Skin Drug Delivery From Different Lipid Vesicular Systems [Elektronische Ressource] / Ming Chen. Gutachter: Alfred Fahr ; Gerrit L. Scherphof

Skin Drug Delivery
From Different Lipid Vesicular Systems







Dissertation
For the obtainment of the academic degree doctor rerum naturalium
(Dr. rer. nat.)

Presented to the Council of the Faculty of Biology and Pharmacy of
the Friedrich-Schiller-Universität Jena



Submitted by

Ming Chen

Master of Pharmaceutics (M.S.)
Born on 24th of December, 1979 in Jiangsu Province, P.R.China








 
 Reviewers:
Reviewer 1:
Prof. Dr. Alfred Fahr
Friedrich-Schiller-Universitaet Jena
Biologisch-Pharmazeutische Fakultaet
Institut fuer Pharmazie, Lehrstuhl fuer Pharmazeutische Technologie
Lessingstrasse 8, 07743 Jena, Deutschland
Reviewer 2:
Prof. Dr. Dagmar Fischer
Friedrich-Schiller-Universitaet Jena
Biologisch-Pharmazeutische Fakultaet,
Institut fuer Pharmazie, Lehrstuhl fuer Pharmazeutische Technologie
Otto-Schott-Strasse 41, 07745 Jena, Deutschland
Reviewer 3:
Prof. Dr. Gerrit Scherphof
University Groningen
Faculty of Medical Sciences
Department of Cell Biology-General
Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands
06.05.2011Day of the public defense:Contents
Part one: General Introduction .................................................................................1
1.1 The Aim of research ..................................................................................2
1.2 The Structure of Skin ...............................................................................3
1.3 Skin Penetration Routes ...........................................................................9
1.4 Liposomal Systems for Skin Drug Delivery...........................................10
Part Two: Publication Overview..............................................................................13
Part Three: Publications ..........................................................................................16
3.1 Publication 1.............................................................................................16
3.2 Publication 2.............................................................................................29
3.3 Publication 3.............................................................................................39
Part Four: Final Discussion .....................................................................................97
4.1 Preparation and Characterization of Lipid vesicular systems............98
4.2 Human Skin Preparation.......................................................................100
4.3 The Interaction among conventional liposomes, Model drugs and
Skin..........................................................................................................101
4.4 The Interaction among Deformable Liposomes/Invasomes, Model
drugs and Skin........................................................................................102
4.5 The Interaction between Ethosomes, Model drugs and Skin.............104
4.6 The Effect of Application mode on Skin Drug Delivery.....................106
Part Five: Summary/Zusammenfassung...............................................................108
Part Six: Reference...................................................................................................110
Acknowledgement....................................................................................................114
Curriculum Vitae.....................................................................................................115
Statement...................................................................................................................117Part One General Introduction
Part One
General Introduction

Skin is the largest organ of the human body, which interfaces with the
2
environment and covers a surface area between 1.5 and 2.0 m. From a
pharmaceutical point of view, skin offers a glorious route for delivering drugs because
skin drug delivery brings forth many attractive advantages over other routes of
administration, including avoidance of first-pass metabolism, sustained and controlled
delivery over a prolonged period of time, reduction in side effects associated with
systemic toxicity, improved patient acceptance and compliance, direct access to target
or diseased site, convenient and painless administration and so on (Brown et al., 2006).
On the other hand, however, skin is also an excellent biological barrier, which is
2 4as much as 10 -10 times less permeable than a blood capillary wall (Cevc and Vierl,
2010) and imposes physicochemical limitations to the type of permeants which can
traverse it. For a drug to be delivered successfully and passively into or through the
skin, small molecular size (ideally a molecular weight less than 500Da) and sufficient
aqueous and lipid solubility (a LogP between 1 and 3) are essential and octanol/water
required (Yano et al., 1986). In addition, the presence of enzymes in the skin such as
peptidases and esterases might metabolize the drug into a form which could be
therapeutically inactive, thereby reducing the efficacy of the drug (Steinstrasser and
Merkle, 1995). Moreover, skin irritation and sensitization provoked by exposure to
certain stimuli such as drugs, excipients or any other component of topical
formulations could also be a limitation to the product on market (Carmichael, 1994;
Hogan and Maibach, 1990; Toole et al., 2002). Thus, all of these requirements
mentioned above, at least, have limited the number of commercially available
products based on skin delivery.
Over the past decades, numerous studies have been performed to overcome the
problems associated with skin delivery and also a number of novel skin delivery
systems and approaches have been developed, including the use of chemical
penetration enhancers(Goodman and Barry, 1988; Williams and Barry, 2004),
modifying chemical potential of the drug (Megrab, 1995), the application of
liposomes and other colloidal drug carrier systems, electrically driving molecules into
1
Part One General Introduction
or through the tissue employing iontophoresis (Miller et al., 1990), or physically
disrupting the skin structure by electroporation or sonophoresis (Prausnitz et al.,
1993a; Prausnitz et al., 1993b) and others (Nanda A, 2006). Among these novel
techniques, lipid vesicular systems such as conventional liposomes, deformable
liposomes (transfersomes), and ethosomes may offer a promising strategy for
successfully improving skin drug delivery.
1 The Aim of Research
As mentioned, skin is known to exhibit selective permeability with respect to the
type of diffusing molecules. In fact, the ability of each drug to penetrate into the skin
and the diffusion route it takes are dependent on its own physicochemical properties
and the interactions it has with the skin’s various conduit regimes (Lu and Flynn,
2009). When it comes to liposomal drug carrier systems, the situation could be more
complicated. Firstly, encapsulated drug could be located at different position
according to their lipophilicity. For instance, lipophilic drugs could be incorporated
into the bilayers; while the hydrophilic one could be loaded within the water phase
inside the vesicles and could be also found outside the liposomes in high amounts.
This could affect the interaction between drugs and lipid carrier systems and in turn
influence the penetration and deposition behavior of drugs. Moreover, the function of
liposomal systems varies with type and composition. For instance, liposomal systems
may act as drug carriers controlling release of the medicinal agent. They may also
provide a localized depot in the skin so minimizing systemic. Alternatively, liposomes
may enhance transdermal drug delivery, increasing systemic drug concentrations. In
addition, liposomal systems can also be used for targeting delivery to skin appendages.
Thus, how the fate of drugs could be changed by different liposomal systems?
More specifically, do the liposomal systems enhance drug deposition into the skin? Or
do they enhance drug transport across the skin? Or do they enhance both dermal and
transdermal delivery? Moreover, the compositions of liposomal systems could change
due to penetration into the skin or evaporation of volatile components. These changes
depend on the amount of liposome applied and occlusion conditions. And these
differences may result in variations in the effects of liposomal systems as skin drug
delivery tools. Hence, do application mode and the amount of liposomes applied have
an impact on their effectiveness as skin drug delivery tools? At last but not the least,
what are reasonable mechanisms of different liposomal systems to deliver therapeutic
2
Part One General Introduction
agents to and through the s