the use of external energy to act as a driving force and/or to reduce the barrier properties of SC and enhance the drug delivery [30]. This includes the techniques like iontophoresis, electroporation, laser microporation, microneedles, sonophoresis, phonophoresis etc. [29]. The Fifth chapter of this thesis presents the iontophoretic

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delivery of an anticancer drug that could have beneficial effects in the treatment of NMSC, so below iontophoretic drug delivery technique is discussed briefly.

Iontophoresis

Iontophoresis involves the application of a small electric current either directly to the skin or indirectly via the dosage form to enhance deposition and/or permeation of the therapeutic agents. Enhancing the drug delivery as a result of this technique can be attributed by either one or a combination of the following mechanisms; electromigration (EM) (for charged solutes), electro-osmosis (EO) (for uncharged solutes) [58, 59].

Parameters that affect the design of an iontophoretic skin delivery system include electrode type, current intensity, drug concentration, pH of the system, competitive ion effect, and permeant [58]. Figure 2 shows an iontophoretic set up illustrating the diffusion of charged or uncharged drug molecules during iontophoresis. The total iontophoretic flux (JT) is the sum of the fluxes due to EM (JEM) and EO (JEO) considering that the passive permeability (J_P) is insignificant.

JT = J_EM + J_EO + J_P (1)

Electromigration refers to the orderly movement of charged molecules in the presence of small constant electric current across the membrane. For instance, positively charged drugs when placed in the anodal compartment (positive electrode) migrate away from the electrode and pushed into the skin. The same occurs when negatively charged drugs are placed in contact with the cathode compartment. The electromigration contribution to a drug’s skin penetration depends on the concentration and the electrical mobility of the charged drug molecule. High-molecular weight drugs i.e. peptides and proteins are generally having a low electric mobility, which results in the decrease in electromigration contribution in total delivery [58].

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Figure 2. A schematic representation of an iontophoretic delivery system. The anodal compartment contains a cationic or neutral drug (D⁺/D) and cathodal compartment contains an anionic drug (D⁻). Upon application of an electric potential electromigration takes place where D⁺/D⁻ transported into the skin from their respective compartments.

Electroosmotic (EO) flow from anode to cathode direction carries the neutral drug molecules from the anodal compartment to the skin (skin layer thicknesses not drawn to scale).

Electroosmosis refers to the solvent flow after an electric potential is applied across the skin [60]. Under physiological condition, EO flow occurs from the anode to the cathode direction since the isoelectric point of the skin is 4-4.5 (cation permselectivity) [61]. As a result of solvent flow, transport of cations enhances and the transport of anions is impeded. This also favors transport of the neutral and high molecular weight drugs with the solvent flow [62, 63]. Hence, iontophoresis has been successfully used in the delivery of several therapeutic areas like pain management, neurodegenerative diseases and for local dermatological conditions.

Iontophoretic delivery of khellin which is used in the photochemotherapeutic treatment of vitiligo was studied in vitro using an excised human skin. Passive and iontophoretic

Power source

Stratum corneum

Epidermis

Dermis

D⁺ D⁺ D

Anode (+) Cathode (−)

D⁻ D⁻ D⁻

D⁺

D⁺ D

D D⁺

D⁻

D⁻ D⁻

EO EO

e

Na⁺

Cl⁻ Na⁺

Cl⁻

D⁺ D⁻

e

EM EM

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deliveries were compared and the drug concentration profile within the skin as a function of depth also determined. Anodal iontophoresis for 30 min at 0.5 mA/cm² followed by passive delivery for 30 min was shown to increase the amount of drug deposited in the skin, especially in the upper 50 µm of the membrane as compared to passive delivery and iontophoretic delivery alone. Although khellin is a neutral molecule, its permeation was enhanced by iontophoresis on account of EO. The increased quantities of khellin observed in the skin following passive diffusion after an iontophoretic pretreatment was probably due to the residual permeabilization of the membrane subsequent to iontophoresis [64]. Lopez et al investigated the iontophoretic delivery of 5- aminolevulinic acid (5-ALA) as a function of pH and demonstrated that at physiological pH (7.4) electroosmosis provided the principal driving force for delivery. 5-ALA has potential in the treatment of skin cancers by photodynamic therapy. The molecule has two ionizable groups (pKa 4.0 and 8.4) and exists as a zwitterion under physiological conditions [65]. Thus, iontophoresis has an enormous potential for delivery of neutral drug molecules in the treatment of localized skin condition with the possibility to explore potent anticancer drugs. Iontophoretic therapy with anticancer drugs is an appealing option for the therapy of skin cancers since it could reduce many of the complications associated with radiotherapy and the scar formation in the case of surgery. It may be particularly suitable for recalcitrant tumors or where surgery is not an option either because of poor patient condition or for cosmetic reasons, e.g. facial tumors. The precise control of drug delivery to the tumor by electrical current adjustments and formulation characteristics could be achieved. Moreover, short duration of application may rapidly target the drug to the tumor in high concentrations with no/minimal exposure to the systemic circulation.

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5. Drug bioavailability in the skin

In the development of a new drug or new dosage forms human studies are generally not feasible. As a result, in vitro and animal models are often used as screening models to investigate local and transdermal drug absorption into and across the skin. Drugs used in the treatment of skin diseases mostly have a target site in the skin layers depending on disease i.e. it could be stratum corneum, viable epidermis or dermis. During the product development study it remains of great importance whether given formulation are able to deliver and drug achieves desired concentration in the target compartment or not along with a minimal systemic exposure. Bioavailability (BA) is defined as the “rate and extent to which the drug is absorbed from the formulation and becomes available at the site of action”. Ideal skin delivery refers to transport the right chemical, to the right site in the skin, at the right concentration for the correct period of time [26], fulfilling this condition could lead to more efficacy and safe use of the topical pharmaceutical products [31].

To study BA of a drug in the skin several in vivo and in vitro methods have been evaluated e.g., dermatopharmakokinetics, dermal microdialysis, skin-blanching assay (for corticosteroids), and different imaging method [66, 67]. These different approaches have their advantages and disadvantages, so new techniques which can provide more detailed information on drug bioavailability at the target site need to be used. In this thesis to determine the amount of drug present at the given site was studied using “biodistribution methodologies” developed in our laboratory. Once the amount of drug present in the corresponding area is determined it could provide a clear estimation of the concentrations achieved in the given cutaneous layers or follicular structures and easily correlated with the desired therapeutic concentration. This gives very indicative information about the delivery performance of the developed formulation or delivery technique. The methodologies used for same are punch biopsy followed by horizontal slicing; follicular

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punch biopsy followed by drug extraction and quantification using highly precise and sensitive analytical method (UHPLC-MS/MS) was performed. These techniques are discussed briefly below.

5.1. Punch biopsy followed by horizontal slicing in vitro

After delivery of the drug into the skin the amount present in the various layers of the skin i.e. upper layer (mainly SC), viable epidermis, and dermis could be easily quantified using this method. In this method after finishing the delivery experiment skin is snap frozen into the isopentane cooled in liquid nitrogen (−160°C) and then sliced using the cryotome. The skin can be sliced up to 20 m thick lamellae going from skin surface to the dermis. Each slice is then extracted into the extraction media and the amount of drug present is quantified. The cutaneous biodistribution of tacrolimus [42], triamcinolone acetonide [68], acyclovir [69] has been reported using this methodology. From the amount of drug present in each slice, the concentration obtained in each slice could be easily calculated and correlated with the required therapeutic concentrations. This in vitro biodistribution approach could also be used to study the bioequivalence of different topical generic formulation, since it provides the detailed information about the amount of deposited into the skin layers. To use this technique successfully the highly sensitive analytical instruments (e.g. UHPLC-MS/MS) are required.

5.2. Drug bioavailability in follicular structures

Nanocarriers selectively accumulate in follicular structures after application with massage to the skin [70]. Although the follicles occupy a relatively small fractional area (on average, 0.1%) of the total skin surface, it appears that diffusion via these appendages is fast relative to that through intact SC [71, 72]. Targeted delivery into the hair follicle has become an area of major interest in recent years for treatment of acne; alopecia etc. and a

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number of techniques have been used to identify and to quantify the contribution of follicular delivery. To investigate the drug deposition into the hair follicles techniques like cyanoacrylate biopsy, tape stripping, and punch biopsy are reported [73-75]. PSU punch biopsy technique is discussed in brief below.

PSU punch biopsy technique

To determine the amount of drug present in follicular associated and non-follicular skin area punch biopsy using 1 mm diameter metal punch was performed. In short, PSU or PSU-free area was punched out and extracted in the extraction medium and amount of drug present was quantified using UHPLC-MS/MS analytical method [45, 75]. The drug deposition in the PSU and PSU-free biopsies were compared to study the selective delivery to the follicular structures.

6. Conclusions and future perspective

Topical treatment is most convenient way to treat dermatological diseases. However, the stratum corneum counteracts the entry of the active into the skin (i.e. target site) leading to only a small factor of the applied active reaching the target site. To achieve the localized effect, an easy and non-invasive option such as novel topical formulation and delivery technologies are ideal and desirable for this purpose. The recent innovations mainly focused on exploring the novel carriers such as vesicles, lipid-based, polymeric delivery systems. Nanocarriers can accumulate in the skin furrows and hair follicles and create high local concentrations of loaded drugs that can further diffuse to the viable layers of the skin. Few therapeutic and cosmetic products based on nano-sized particles are marketed and some are under clinical evaluation. However, several questions arise during new pharmaceutical product development, e.g. with respect to

Nanocarrier systems and iontophoresis: complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

Thesis

Reference

Nanocarrier systems and iontophoresis: complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

Nanocarrier systems and iontophoresis:

Complementary approaches for targeted cutaneous delivery of hydrophobic and hydrophilic drugs

THÈSE

“You can't cross the sea merely by standing and staring at the water.”

Rabindranath Tagore

“It always seems impossible until it's done.”

Nelson Mandela

Dedicated to my beloved family

Contents

Résumé

Summary

Chapter I

Market potential, challenges and opportunities in dermal drug

delivery

Market potential, challenges and opportunities in dermal drug delivery

Abstract

1. Anatomy of the human skin

2. Dermatological disorders

3. Market potential and trend in dermatological product development

4. Dermal drug delivery challenges

Anode (+) Cathode (−)

e

e

5. Drug bioavailability in the skin

6. Conclusions and future perspective