Investigation of The Stabilization of Supersaturated Drug-in-Adhesive Transdermal Drug Delivery Systems - Minthi Bui

Investigation of the Stabilization of Supersaturated Drug-in-
Adhesive Transdermal Drug Delivery Systems
by
Minhthi Bui
A thesis submitted in conformity with the requirements

for the degree of Master of Science
Graduate Department of Pharmaceutical Sciences
University of Toronto
© Copyright by Minhthi Bui [2019]

Investigation of the Stabilization of Supersaturated Drug-in-Adhesive
Transdermal Drug Delivery Systems
Minhthi Bui
Master of Science
Pharmaceutical Sciences
University of Toronto
2019
Abstract
Transdermal drug delivery systems have become an attractive drug delivery method due to various
advantages. Diffusion of drug through the epidermis is often limited by the stratum corneum,
which acts as a diffusion barrier. Therefore, permeation enhancement strategies are often applied
to improve the resulting systemic bioavailability. Supersaturation is an attractive enhancement
approach since it does not compromise the integrity of the stratum corneum. However,
supersaturated systems are metastable which may result in reduced diffusional driving force and
bioavailability due to spontaneous crystallization. Stabilization of such systems using additives is
crucial to avoid reduced product performance. Various additives were evaluated and identified for
their suitability to sufficiently inhibit crystallization in our systems. Dissolution testing revealed
that patches exhibit different release mechanisms depending on the adhesive selected. Finally,
mathematical modeling was applied to analyze the data and gain further understanding of the
mechanisms governing drug release from our systems.
ii
Acknowledgements
I would like to first convey my deepest thanks and appreciation to my supervisor Dr. Ping Lee for
his advice and support throughout the course of my graduate degree. His passion and knowledge
for science is admirable and I feel truly fortunate to have had him as my supervisor. I will always
be grateful for his encouragement, support, and opportunity he has given me to be part of his
research group.
I would also like to thank to NAL Pharma giving me the opportunity for working on an industrial
MSc project. Without their financial support, my research project would not have been possible.
I am also thankful to my advisory committee members, Dr. Christine Allen and Dr. Edgar Acosta
for always providing me with insightful feedback on my research project during my advisory
committee meetings.
Thanks to Dr. Dubins who was always willing to help me throughout my degree and also helped
build the stability chamber used for my long-term physical stability studies.
I would also like to thank the current and past members of the Ping Lee group, Toye Ojo, Nellie
Han, Joy Yang, Yuji Yin, Silvia Zarate-Munoz, Yingshan Ma, Davide Frascio, Giovanna Schver
and many other students from the Department of Pharmaceutical Sciences at U of T for their
support and friendship throughout my time in the department. They have made my experience at
U of T even more memorable and enjoyable. I would also like to thank Danielle and Shama from
the P. G Wells lab for the mouse skin used in Chapter 3.
Lastly, I would like to thank my family and friends, especially all my family in Ottawa, I will
forever be grateful for their constant support and faith in me. Without them, I would not be where
I am today. Special thanks to my boyfriend Steven Daniluk, who has provided me with endless
support throughout the ups and downs during my graduate degree. He has spent countless hours
listening to me talk about my research and coursework, and also helping and teaching me during
the development of my mathematical model presented in Chapter 5. He has pushed me to be the
best that I can be, and I will always be grateful for that.
iii
Table of Contents
Abstract ………………………………………………………………………………………...... ii
Acknowledgement ……………………………………………………………………………… iii
Table of Contents ………………………………………………………………………………... iv
List of Tables ……………………………………………………………………………………. vi
List of Figures …………………………………………………………………………………... vii
List of Abbreviations …………………………………………………………………………….. x
1 General Introduction ………………………………………………………………………... 1
1.1 Introduction ……………………………………………………………………………... 1
1.1.2 Types of transdermal patches …………………………………………………………...1
1.1.3 Structure of the skin ………………………………………………………………….... 6
1.1.4 Physical and Chemical Enhancement Strategies …………………………………........ 9
1.1.5 Passive Enhancement ……………………………………………………………….... 11
1.1.6 Stabilizing Supersaturated Systems ………………………………………………...... 14
1.1.7 Significance ………………………………………………………………………….. 14
1.1.8 Hypothesis …………………………………………………………………………… 15
1.1.9 Research Objectives …………………………………………………………………. 15
2 Selection of Crystallization Inhibitors for Drug-in-Adhesive Patches …………………….. 16
2.1 Introduction …………………………………………………………………………….. 16
2.2 Materials and Methods …………………………………………………………………. 18
2.2.1 Materials ……………………………………………………………….…. 18
2.2.2 Slide Crystallization Evaluation Using Binary Mixtures ………………… 18
2.2.3 Physical Stability of Drug-in-Adhesive System …………………………... 18
2.2.4 Determination of Drug Saturation Solubility in Adhesive ……………….. 19
2.2.5 DSC for Characterizing Effectiveness of Additives ……………………… 19
2.2.6 Crystal Area Measurement using PLM …………………………………… 19
2.3 Results and Discussion …………………………………………………………………. 20
2.3.1 Slide Crystallization Evaluation Using Binary Mixtures ………………… 20
2.3.2 Drug Saturation Solubility of Rotigotine in Duro-Tak 87-2074 …………. 22
2.3.3 Slide Crystallization Evaluation with Adhesive System …………………. 22
2.3.3.1 Acrylate Copolymer Adhesive Slides …………………………... 23
2.3.3.2 Polyisobutylene (PIB) Adhesive Slides ………………………… 25
2.3.4 Characterizing Additives Using DSC …………………………………….. 28
2.3.5 Conclusion ………………………………………………………………... 29
3 Evaluating the Physical Stability and Performance of Transdermal Patches Using Identified
Crystallization Inhibitors …………………………………………………………………... 31
3.1 Introduction …………………………………………………………………………….. 31
3.2 Materials and Methods …………………………………………………………………. 32
3.2.1 Materials ………………………………………………………………….. 32
3.2.2 Preparation of Drug-in-Adhesive Transdermal Patches ………………….. 33
iv
3.2.3 Evaluating the Crystallinity of Adhesive Slides and Patches Using DSC... 33
3.2.4 In vitro Dissolution Testing of Transdermal Patches ……………………... 33
3.2.5 Skin Preparation …………………………………………………………... 34
3.2.6 In vitro Skin Permeation Study …………………………………………… 35
3.2.7 HPLC analysis of Rotigotine ……………………………………………… 35
3.3 Results and Discussion ………………………………………………………………… 36
3.3.1 Transdermal Components ……………………………………………….... 36
3.3.2 Evaluating the Crystallinity of Adhesive Slides and Patches Using DSC… 36
3.3.3 Evaluating the Crystallinity of Adhesive Slides and Patches Using PLM… 37
3.3.4 In vitro Dissolution Testing of Rotigotine Transdermal Patches ………… 39
3.3.5 In vitro Dissolution Testing of Rotigotine Transdermal Patches with
Varying Thicknesses …………………………………………………………..... 44
3.3.6 In vitro Dissolution Testing of Diclofenac Transdermal Patches ………… 47
3.3.7 In vitro Skin Permeation Studies for Rotigotine Patches ………………… 48
3.3.8 In vitro Skin Permeation Studies for Diclofenac Patches ………………… 52
3.3.9 Conclusion ………………………………………………………………... 53
4 Mathematical Modeling of the Rotigotine Drug Release from the Microreservoirs ………. 55
4.1 Introduction …………………………………………………………………………..... 55
4.2 Results and Discussion ………………………………………………………………..... 56
4.2.1 Predicting the total amount release with considerations of m∞……........… 56
4.2.2 Conclusion ………………………………………………………………... 65
5 Summary and Future Directions …………………………………………………................. 66
5.1 Summary …………………………………………………………………….................. 66
5.2 Future Directions ……………………………………………………………................. 68
References ………………………………………………………………………………............ 71
v
List of Tables
Chapter 1
Table 1.1 List of transdermal patches approved by the US FDA………………………………… 4
Table 1.2 Examples of chemical penetration enhancers used for transdermal delivery systems …11
Chapter 2
Table 2.1 Chemical name, structural formula and molecular weight of additives investigated for
binary mixtures………………………………………………………………………………….. 21
adhesive slide samples…………………………………………………………………………... 26
Chapter 3
Table 3.1 Summary of long-term physical stability studies for various rotigotine containing
patches…………………………………………………………………………………………... 38
Table 3.2 Summary of long-term physical stability studies for various diclofenac containing
patches ………………………………………………………………………………………….. 39
Chapter 4
Table 4.1 Estimated parameters and R2 of fitted data …………………………………………... 64
vi
List of Figures
Chapter 1
Figure 1.1 Schematic representation of transdermal reservoir-type patches……………………... 3
Figure 1.2 Schematic representation of transdermal drug-in-adhesive-type patches…………….. 4
Figure 1.3 Schematic representation of cross-section of human skin…………………………….. 7
Figure 1.4 “Brick and mortar” structure of the stratum corneum………………………………… 8
Figure 1.5 Permeation pathways through the skin………………………………………………... 9
Figure 1.6 Representation of a stable, unstable and metastable solution………………………... 12
Figure 1.7 Crystal formation of the rotigotine Neupro® patch………………………………….. 13
Chapter 2
Figure 2.1 Crystal growth comparison of 50% rotigotine (RTG), 50% RTG+10% oleic acid and
50% RTG + 10% Plasdone K90, as a function of time for slides kept at 65°C…………………. 25
Figure 2.2 Proposed drug-additive interaction between rotigotine and fatty acid………………. 25
Figure 2.3 Microscopic images of PIB adhesive containing 20% oleic acid and varying
concentrations of rotigotine at 10X, day 1 and day 19…………………………………………... 28
Figure 2.4 Crystal area development in PIB adhesive containing 20% oleic acid and varying
concentrations of rotigotine under 50ºC…………………………………………………………. 28
Chapter 3
Figure 3.1 Schematic representation of the USP Apparatus 5 and 6 for dissolution testing……. 32
Figure 3.2 Microscopic images of 15% RTG and 20% oleic acid PIB adhesive slide samples
confirming location of rotigotine in transdermal patches at 10X objective……………………... 38
Figure 3.3 Microscopic images of 5% K17+10% RTG+20% oleic acid patches prepared with PIB
adhesive after 7.5 months at 10X objective……………………………………………………… 39
Figure 3.4 Dissolution profiles of rotigotine in various transdermal patch formulations using Duro-
Tak 87-6908 with standard deviations (n=3). The RTG content for 15% RTG+20% OA was 11.8
mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12%
OA………………………………………………………………………………………………. 41
vii
Tak 87-2074 with standard deviations (n=3). The RTG content for 15% RTG+20% OA was 11.8
mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12%
OA.……………………………………………………………………………………………… 42
Figure 3.6 Comparison of rotigotine transdermal patches dissolution profiles for acrylate and PIB
adhesive (a) 15% RTG+20% OA (b) 5% Plasdone K17+10% RTG+12% OA (c) 5% Kollidon
VA64+10% RTG+12% OA with standard deviations (n=3). The RTG content for 15% RTG+20%
OA was 11.8 mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12%
OA.……………………………………………………………………………………………… 43
Figure 3.7 Dissolution profiles of rotigotine patches with various thicknesses (a) 15% RTG+20%
OA (b) 5% K17+10% RTG+12% OA (c) 5% VA64+10% RTG+12% OA with standard deviations
(n=3). The RTG content for 15% RTG+20% OA was 11.8 mg and 7.8 mg for 5% K17+10%
RTG+12% OA and 5% VA64+10% RTG+12% OA.…………………………………………… 46
Figure 3.8 Cumulative drug released (µg/cm2) of diclofenac in various transdermal patch
formulations using Duro-Tak 87-2074 with standard deviations (n=4). The DCF content for 15%
DCF+20% OA was 11.8 mg and 7.8 mg for 5% K17+10% DCF+12% OA and 5% VA64+10%
DCF+12% OA.………………………………………………………………………………….. 48
Figure 3.9 Cumulative drug permeated (µg/cm2) of rotigotine in various transdermal patch
formulations using Duro-Tak 87-6908 with standard deviations (n=4). The RTG content for 15%
RTG+20% OA was 11.8 mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10%
RTG+12% OA.………………………………………………………………………………….. 49
formulations using Duro-Tak 87-2074 with standard deviations (n=4). The RTG content for 15%
RTG+12% OA.………………………………………………………………………………….. 49
Figure 3.11 Comparison of the cumulative drug permeated (µg) of rotigotine for marketed
Neupro® patch and various transdermal patch formulations using Duro-Tak 87-6908 with standard
deviations (n=4). The RTG content for 15% RTG+20% OA was 11.8 mg, 7.8 mg for 5% K17+10%
RTG+12% OA and 5% VA64+10% RTG+12% OA and 4.5 mg for the Neupro®
patch.……………………………………………………………………………………………. 51
Figure 3.12 FT-IR spectra of oleic acid …………………………………………………………. 51
Figure 3.13 FT-IR spectra of a transdermal patch containing 15% RTG+20% OA ……………. 51
Figure 3.14 Cumulative drug permeated (µg/cm2) of diclofenac in various transdermal patch
formulations using Duro-Tak 87-2074 (n=4) with standard deviations. The DCF content for 15%
DCF+20% OA was 11.8 mg, 7.8 mg for 5% K17+10% DCF+12% OA and 5% VA64+10%
DCF+12% OA ………………………………………………………………………………….. 53
viii
Chapter 4
Figure 4.1 Histogram of microreservoir sizes for 15% RTG + 20% OA formulation (n=371) … 57
Figure 4.2 Q-Q Plot of sample data vs. (a) normal distribution, and (b) gamma distribution ….. 58
Figure 4.3 Measured and predicted amount released of RTG for 15% RTG + 20% OA patch at
different time scales …………………………………………………………………………….. 62
Figure 4.4 Measured and predicted amount released of RTG for 5% K17 + 10% RTG + 20% OA
patch at different time scales ……………………………………………………………………. 63
Figure 4.5 Measured and predicted amount released of RTG for 5% VA64 + 10% RTG + 20% OA
patch at different time scales ……………………………………………………………………. 64
ix
List of Abbreviations
DCF diclofenac
DIA drug-in-adhesive
DSC differential scanning calorimetry
EMA European Medicines Agency
FDA Food and Drug Administration
FT-IR Fourier-transform infrared spectroscopy
HPLC high-pressure liquid chromatography
HPMC hydroxypropyl methyl cellulose
K17 Plasdone K17
logP partition coefficient
MP melting point
OA oleic acid
PEG polyethylene glycol
PIB polyisobutylene
PLM polarized light microscopy
PSA pressure-sensitive adhesive
PVP polyvinyl pyrrolidone
RTG rotigotine
SLS sodium lauryl sulphate
SC stratum corneum
TDS transdermal delivery system
Tg glass transition temperature
Tm melting temperature
USP United States Pharmacopeia
UV-Vis ultraviolet-visible
VA64 KollidonÒ VA64
XRD x-ray diffraction
x
Chapter 1
General Introduction
1.1 Introduction
Transdermal delivery systems (TDSs) are an attractive method for drug delivery into the systemic
circulation due to their abilities to avoid the first-pass effect, being non-invasive, and their
avoidance of frequent dosing by providing a steady state delivery over an extended period of time,
thereby increasing patient compliance.1 For these reasons, transdermal delivery systems are a more
appealing approach to deliver drugs into the systemic circulation compared to oral delivery.2
Transdermal drug delivery systems differentiate themselves from topical products as they are
intended to reach the systemic circulation, whereas topical products are used to treat the local site
of application. The first transdermal system that was approved in the United States was a three-
day patch containing scopolamine to treat motion sickness and was released in 1979.2 Nicotine
patches became the first transdermal blockbuster drug and were released a decade after the
approval of the scopolamine patches. It was this specific product that increased the popularity in
the development of new transdermal products.2 Currently, there are over 20 transdermal delivery
systems available on the market for the delivery of a range of drugs including estradiol, fentanyl,
lidocaine, nitroglycerin, and oxybutynin (Table 1.1).23
1.1.2 Types of transdermal patches
Before introducing the different types of transdermal patches, it is important to first understand the
common components of transdermal patches and their functions. In general, all transdermal
patches, whether they are reservoir or matrix type patches, share 3 common components: a release
liner, an adhesive, and a backing film. The release liner is a protective liner that is removed prior
to the application onto the skin.1,44 An ideal release liner should be easily removed without
1
damaging the adhesive layer or its adhesive function upon removal yet remain attached firmly in
place during storage. The adhesive is responsible for proper adhesion onto the skin with minimal
applied pressure and for ensuring that the patch will remain in place for the duration of intended
drug delivery. In addition, the adhesive should have the following properties1:
1. It should be non-irritating to the skin.
2. It should be easily removed after its intended use.
3. It should be compatible with all the components of the system, including the drug.
Pressure-sensitive adhesives (PSAs) are often used as the adhesive layer of transdermal systems.
The three major PSAs used in these systems are: silicone adhesives, acrylate adhesives, and
polyisobutylene adhesives. These adhesives are typically solvent-based, whereupon mixing all
components of the adhesive layer, a thin film is cast, and a release liner and the solvent is
evaporated to yield the adhesive matrix. Afterwards, a backing film is laminated onto the adhesive
matrix. The backing film must be impermeable and occlusive since its role is to prevent backward
drug migration and to retain skin moisture such that the only drug migration is through the skin,
and the site of application is hydrated. Materials such as polyethylene, polyester, and polyurethane
are commonly used as backing films.
Existing transdermal patches can be categorized into two main types: reservoir and matrix patches.
Reservoir-type patches consist of five major components: a backing film, a reservoir containing
drug in a liquid or gel state, a rate controlling membrane, an adhesive layer, and a release liner film
(Figure 1.1). In these types of systems, a high concentration of drug is incorporated into either a
liquid or gel to be used as a reservoir, which is separated from the adhesive layer by a permeable
rate-controlling membrane. Reservoir patches are advantageous because they can provide a
constant release rate of the drug and there is less concern for drug crystallization. A disadvantage
2
of reservoir patches is their relatively thicker size, making them more uncomfortable to wear. They
also have a higher potential for reservoir leakage when damaged.23 Manufacturing defects are often
the culprit for dangerous drug leakage from reservoir patches. An example is the fentanyl reservoir
patch marketed as Duragesic®, which has been recalled twice since its approval due to
manufacturing defects. The first recall was in 2004, where there was a seal breach along the edge
of the patch, and the second was in 2008 where patches had a sliced edge resulting in leakage.31
This was a large safety concern, especially for a drug such as fentanyl since leakage could lead to
drug overdosing (dose dumping). In 2009, Duragesic’s manufacturer addressed this problem by
reformulating the reservoir patch into a drug-in-adhesive design.23
Patches that do not have a reservoir component are generally referred to as matrix patches. Drug-
in-adhesive (DIA) patches fall under the category of matrix patches and are much simpler in their
designs. The DIA patch consists of three components: a backing film, an adhesive layer where the
drug and excipients are evenly dispersed, and a release liner film (Figure 1.2).
Figure 1.1 Schematic representation of transdermal reservoir-type patch1
3
Figure 1.2 Schematic representation of transdermal drug-in-adhesive-type patch1
In this specific patch design, the drug and excipients are directly incorporated and evenly
distributed in the adhesive matrix, which is sandwiched between the backing film and release liner.
Currently, DIA patches are the dominant product design on the transdermal market (Table 1.1).
They are popular among patch formulations because they are generally thinner, more flexible,
more comfortable, less prone to dose dumping, and cheaper to manufacture. However, the major
drawback of DIA patches is that formulation development can be quite challenging.23
Table 1.1 List of transdermal patches approved by the US FDA 2, 23

Year
Drug (Product name) Indication Patch design
approved
Scopolamine (Transderm
Motion sickness Reservoir 1979
Scop®)
Nitroglycerin (Transderm-
Angina pectoris Reservoir 1981
Nitro®)
Clonidine (Catapres-TTS®) Hypertension Reservoir 1984
Estradiol (Estraderm®) Menopausal symptoms Reservoir 1986
Fentanyl (Duragesic®) Chronic pain Reservoir/DIA 1990
Nicotine (Habitrol®) Smoking cessation Matrix 1990
Nicotine (Nicoderm®) Smoking cessation Reservoir 1991
Estradiol (Vivelle®) Menopausal symptoms DIA 1994
4
Testosterone (Androderm®) Hypogonadism Reservoir 1995
Nitroglycerin (Nitro-Dur®) Angina pectoris DIA 1995
Nitroglycerin (Minitran®) Angina pectoria DIA 1996
Estradiol (Alora®) Menopausal symptoms DIA 1996
Estradiol with norethidrone

Menopausal symptoms DIA 1998
(Combipatch®)
Post-herpetic neuralgia
Lidocaine (Lidoderm®) DIA 1999
pain
Ethinyl estradiol with
Contraception DIA 2001
norelgestromin (Ortho Evra®)
Estradiol with levonorgestrel
Menopausal symptoms DIA 2003
(Climara Pro®)
Oxybutynin (Oxytrol®) Overactive bladder DIA 2003
Attention deficit
Methylphenidate (Daytrana®) DIA 2006
hyperactivity disorder
Major depressive
Selegiline (Emsam®) DIA 2006
disorder
Parkinson’s
Rotigotine (Neupro®) disease/restless leg DIA 2007
syndrome
Alzheimer’s and
Rivastigmine (Exelon®) Matrix 2007
Parkinson’s disease
Diclofenac epolamine Topical treatment acute
DIA 2007
(Flector®) pain
Chemotherapy-induced
Granisetron (Sancuso®) DIA 2008
nausea and vomiting
Capsaicin (Qutenza®) Neuropathic pain DIA 2009
Buprenorphine (Butrans®) Chronic pain DIA 2010
Estradiol (Minivelle®) Menopausal symptoms DIA 2012
One of the major challenges of formulating transdermal patches is that not all drugs are suitable
for transdermal delivery. Physicochemical properties of a drug are crucial to determining its
suitability for delivery through the dermis. The ideal candidate should have a molecular weight of
5
500 Da or less, should have a melting point (MP) less than 250°C, should be fairly lipophilic with
a partition coefficient, logP, between 1-5, and should be sufficiently potent to require a therapeutic
dose of less than a few milligrams per day.1,2, 23 Though the drug should be fairly lipophilic, the
balance between the lipophilicity and hydrophilicity is important. If the drug is too hydrophilic, it
will not partition into the SC, and if it is too lipophilic, it will not travel down to the aqueous layer
in the epidermis.42 These general requirements are due to the complex structure of the dermis, and
the barrier nature of the stratum corneum, the outermost layer of the skin (Fig. 1.3). The skin is the
largest organ in the body and its main function is to protect the body from the external
environment.6 It prevents excessive loss of water and exogenous substances from entering the body
transdermally.4,6 Therefore, the skin acts as a diffusional barrier to limit potentially harmful
substances from entering the body.
1.1.3 Structure of the skin
There are four main regions in human skin: the stratum corneum, epidermis, dermis, and
subcutaneous tissues (Fig. 1.3).5 The stratum corneum (SC) is of particular interest when it comes
to transdermal delivery since it plays an important role in the skin’s barrier properties. The SC is
the thin (10-20 µm) outermost layer of the epidermis. It consists of corneocytes, which are
surrounded by a lipid matrix composed of ceramides, cholesterol, and free fatty acids.5 The
structural arrangement of the SC is often referred to as “bricks and mortar”, where the corneocytes
are likes bricks imparting structure, and the intercellular lipids are like mortar holding them
together and filling in the gaps (Fig 1.4). This particular arrangement prevents water loss and
blocks entry of most topically applied drugs. For these reasons, the SC poses a significant
challenge in transdermal delivery by acting as a barrier for drug diffusion into the epidermis. The
6
diffusion of drug from the TDS to the skin surface can be described by Fick’s first law of
diffusion34:
('( ) '* ) /'

𝐽 = 𝐷 % ,
- = −𝐷
/0
Equation 1.1
Where J is the diffusion flux; D is the diffusion coefficient; C1 and C2 are the concentrations in
the donor and receptor compartments respectively; h is the thickness across which the diffusion
gradient occurs in the direction of the x-axis; and dC/dx is the concentration gradient. It is
important to note that in this case, the concentration gradient is the driving force for diffusion.
Since the drug is contained in the TDS, it is natural that it will diffuse towards a region of lesser
concentration: the stratum corneum. Since the SC is a very effective barrier, it is crucial to
maximize the permeation of the drug through this layer.5 It is for this reason that various efforts
have been made to improve drug penetration through the skin using either chemical or physical
penetration enhancement methods, thereby improving the topical bioavailability of transdermal
patches.6,7 Based on Fick’s first law, permeation enhancement strategies can be achieved by either
increasing the diffusion coefficient (D) and/or the concentration gradient (dC/dx). Increasing D
would involve using physical or chemical enhancement strategies whereas increasing dC/dx can
be achieved using a supersaturated system.29
Figure 1.3 Schematic representation of cross-section of human skin29
7
Figure 1.4 “Brick and mortar” structure of the stratum corneum6
There are three potential pathways for drugs to penetrate across the epidermis (Fig. 1.5)24, 29,43:
1. Transcellular pathway
2. Intercellular pathway
3. Transappendageal pathway
The transcellular pathway involves direct permeation through the corneocytes and lipids in the
stratum corneum, which can be enhanced by using electroporation.4,24 The intercellular pathway
involves diffusion of the drug through intercellular junctions. This pathway is the most common
route of permeation for lipophilic drug molecules and can be enhanced using chemical
permeation enhancers.29 The transappendageal pathway involves the permeation of a drug
through the hair follicles, sebaceous and sweat glands. This particular pathway can be enhanced
by using iontophoresis.4
8
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29
Figure 1.5 Permeation pathways
0,'(-C A%';%%/ through the skin
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1.1.4 Physical and Chemical Enhancement Strategies
There are various methods to facilitate the delivery of a drug through the stratum corneum.
Common physical enhancement techniques that have been developed are: iontophoresis,
electroporation, microneedle-based devices, and sonophoresis.6 Iontophoresis and electroporation
utilize electrically assisted approaches to enhance the permeation across the stratum corneum.4
Iontophoresis utilizes low currents for minutes to hours to facilitate charged and uncharged
molecules to penetrate across the skin primarily by electrophoresis.4,26 Electroporation is another
physical enhancement technique that utilizes electric fields. This method requires very short and
high-voltage electrical pulses which are applied to the skin. The goal is to form pores in the stratum
corneum by inducing the structural rearrangement.4,26 Sonophoresis on the other hand uses low-
frequency ultrasound (f < 100kHz). In this case, it is hypothesized that enhancement of transdermal
transport is due to the disruption of the stratum corneum lipid bilayers by the ultrasonic waves.26
Microneedles are another physical enhancement strategy that is used on a micron-scale which
9
provides a minimally invasive means to transport molecules into the skin. These microneedles
measure around 0.1-1 mm in length and can be solid or hollow. They work by piercing microscopic
holes into the skin to deliver the desired drug.4
The chemical permeation enhancement approach utilizes chemicals such as sulfoxides, fatty acids,
alcohols, and glycols (Table 1.2). They are able to enhance permeation of a drug across the skin
by various mechanisms such as: partitioning and interacting with the SC, enhancing the solubility
of the drug, and increasing the fluidity of the SC lipids.27,28,48 Chemical enhancers are seen to be a
more attractive approach as a permeation enhancement strategy because they do not require
specialized equipment, are relatively inexpensive, and simple to incorporate into a transdermal
formulation.6 However, some chemical enhancers have been shown to cause skin irritation, or are
not suitable for the delivery of macromolecules. An ideal chemical penetration enhancer should
have the following criteria to be a viable candidate6:
1. It should be non-irritating to the skin and be non-toxic and non-allergenic;
2. It should have a rapid but reproducible and predictable effect;
3. It should not have any pharmacological activity;
4. It should be unidirectional (enhance drug penetration into the skin whilst preventing loss
of endogenous materials from the body);
5. Once removed, a quick recovery of skin properties is expected;
6. It should be colorless, odorless, and should not stain the site of actions;
7. It should be compatible with drugs and other excipients in the formulation;
8. It should be pharmaceutically acceptable.
10
Table 1.2 Examples of chemical penetration enhancers used for transdermal delivery systems 6
Chemical Class Enhancer
Ethanol
Isopropyl alcohol
Alcohols Decanol
Octanol
Propylene glycol
Cyclic amides
Amides
Azone®
Lauric acid
Fatty acids Oleic acid
Linoleic acid
Ethyl acetate
Butyl acetate
Esters Methyl acetate
Isopropyl myristate
Isopropyl palmitate
Ether alcohols Transcutol® (diethylene glycol monethyl ether)
Sodium lauryl sulphate (SLS)
Benzalkonium chloride
Cetylpyridinium chloride
Surfactants
Cetyltrimethylammonium bromide
Polysorbates (Tween® 20, Tween® 80)
Dodecyl betaine
1.1.5 Passive Enhancement
Passive permeation enhancement utilizing supersaturating systems may be a more desirable
approach to optimize permeation that can avoid the drawbacks of chemical and physical
enhancers.38 Optimized formulations based on the principle of supersaturation have been
demonstrated to improve permeation and topical availability.7,8,34 Applying the concept of
supersaturated solutions in transdermal drug delivery was first considered by Higuchi.9 In the case
of TDS, supersaturation allows us to maximize the rate of permeation by increasing the diffusional
driving force, thereby increasing the drug flux across the SC using a typical drug-in-adhesive
patch.9,41 A supersaturated system implies that the concentration of a chemical compound in
solution exceeds its equilibrium (saturation) solubility thereby increasing its thermodynamic
activity (or approximated by its degree of supersaturation), which is the thermodynamic driving
11
force for diffusion.10,47 Supersaturated systems are metastable, which may result in spontaneous
crystal formation.7 Representation of a stable, unstable and metastable solution in terms of its free
energy level is demonstrated in Figure 1.6. A stable solution is represented as a free energy
minimum where a large change or disturbance is needed to change its state. An unstable solution
on the other hand is represented by a maximum, where a change in the state of the system requires
only a small change or disturbance in the system. Lastly, a metastable solution can be represented
by an inflection point, where only a small but finite change is needed to change the state of the
system.10
Figure 1.6 Representation of a stable, unstable and metastable solution10
If drug crystallization occurs in DIA patches, it poses a serious problem on the physical stability
of the product. Since only dissolved drug can permeate through the skin and be absorbed, drug
crystallization reduces the amount of the available dissolved drug.11 Therefore, drug crystallization
during storage can reduce the bioavailability of the transdermal patch. An example of this is the
original Neupro® patch for rotigotine which was approved by the European Medicines Agency
(EMA) in 2006, and by the Food and Drug Administration (FDA) in 2007.12 Rotigotine is a non-
ergolinic dopamine agonist with activity across D1 through D5 receptors and is used for the
12
treatment Parkinson’s disease and Restless Leg Syndrome. Rotigotine is also the first and only
new chemical entity to be formulated for transdermal delivery.40,45 The Neupro® patch is a DIA
patch composed of a silicone adhesive layer where rotigotine is evenly dispersed in the adhesive
matrix, a polyester baking and release liner film. However, in 2008 it was reported that snowflake
crystals consisting of pure rotigotine began to form within the patch during storage at room
temperature (Figure 1.7). The formation of the crystals was caused by a polymorphic form of
rotigotine (form II), which was previously unknown during the pharmaceutical development of the
transdermal patch.12 This polymorphic form was thermodynamically more stable than the original
form (form I) but less soluble, which led to the unexpected crystallization of rotigotine (form II)
during storage.25 Though the appearance of crystals did not pose any safety issues, there were
concerns that the formation of less soluble crystals reduces the bioavailability since only dissolved
drug can permeate through the skin, thereby compromising therapeutic efficacy.11 It was for this
reason, the Neupro® patches had to be withdrawn from the US market. Eventually in 2012, the
manufacturer of the Neupro® patch, UCB Pharma, introduced a re-formulated room temperature
stable rotigotine formulation which was approved by both the FDA and EMA. This incident
highlights the importance of formulating a room temperature stable transdermal product.
Therefore, to develop a supersaturated system for effective transdermal enhancement, it is crucial
to ensure the system is physically stable.34-37
Figure 1.7 Crystal formation of the rotigotine Neupro® patch25
13
1.1.6 Stabilizing Supersaturated Systems
The stabilization of supersaturated transdermal patches is most commonly done by incorporating
anti-nucleating polymers to prevent crystal formation and growth. Common polymers that have
been reported as effective anti-nucleants include: hydroxypropyl methyl cellulose (HPMC),
polyvinyl pyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol (PEG), and Eudragit (acrylic
polymers).6 The mechanism governing the inhibition of nucleation and crystallization in a drug
supersaturated polymer matrix remains inadequately understood.13 The following has been
hypothesized to inhibit crystal growth3:
1. Adsorption of polymers onto the crystal surface and sterically hinder nucleation
2. Solubilisation of drug, which decreases the degree of supersaturation
3. Increased viscosity of the system, which limits the diffusion of drug molecules
1.1.7 Significance
Utilizing supersaturation as a passive enhancement strategy in transdermal systems is a promising
and attractive approach that avoids the need of using physical and chemical enhancers, which
requires expensive equipment and potentially causes undesirable skin irritation and cellular
damage. However, since supersaturated systems are thermodynamically unstable, there is a risk of
crystallization over time that may compromise the product performance. Further understanding the
mechanism of the inhibition of nucleation and crystal growth will allow us to select more effective
excipients for transdermal drug-in-adhesive patches.
14
1.1.8 Hypothesis
A stabilized supersaturated drug-in-adhesive transdermal drug delivery system can be
advantageously developed through incorporating appropriate additives to achieve effective
inhibition of nucleation and crystal growth. Gaining further insight on the mechanism governing
the inhibition of crystal growth will facilitate the formulation of such systems.
1.1.9 Research Objectives
1. To identify effective crystallization inhibitors based on polymers and liquid excipients for
use in room temperature stable, supersaturating drug-in adhesive transdermal patches in
adhesives of different physicochemical properties for selected model drugs.
2. To prepare and characterize the physical stability of supersaturating drug-in-adhesive
transdermal patches based on the identified crystallization inhibiting additives.
3. To compare the performance of resulting transdermal patches based on acrylate adhesive
versus the polyisobutylene (PIB) adhesive by evaluating the drug release rates and skin
permeation rates of the transdermal patches.
4. To investigate mechanisms controlling drug release from microreservoir-based
supersaturated drug-in-adhesive patches.
15
Chapter 2
Selection of Crystallization Inhibitors for Drug-in-Adhesive Patches
2.1 Introduction
The model drugs selected were rotigotine (a weak base) and diclofenac (a weak acid). Both drugs
have a low aqueous solubility and are currently used in commercial transdermal patches. The
formulation development of the system was emphasized more towards rotigotine due to its
therapeutic importance, and diclofenac was used as a comparison during performance studies. The
first objective was to identify effective crystallization inhibitors for rotigotine to ensure our patch
system is stable at room temperature. This is especially important since drug-in-adhesive patches
often require high drug loadings to maintain a sufficiently high diffusion flux across the skin. For
this reason, supersaturation is often used as a passive permeation enhancement strategy as it
increases the driving force for skin diffusion without the use of any chemical enhancers. The major
drawback is that the metastable supersaturated state may result in spontaneous crystal formation.35
It is also important to note that only dissolved drug is able to cross the skin, therefore crystal
formation would reduce the drug’s thermodynamic activity and this consequently may the
diffusional driving force and the associated skin flux thought the SC.36,39 It is for these reasons the
prevention of drug nucleation and crystal growth is imperative to ensure the efficiency and quality
of transdermal patches.36 Therefore, identifying potential crystallization inhibitors for our patches
became the first task before further development of the patch system to ensure its physical
stabilization (i.e. minimizing the crystal formation). Most of the additives that were investigated
were pharmaceutically accepted polymers that have previously been reported as effective anti-
nucleants. This objective was achieved initially through binary studies, which involved preparing
and dissolving the drug and additive at different ratios in a suitable solvent, which was then applied
16
onto a microscope slide and dried to a thin film coating. Jain & Banga have previously used this
method to investigate additives for their abilities to inhibit the crystallization of drugs in
adhesive.14 The coated film samples were kept at an elevated temperature to accelerate the
crystallization process and monitored regularly under polarized light microscopy (PLM). PLM was
selected as the method for the detection of crystallization at this stage, rather than X-ray diffraction
(XRD) or differential scanning calorimetry (DSC), due to its higher sensitivity. The additives
which were evaluated for crystallization inhibition included: Plasdone K90, Plasdone K30,
Soluplus®, Kollidon® VA 64, Eudragit® L100-55, RL PO, and RS PO. Plasdones and Eudragit
were chosen since they have previously shown promise as effective anti-nucleants.15,36,37,46
Following this evaluation, the drug and additive were directly incorporated into solvent-based
adhesives (Duro-Tak 87-2074 and Duro-Tak 87-6908) to generate data more relevant to the final
patches. Additives investigated here consisted of Plasdone K90, Kollidon® VA64 oleic acid,
Plurol® Oleique, Soluplus®, Transcutol® P, Labrasol®, Lauroglycol™ 90, Capryol™ 90,
isopropyl myristate, where Transcutol® P, Labrasol®, Lauroglycol™ 90, Capryol™ 90, isopropyl
myristate are liquid excipients. In addition, an attempt was made to use DSC as a screening tool
as proposed by R. Lipp in order to identify potential crystallization inhibitors by getting a sense of
the polymer-drug interaction from the changes in the heat of fusion.16 However, this method was
found to be unsuccessful due to a lack of sensitivity. Overall, it was found that Plasdone K90 and
oleic acid sufficiently inhibited rotigotine crystallization through the binary mixture and adhesive
slide method.
17
2.2 Materials and Methods
2.2.1 Materials
Rotigotine was obtained from PLIVA Pharma (Croatia). Plasdone K90 and Plasdone K30 were
obtained from ISP Technologies Inc., Soluplus® and Kollidon® VA64 from BASF, and
Eudragit® L100-55, RL PO, and RS PO from Degussa. Oleic acid was obtained from BDH
Chemicals and isopropyl myristate from Sigma-Aldrich. Plurol® Oleique CC 9497, Transcutol®
P, and Labrasol®, Lauroglycol™ 90, Capryol™ 90 were obtained from Gattefossee Company.
Acrylate adhesives in solvent, Duro-Tak 87-2074, and polyisobutylene adhesive in solvent, Duro-
Tak 87-6908 were obtained from Henkel. All solvents were reagent grade obtained commercially
and used as received.
2.2.2 Slide Crystallization Evaluation Using Binary Mixtures
The drug and additives were dissolved in a minimal amount of ethanol at selected polymer to drug
ratios (2:8, 5:5, 7:3, 8:2). Droplets of this solution were placed on a microscope slide, and solvent
was evaporated at room temperature. The slides were kept at an elevated temperature (65°C). At
selected time intervals, the slides were monitored under a cross-polarized microscope for the
appearance of crystals.
2.2.3 Physical Stability of Drug-in-Adhesive Systems
The drug and additive were added directly to the adhesive at selected ratios and stirred with a
magnetic stir bar for 15 minutes to ensure a homogeneous mixture. A minimal amount of organic
solvent was added (75-100mg). The mixture was then cast onto a microscope slide using a film
casting knife. Samples were left at room temperature for 15 minutes then at 60°C in an oven for
18
another 15 minutes to ensure complete evaporation of the solvent. At selected time intervals, the
slides were monitored under a crossed-polarized microscope for appearance of crystals.
2.2.4 Determination of Drug Saturation Solubility in Adhesive
The determination of the drug saturation solubility of rotigotine in Duro-Tak 87-2074 was done
by preparing various rotigotine loading amounts (10%, 15%, 30%, 40%, 45%) in the acrylate
adhesive (%w/w). The samples were stirred mechanically to ensure a homogenous mixture before
being cast onto a microscope slide using a film casting knife. Each sample was observed under
PLM, and the drug saturation solubility level was identified from the loading level below which
no crystallization occurred after a reasonable induction time (1-2 days) at 65°C.
2.2.5 DSC for Characterizing Effectiveness of Additives
An attempt to apply DSC to identify potential crystallization inhibitors by characterizing the
polymer-drug interaction from the change in the heat of fusion. A TA Instrument DSC 2010
(Delaware, USA) was used. 1:1 binary mixtures of the model drug and additive were weighed and
placed onto an aluminum pan and sealed. The samples were heated from ambient temperature to
200°C at a rate of 10°C/minute.
2.2.6 Crystal Area Measurement using PLM
Images taken from the slide crystallization evaluation were analyzed using ImageJ. The area was
measured using the “Wand Tracing Tool” while keeping the threshold limits consistent between
each image. Spatial calibration allowed the software to convert the number of pixels of the crystal
into an area measurement in µm2.
19
2.3 Results and Discussion
2.3.1 Slide Crystallization Evaluation Using Binary Mixtures
The additives investigated for the preparation of binary mixtures were Plasdone K90, Plasdone
K30, Soluplus®, Kollidon® VA64, Eudragit® L100-55, RL PO, and RS PO (Table 2.1). The
prepared binary mixture samples containing various additive to drug ratios were initially kept at
room temperature. However, due to lack of any significant crystal growth at these storage
conditions, an elevated temperature (65°C) was used to accelerate the nucleation and
crystallization process. As expected from the nucleation theory, as the drug supersaturation
decreases (or polymer concentration increases), the induction time increases. Based on the crystal
area measurements as a function of time using the ImageJ software, we were able to identify the
ranking order of the effectiveness of these additives for inhibiting rotigotine crystallization through
induction time measurements. In cases where the crystal area measurement was not feasible with
the ImageJ software, direct visual comparison of stability samples had to be conducted to establish
the ranking order of crystallization inhibitory efficiency for rotigotine. The effectiveness of
polymer additives for crystallization inhibition exhibits the following ranking order: Plasdone K90
> Plasdone K30 > Kollidon® VA64 > Soluplus® > Eudragit® L100-55 > Eudragit® RS PO and
RL PO. Among all investigated additives, Plasdone K90 appears to be the most effective
crystallization inhibitor. This may be attributed to Plasdone K90’s high glass transition
temperature (Tg) and high molecular weight as well as potential hydrogen bonding interactions
with the drug, which directly affects its effectiveness to inhibit the nucleation and crystallization
process.
20
binary mixtures
Molecular
Polymer Chemical Name Structural Formula
Weight (g/mol)
Plasdone K90 Polyvinylpyrrolidone 1,300,000
Plasdone K30 Polyvinylpyrrolidone 58,000
Poly(methacrylic
Eudragit®
acid co-ethyl 250,000
L100-55
acrylate)
Poly(methacrylic
Eudragit®
RL PO
acrylate)
Poly(methacrylic
Eudragit® RS
PO
acrylate)
21
Polyvinyl
caprolactam- 90,000 –
Soluplus®
polyvinyl acetate- 140,000
polyethylene glycol
Vinylpyrrolidone-
Kollidon®
vinyl acetate 45,000-70,000
VA64
copolymer
2.3.2 Drug Saturation Solubility of Rotigotine in Duro-Tak 87-2074
Before the preparation of adhesive slides, the drug saturation solubility of rotigotine in the
pressure-sensitive adhesives of interest was determined. This was done experimentally by varying
the concentration of rotigotine in Duro-Tak 87-2074 (solvent-based acrylate copolymer adhesive)
and casting the mixture onto microscopic slides. After drying, the samples were monitored under
PLM, and the results indicated that the saturation concentration of rotigotine in Duro-Tak 87-2074
was between 40-45%. This level was identified from the loading level below which no
crystallization occurred after a reasonable induction time (1-2 days) at 65°C. This concentration
served as a starting point for evaluating drug loading effect for the adhesive slide samples when
polymer additives or liquid enhancers were introduced into the mixture in order to determine the
crystallization inhibition efficacy under a polarized light microscope. The determination of the
drug saturation solubility of rotigotine in Duro-Tak 87-6908 (solvent-based PIB adhesive) was not
22
possible since rotigotine is not soluble in PIB on its own. Therefore, as will be described later, a
solubilizer is needed for rotigotine to be incorporated into the PIB adhesive.
2.3.3 Physical Stability of Drug-in-Adhesive Systems
Incorporating the drug and additive into the selected pressure-sensitive adhesive is intended to gain
a more complete picture on the effect of drug and polymer interaction on rotigotine crystallization.
A large range of Duro-Tak adhesives were initially investigated and was later narrowed down to
two different adhesive-types for further studies. The pressure-sensitive adhesives that were
selected were a solvent-based acrylate copolymer adhesive and a polyisobutylene (PIB) adhesive.
Samples were typically prepared in milligram scales, allowing us to minimize the amount of
material utilized compared to preparing a full-sized patch.
2.3.3.1 Acrylate Copolymer Adhesive Slides
The determined drug saturation solubility of rotigotine in Duro-Tak 87-2074 was used as the
starting point for drug loading for the adhesive slides. Samples were prepared containing 45%
RTG (w/w) along with a selected additive. The additives investigated were: Plasdone K90, oleic
acid, Plurol® Oleique CC 497, Soluplus®, Transcutol® P and Labrasol® (Table 2.2). We were
particularly interested in studying the crystallization inhibitory effect of oleic acid. The reason for
this is that Lee and colleagues have reported at the 2016 AAPS meeting that oleic acid appeared
to be an effective crystal growth inhibitor for rotigotine when compared to PVP, Kollidon® VA64,
and ɑ-tocophenol.17 However, when incorporating the oleic acid as an additive to the samples, the
crystallization rate was too slow using a drug loading of 45% RTG. Therefore, the drug loading
was increased, and the composition used to prepare the samples were: 50% RTG, 10% of additive,
and 40% of Duro-Tak 87-2074. The crystallization inhibitory efficacy of additives was then
23
evaluated similarly by determining the crystal area change of the samples. It was found that
Plurol® Oleique CC 497, Soluplus®, Transcutol® P, and Labrasol® were poor crystallization
inhibitors for rotigotine as significant drug crystallization occurred after only one day or
immediately after drying. Therefore, these have been ruled out as crystallization inhibitors. Similar
to the results from the binary mixtures, Plasdone K90 was found to be the most effective additive
in the presence of the adhesive. The change in crystal area for both Plasdone K90 and oleic acid
containing samples was compared with a positive control (50% RTG). From this, a plot of the
crystal area growth as a function of time was generated (Fig. 2.1). It can be seen that the total
crystal area change measured for the oleic acid containing sample is slightly higher compared to
the Plasdone K90 sample, however, they are still relatively comparable. These results demonstrate
that oleic acid may be a viable crystallization inhibitor for rotigotine. Weng and colleagues have
demonstrated that fatty acids greatly inhibited the crystallization of risperidone.18 They
hypothesized that the inhibition of crystallization was due to the drug-additive interactions between
the amino group of risperidone and the carboxyl group of the fatty acid. This hypothesis is
applicable to rotigotine since it also contains an amino group (Fig. 2.2). Oleic acid could also
contribute to other factors, such as increasing the drug solubility of rotigotine in the adhesive and
therefore decreasing its degree of saturation.
24
50% RTG 50% RTG/10% OA 50% RTG/10% Plasdone K-90
200000
180000
160000
Crystal Area(µm2)
140000
120000
100000
80000
60000
40000
20000
0
0 2 4 6 8 10 12
Day
Figure 2.1 Crystal growth comparison of 50% rotigotine (RTG), 50% RTG+10% oleic acid and
50% RTG + 10% Plasdone K90, as a function of time for slides kept at 65°C (n=1)
S
HO R
OH
O
Figure 2.2 Proposed drug-additive interaction between rotigotine and fatty acid
2.3.3.2 Polyisobutylene (PIB) Adhesive Slides
Determination of the drug saturation solubility of rotigotine in the PIB adhesive was not possible
since rotigotine is not soluble in this adhesive on its own. Therefore, an additive miscible in the
PIB adhesive and able to aid in the solubilisation of rotigotine is needed for rotigotine to be
incorporated into this adhesive. Due to the hydrophobic nature of polyisobutylene, the range of
25
additives that are able to be incorporated in PIB is quite limited compared to those investigated for
the acrylate copolymer adhesive. The additives that were investigated are: oleic acid, Plasdone
K90, Plasdone K17, Kollidon® VA64, Labrasol®, Lauroglycol™ 90, Capryol™ 90, Transcutol®
P, Plurol® Oleique CC 497, and isopropyl myristate (Table 2.2). Through direct visualization,
oleic acid was the only additive that demonstrated inhibition of rotigotine crystallization in the PIB
adhesive on its own. Though, a lower molecular weight PVP (Plasdone K17) and Kollidon® VA64
were also viable candidates if oleic acid was incorporated to act as a solubilizer.
adhesive slide samples
Molecular
Polymer Chemical Name Structural Formula
Weight (g/mol)
Plasdone K90 Polyvinylpyrrolidone 1,300,000
Oleic acid - 282.47
Plurol®
Polyglyceryl-3-
Oleique CC 835.03
dioleate
497
26
Polyvinyl
caprolactam- 90,000 –
Soluplus®
polyvinyl acetate- 140,000
polyethylene glycol
Diethylene glycol
Transcutol® P 134.17
monoethyl ether
Consists of a small fraction of
Caprylocaproyl mono-, di- and triglycerides and
Labrasol® Polyoxyl-8- mainly PEG-8 mono- and diesters 200-400
glycerides of caprylic (C8) and capric (C10)
acids
Lauroglycol™ Propylene glycol

258.4
90 monolaurate
Propylene glycol
Capryol™ 90 202.29
monocaprylate
Isopropyl
- 270.46
myristate
PIB adhesive mixtures were prepared with 20% oleic acid and varying concentrations of rotigotine
(10%, 11%, 12%) and then cast onto microscope slides. The samples were originally kept at 65ºC,
but this temperature caused the resulting adhesive layer to turn dark brown in color over time,
indicating potential degradation reactions. Therefore, a lower temperature of 50ºC was selected for
samples prepared with PIB adhesive. The samples were viewed under PLM, which revealed
droplet shapes in all the samples and persisted for the whole duration of the experiment (Figure
2.3). Our hypothesis is that these droplets in the solid state are composed of oleic acid-rich phases
containing rotigotine since no sign of crystallinity was observed. Using the crystal area
measurement method described in section 2.2.5, it was confirmed that as the drug loading
27
concentration increases, so does the crystal area (Figure 2.4). The measured crystal area of these
samples was significantly smaller than that in the acrylate adhesive samples. However, drug
loading amount for the PIB samples was significantly less. Though drug loading is limited with
PIB, this may still be a promising system since the crystallization rate appears to be slower due to
the low drug concentrations.
10% 11% 12%
Day 1 Day 1 Day1 1

Day
10% 11%
11% 12%
Day
Day 19
19 Day 19 Day 19
Figure 2.3 Microscopic images of PIB adhesive containing 20% oleic acid and varying
concentrations of rotigotine at 10X, day 1 and day 19
16000
14000
Crystal Area (um2)
12000
10000
8000
6000
4000
2000
0
0 2 4 6 8 10 12 14
Time (Days)
10% RTG 11% RTG 12% RTG
Figure 2.4 Crystal area development in PIB adhesive containing 20% oleic acid and varying
concentrations of rotigotine under 50ºC (n=1)
28
2.3.4 Characterizing Additives Using DSC
An approach to apply a DSC characterization method proposed by R. Lipp to identify potential
crystallization inhibitors for matrix-type transdermal delivery systems was investigated.16 This
method involved the preparation of 1:1 mixtures of the model drug and additive, and the analysis
of the thermal behavior of the mixture using DSC. A significant influence on the melting behaviour
would indicate the presence of drug-excipient interaction. Lipp reported that this method was
effective for the selection of crystallization inhibitors using oestradiol and gestodene as the model
drugs. This approach appeared to be attractive because if effective, one can readily get a sense of
the additive-drug interaction from the change in heat fusion based on a quick DSC run using a
minimum amount of sample. Unfortunately, this approach was not successful when 1:1 binary
mixtures of additives and rotigotine were prepared. When subjected to DSC, our thermographs
showed minimal changes in the heat of fusion. We hypothesized that this may due to the low
melting point of rotigotine (77-97ºC) and high Tg of certain additives, such as Plasdone K90 (Tg =
174ºC), resulting in the lack of detectable physical interactions.19 Therefore, this method was not
utilized for the subsequent evaluation of additional additives.
2.3.5 Conclusion
Various additives were evaluated for their potential to inhibit rotigotine crystallization utilizing a
slide crystallization evaluation technique with binary mixtures, followed by the same technique
while incorporating the adhesive. Samples were monitored under PLM for the appearance of
crystals and the crystal area was measured using the ImageJ software. Overall, Plasdone K90
(polyvinylpyrrolidone, MW = 1,300,000 g/mol) and oleic acid were found to the most suitable
additives to sufficiently inhibit rotigotine crystallization. However, due to the hydrophobic nature
of PIB, lower molecular weight polymers such as Plasdone K17 and Kollidon VA64 were chosen
29
as the additives in addition to oleic acid. Identifying potential crystallization inhibitors using DSC
was not successful due to lack of sensitivity.
30
Chapter 3
Evaluating the Physical Stability and Performance of Transdermal
Patches Using Identified Crystallization Inhibitors
3.1 Introduction
This chapter summarizes the evaluation of the physical stability and performance of our identified
transdermal systems using dissolution testing and skin permeation studies. As mentioned
previously, the stabilization of drug-in-adhesive patches plays a crucial role in the performance
and appearance of these systems. Therefore, formulations that exhibited promising results from
the adhesive slide testing were subjected to long term stability studies. Patches were prepared and
placed in a stability chamber which followed the ICH Guidelines for Stability Testing using
accelerated conditions (40°C ± 2°C/75% RH ± 5%). Dissolution testing and skin permeation
studies are used as methods to evaluate the performance of transdermal systems. The dissolution
testing will allow us to understand the release properties of our patch formulation and the
permeation studies provide us with information on the drug’s permeability using an animal skin
model. Formulations that demonstrated promising results from the adhesive slide testing and
stability study were characterized using dissolution testing. Dissolution of transdermal systems is
typically done using either the USP Apparatus 5 or 6 as a quality control measure. Apparatus 5
involves the system being placed at the bottom of the vessel and weighted down by a stainless steel
disk assembly while a paddle is stirring overhead.20 Apparatus 6 involves placing the system on a
stainless steel cylinder stirring element with the adhesive layer facing the dissolution medium (Fig.
3.1).20 Dissolution testing of our patches was performed on a dissolution apparatus using a
modified USP Apparatus 6 setup. Skin permeation studies are often done using Franz cells
(horizontal or vertical) using an animal skin model or permeable membrane. Rodent skin is often
31
used in the literature since it is easily accessible but synthetic membranes have also been tried as
an alternative to animal skin. Permeation studies for our systems were performed using vertical
Franz diffusion cells and mouse skin as the animal skin model. Permeation data would allow us to
determine the ease of absorption of our model drug through the stratum corneum, which is the rate
limiting step for diffusion of our model drug across the skin, while dissolution data would give us
an understanding on the release mechanism and kinetics.
(a) (b)
Figure 3.1 Schematic representation of the (a) USP Apparatus 5 and (b) USP Apparatus 6 for
dissolution testing
3.2 Materials and Methods
3.2.1 Materials
Rotigotine was obtained from PLIVA Pharma (Croatia) and diclofenac was purchased from
Sigma-Aldrich. Plasdone K17 was obtained from ISP Technologies Inc., Kollidon® VA64 from
BASF, The Chemical Company. Oleic acid was obtained from BDH Chemicals. Duro-Tak 87-
2074 and 87-6908 were obtained from Henkel. 3M Scotchpak™ 1022 release liner, 9741 release
liner, 9733 backing film, and 1012 backing film were obtained from 3M Scotchpak. All solvents
were reagent grade obtained commercially and used as received.

32
3.2.2 Preparation of Drug-in-Adhesive Transdermal Patches
The pressure-sensitive adhesive was weighed directly into a pre-weighed glass vial. In a separate
pre-weighed vial, rotigotine and an additive were dissolved in a minimal amount of ethyl acetate
and ethanol, heated at 50°C for 15 mins, and mechanically stirred until rotigotine was completely
dissolved. The rotigotine and the additive mixture was directly added to the weighed adhesive. The
mixture was mechanically stirred for 1 hour to ensure homogeneity before casting onto a release
liner fixed on a vacuum plate using a film casting knife. Following this, the adhesive matrix on
release liner was left to dry at room temperature for 15 minutes and an additional 15 minutes in
the oven at 60°C to remove any trace of organic solvent. After drying, a backing film was laminated
onto the adhesive matrix using a roller. Films were cut into 10 cm2 square patches using a pair of
scissors.
3.2.3 Evaluating the Crystallinity of Adhesive Slides and Patches Using DSC
A TA Instruments DSC 2010 (Delaware, USA) was used to determine the melting point of
rotigotine. Varying amounts of rotigotine ranging from 0.2 mg to 5 mg were directly weighed into
aluminum pans and sealed. A heating rate of 10°C/min was used for each sample and were heated
from ambient temperature to 120°C for rotigotine and 200°C for diclofenac.
3.2.4 In vitro Dissolution Testing of Transdermal Patches
In vitro dissolution testing of the transdermal patches was carried out using a modified USP
Apparatus 6 which consists of a transdermal patch attached onto the surface of a stainless steel
cylinder that is immersed in a medium. The transdermal patch was placed onto the cylinder by
applying either Duro-Tak 87-2074 or Duro-Tak 87-6908 directly on the occlusive backing
membrane, ensuring the adhesive layer is facing the dissolution medium. The dissolution testing
33
was performed using a Vankel 7000 dissolution apparatus (IntersScience Inc., ON, Canada). The
medium was maintained at 32ºC ± 0.5ºC, and a paddle speed of 50 rpm was used for both model
drugs. Sink conditions were maintained during the entire duration of the dissolution testing. For
patches containing rotigotine, 100 mL of acetate buffer pH 4.5 was used as the dissolution medium.
At pre-determined time intervals (1 min, 5 mins, 10 mins, 15 mins, 30 mins, 1 h, 1.5 h, 2 h, 2.5 h,
3 h, 4 h, 5 h, 6 h, 7 h, 8 h, and 24 h), 0.5 mL was removed and replenished with fresh dissolution
to maintain a constant dissolution volume. The samples were quantified using high-pressure liquid
chromatography (Hitachi LaChrom Elite® HPLC System, Japan). For patches containing
diclofenac, 200 mL of phosphate buffer solution pH 7.4 was used as the dissolution medium. At
pre-determined time intervals (1 min, 5 mins, 10 mins, 15 mins, 30 mins, 1 h, 1.5 h, 2 h, 2.5 h, 3
h, 4 h, 5 h, 6 h, 7 h, 8 h, and 24 h), 1 mL was removed and replenished with fresh dissolution media
to maintain a constant dissolution volume. The samples were quantified spectrophotometrically at
276 nm (Cary 50 UV-Vis spectrophotometer, Varian, ON, Canada). Triplicate measurements were
collected, and standard deviations are presented for all dissolution results.
3.2.5 Skin Preparation
Dorsal mouse skin was used as the animal skin model. The skin preparation consisted of carefully
removing the mouse hair using clippers, without damaging the stratum corneum. Dorsal skin was
then excised, and the fatty tissue of the skin was removed using a scalpel, iris scissors, and forceps.
The skin was stored in 1X PBS pH 7.4 overnight at 4ºC for up to a day. Otherwise, the skin was
stored at -20ºC in glycerol for up to 1 week until use.
34
3.2.6 In vitro Skin Permeation Study
In vitro skin permeation studies of the transdermal patches were carried out using Franz diffusion
cells (PermeGear) with an effective diffusion area of 3.14 cm2. Dorsal mouse skin was cleaned
with deionized water, cut into appropriate sizes, and mounted onto the Franz diffusion cell with
the dermis side facing the receptor compartment. The receptor compartment was filled with 6 mL
of the receptor medium (acetate buffer pH 4.5 or phosphate buffer solution pH 7.4). The receptor
medium is mechanically stirred at a constant rate using a magnetic stir bar and left to equilibrate
for 30 minutes at 32ºC. The transdermal patch is then applied onto the surface of the mouse skin,
on the stratum corneum side, ensuring there are no air pockets between the skin and patch. At
selected time intervals (20 mins, 30 mins, 40 mins, 50 mins, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h,
and 24 h), 3 mL of the receptor solution was withdrawn and replaced with fresh medium. It was
important to ensure that there were no air bubbles present on the dermis side when replacing the
fresh medium so that the area of medium exposed to the skin remained constant. The samples were
analyzed using either high-pressure liquid chromatography (HPLC) or ultraviolet-visible
spectroscopy (UV-Vis). Quadruplicate measurements were collected, and standard deviations are
presented for all dissolution results.
3.2.7 HPLC Analysis of Rotigotine
Rotigotine samples were analyzed and quantified using a Hitachi LaChrom Elite® HPLC System
at room temperature. The column was a Spursil™ C18-EP column (150 mm x 4.6 mm, 3 µm;
Dikma Technologies Inc.). The mobile phase consisted of 50:50 acetonitrile:acetate buffer pH 4.5.
The flow rate was maintained at 0.5 mL/min and the wavelength was set at 271 nm. The injection
volume was 20 µL.
35
3.3.1 Transdermal Components
Transdermal patches were cast from formulations that exhibited promising results from the
adhesive slide testing and the long-term stability study. These patches were then used for
dissolution testing and the evaluation of permeation rates. Therefore, the consideration of potential
effects of other transdermal components involved is important. This entails finding suitable release
liner and backing material. Ideally, the adhesive layer needs to adhere sufficiently to the release
liner when cast, but once the backing film is laminated, the release liner needs to be easily removed
from the adhesive matrix while the latter remains adhering to the backing film. It was found that
samples containing Duro-Tak 87-6908 (PIB adhesive) were best cast onto 3M Scotchpak™ 9741
Release Liner Fluoropolymer Coated Polypropylene Film and laminated with 3M Scotchpak™
9733 Backing Polyester Film Laminate. On the other hand, 3M Scotchpak™ 1022 Release Liner
Fluoropolymer Coated Polyester Film and 3M Scotchpak™ 1012 Backing Polyester Film
Laminate were found to be more suitable for samples containing Duro-Tak 87-2074 (acrylate
copolymer).
3.3.2 Evaluating the Crystallinity of Adhesive Slides and Patches Using DSC
The DSC was able to detect an endothermic peak with a rotigotine amount as low as 0.2 mg. This
was used as a reference point to evaluate the crystallinity of the slide samples and prepared
transdermal patches. All samples that were subjected to DSC did not display an endothermic peak,
signifying there was less than 0.2 mg of drug crystal in each sample.
36
3.3.3 Evaluating the Crystallinity of Adhesive Slides and Patches Using PLM
Tables 3.1 and 3.2 summarize the formulations and adhesives used for the drug-in-adhesive
patches that were prepared and subjected to the long-term physical stability study (40°C ±
2°C/75% RH ± 5%). The PIB formulations containing 15% RTG+20% OA and 5% Kollidon®
VA64+10% RTG+12% OA have displayed a minimal amount of drug crystals suggesting they
were physically stable for 8.5 months and 6.5 months, respectively. Though patches containing
5% Plasdone K17+10% RTG+12% OA have formed crystals along the edges of the patch after 7.5
months (Fig. 3.3), all patches with rotigotine prepared with acrylate copolymer were physically
stable for 5 months. As for the diclofenac patches, 5% Plasdone K17+10% DCF+12% OA and 5%
Kollidon® VA64+10% DCF+12% OA were physically stable for 5 months. However, 12%
DCF+20% OA and 15% DCF+20% OA were only physically stable up to 2 months. While
regularly monitoring the patches weekly using PLM, it was revealed that rotigotine drug
crystallization occurred in the microreservoirs, confirming that drug is located in these oleic acid-
rich regions (Fig. 3.2).
37
15% RTG + 20% OA 15% RTG + 20% OA
15% RTG + 20% OA 15% RTG + 20% OA
Figure 3.2 Microscopic images of 15% RTG and 20% oleic acid PIB adhesive slide samples
confirming location of rotigotine in transdermal patches at 10X objective
Table 3.1. Summary of long-term physical stability studies for various rotigotine containing
patches
Composition Adhesive Stability Duration
12% RTG + 20% oleic acid PIB 8.5 months

15% RTG + 20% oleic acid PIB 8.5 months
5% Plasdone™ K17 + 10% RTG +
PIB 7.5 months
12% oleic acid
5% Kollidon® VA 64 + 10% RTG +
PIB 6.5 months
12% oleic acid
12% RTG + 20% oleic acid Acrylate 5 months
15% RTG + 20% oleic acid Acrylate 5 months
5% Plasdone™ K17 + 10% RTG +
Acrylate 5 months
12% oleic acid
5% Kollidon® VA 64 + 10% RTG +
Acrylate 5 months
12% oleic acid
38
Table 3.2. Summary of long-term physical stability studies for various diclofenac containing
patches
Composition Adhesive Stability Duration
12% DCF + 20% oleic acid Acrylate 2 months

15% DCF + 20% oleic acid Acrylate 2 months
5% Plasdone™ K17 + 10% DCF +
Acrylate 5 months
12% oleic acid
5% Kollidon® VA 64 + 10% DCF +
Acrylate 5 months
12% oleic acid
Figure 3.3 Microscopic images of 5% K17+10% RTG+12% oleic acid patches prepared with
PIB adhesive after 7.5 months at 10X objective
3.3.4 In vitro Dissolution Testing of Rotigotine Transdermal Patches
The in vitro dissolution testing data allowed us to understand the release kinetics and mechanism
of the transdermal system. Figure 3.4 demonstrates the comparison of in vitro dissolution profiles
of transdermal patches containing 15% RTG + 20% OA, 5% Plasdone K17 + 10% RTG + 12%
OA, and 5% Kollidon VA64 + 10% RTG + 12% OA for patches prepared with Duro-Tak 87-6908
(PIB adhesive). It was found that the formulation containing 15% RTG + 20% OA displayed the
greatest cumulative amount released (µg), whereas patches containing 5% VA64 + 10% RTG +
20% OA displayed the lowest cumulative amount released (µg). This is not surprising since 15%
RTG + 20% OA has the highest drug loading of the three formulations. Therefore, according to
39
Fick’s first law of diffusion, it will have a higher concentration gradient, thus a higher diffusion
flux. It is also observed in Figure 3.4 that all formulations exhibit a burst release of rotigotine in
the first hour, followed by a near zero-order release profile. This observation is quite interesting
since matrix patches typically follow a first-order release profile (matrix diffusion), and membrane
reservoir patches follow a zero-order release profile (membrane permeation-controlled).21
Therefore, a first-order release profile should have been expected for the prepared transdermal
patches.
The burst release was likely due to the finite drug loading near the outer surface of the transdermal
patch that is exposed to the dissolution medium, which gives rise to a rapid initial rate of drug
release. The release is then gradually retarded since the drug concentration near the surface is
initially depleted and the drug located in the inner region must take time to diffuse to the surface
in order to be released into the dissolution medium. Though it may have also been due to a bimodal
heterogeneity of a combination of two populations of drug release regions: one having a rapid
payload release and the other a slow payload release.22 The near zero-order release profile can be
more reasonably explained by the presence of the microreservoirs where rotigotine was dissolved,
as confirmed by microscopy. In this case, the dissolved drug must first diffuse through the adhesive
matrix from the oleic acid-rich drug reservoir phase to reach the dissolution medium. Therefore,
the adhesive matrix may function equivalently as a rate limiting membrane, giving rise to an
apparent constant release rate for rotigotine.
40
15% RTG + 20% OA 5% K17 + 10% RTG + 12% OA 5% VA64 + 10% RTG + 12% OA
2000
Cumulative Amount Released (µg)
1500
1000
500
0
0 5 10 15 20 25
Time (hours)
Tak 87-6908 (n=3) with standard deviations. The RTG content for 15% RTG+20% OA was 11.8
mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12% OA
In contrast, Figure 3.5 illustrates in vitro rotigotine release profiles of transdermal patches prepared
with the same drug loading and additive amounts as in Figure 3.4, except in an acrylate copolymer
adhesive (Duro-Tak 87-2074). In this case, the release profiles were clearly first order in nature.
When plotted together with their corresponding formulations prepared with the PIB adhesive
(Duro-Tak 87-6908) in Figure 3.6, it can be seen that patches prepared with the acrylate copolymer
adhesive exhibited a significantly greater cumulative amount released than those prepared with the
PIB adhesive. In addition, the observed difference in their characteristic release profiles suggests
that the underlying release mechanisms are different depending on the adhesive being used. Unlike
patches containing Duro-Tak 87-6908 (PIB adhesive), patches containing Duro-Tak 87-2074
(acrylate copolymer adhesive) do not show the presence of microreservoirs but they generate first-
41
order release profiles with initially high rate of drug release, typical of a matrix diffusion regulated
release mechanism as in traditional matrix-type of transdermal patches.
15% RTG + 20% OA 5% K17 + 10% RTG + 12% OA 5% VA64 + 10% RTG + 12% OA
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
0 5 10 15 20 25
Time (hours)
Tak 87-2074 (n=3) with standard deviations. The RTG content for 15% RTG+20% OA was 11.8
mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12% OA
42
(a) Duro-Tak 87-2074 Duro-Tak 87-6908
Cumulative Amount Released (µg) 4500

4000
3500
3000
2500
2000
1500
1000
500
0
0 5 10 15 20 25
Time (hours)
(b) Duro-Tak 87-2074 Duro-Tak 87-6908
4500
4000
3500
3000
2500
2000
1500
1000
500
0
0 5 10 15 20 25
Time (hours)
(c) Duro-Tak 87-2074 Duro-Tak 87-6908
4500
4000
3500
3000
2500
2000
1500
1000
500
0
0 5 10 15 20 25
Time (hours)
Figure 3.6 Comparison of rotigotine transdermal patches dissolution profiles for acrylate and PIB
adhesive (a) 15% RTG+20% OA (b) 5% Plasdone K17+10% RTG+12% OA (c) 5% Kollidon
VA64+10% RTG+12% OA (n=3) with standard deviations. The RTG content for 15% RTG+20%
OA was 11.8 mg and 7.8 mg for 5% K17+10% RTG+12% OA and 5% VA64+10% RTG+12%
OA
43
3.3.5 In vitro Dissolution Testing of Rotigotine Transdermal Patches with Varying
Thicknesses
In addition to the dissolution testing data presented above, further dissolution testing was done on
rotigotine patches prepared with the PIB adhesive while varying the thickness of the adhesive
layer. Patches were cast at 3 different thicknesses (50 µm, 100 µm, and 150 µm) and the dissolution
profiles of various formulations were compared. The dissolution profile of formulations containing
15% RTG + 20% OA, 5% Plasdone K17 + 10% RTG + 12% OA, and 5% Kollidon VA4 + 10%
RTG + 12% OA are presented in Figure 3.7. One would expect that as the thickness of the adhesive
layer increases, the final cumulative amount released would increase since drug loading is higher.
However, this is not what was observed in the dissolution profiles for the first 24 hours. In all
formulations, patches cast at an intermediate thickness (100 µm) had the greatest final cumulative
amount released, followed by those cast at 150 µm. Finally, patches cast at 50 µm had the lowest
cumulative amount released. In the first 4 hours, patches containing 15% RTG + 20% OA with a
thickness of 150 µm had the slowest release, then eventually surpassed those cast at 50 µm. For
patches containing a hydrophilic polymer (Plasdone K17 or Kollidon® VA64), it was observed
that the cumulative amount released was greater in patches with a larger thickness but slowed
down after 4 hours. The initial fast release of patches cast at 150 µm may have been due to their
high drug loading and the reasons stated previously. The drug load near the outer surface of the
transdermal patch would be exposed to the dissolution medium, causing a rapid increase of initial
drug release. However, the thicker adhesive layer may function as an overall thicker rate-
controlling membrane due to the presence of the microreservoirs, some of which would be located
at a greater distance to the surface exposing to the dissolution medium. As a consequence, the drug
from the microreservoirs in this region will have a longer distance to travel before being released.
Therefore, if the observation is carried out for longer than 24 hours, we should eventually see that
44
the thicker patch (150 µm) results in a greater cumulated amount release than the 100 µm and 50
µm patches.
45
(a) 50 µm 100 µm 150 µm
Cumulative amount released (µg) 2500
2000
1500
1000
500
0
0 5 10 15 20 25
Time (hours)
(b) 50 µm 100 µm 150 µm
2200
1700
1200
700
200
0 5 10 15 20 25
Time (hours)
(c) 50 µm 100 µm 150 µm
1800
1600
1400
1200
1000
800
600
400
200
0
0 5 10 15 20 25
Time (hours)
Figure 3.7 Dissolution profiles of rotigotine patches with various thicknesses (a) 15% RTG+20%
OA (b) 5% K17+10% RTG+12% OA (c) 5% VA64+10% RTG+12% OA (n=3) with standard
deviations. The RTG content for 15% RTG+20% OA was 11.8 mg and 7.8 mg for 5% K17+10%
RTG+12% OA and 5% VA64+10% RTG+12% OA
46
3.3.6 In vitro Dissolution Testing of Diclofenac Transdermal Patches
Figure 3.8 compares of the in vitro dissolution profiles of transdermal patches containing 15%
DCF + 20% OA, 5% Plasdone K17 + 10% DCF + 12% OA, and 5% Kollidon VA64 + 10% DCF
+ 12% OA prepared with Duro-Tak 87-2071 (acrylate copolymer adhesive). Similar to the case
with the rogiotine patches, the formation containing the highest drug loading had the greatest
cumulative amount released, and patches containing Kollidon VA64 as the additive displayed the
lowest cumulative amount released. In addition, it is evident that the diclofenac patches gave rise
to first order release profiles. Comparing the cumulative amount released from the diclofenac
patches to that from the rotigotine patches, it can be seen that the amount released for the diclofenac
patches was significantly greater (7 fold greater than PIB patches and 1.5-fold for acrylate
copolymer rotigotine patches) when comparing the formulations containing 15% drug + 20% OA.
Diclofenac released from the patches may have a greater affinity to the dissolution medium than
to the patch components compared to the rotigotine patches, possibly due to differences in
intramolecular interactions. Therefore, interactions between the functional groups of diclofenac
and patch components are less strong, thereby increasing its affinity to diffuse into the dissolution
medium and resulting in a quicker drug release of diclofenac.
47
15% DCF + 20% OA 5% K17+10% DCF+12% OA 5% V64+10% DCF+12% OA
Cumulative Amount Released (ug) 16000.00

14000.00
12000.00
10000.00
8000.00
6000.00
4000.00
2000.00
0.00
0 5 10 15 20 25
Time (hours)
Figure 3.8 Cumulative drug released (µg/cm2) of diclofenac in various transdermal patch
DCF+20% OA was 11.8 mg and 7.8 mg for 5% K17+10% DCF+12% OA and 5% VA64+10%
DCF+12% OA
3.3.7 In vitro Skin Permeation Studies for Rotigotine Patches
Vertical Franz diffusion cells were used to evaluate the drug permeation of our transdermal patch
formulations and mouse skin was used as the animal skin model. The results of the skin permeation
study for rotigotine patches are shown in Fig. 3.9 and 3.10. It was found that the order of
cumulative amount permeated was 15% RTG+20% OA > 5% K17+10% RTG+12% OA > 5%
VA64+10% RTG+12% OA for both adhesives. Though when comparing which adhesive was
used, patches cast with PIB had an overall greater cumulative amount released than those cast with
the acrylate copolymer adhesive. This difference may be caused by intermolecular interactions
between the components of the patch and the adhesive. The acrylate copolymer adhesive contains
two functional groups: -COOH and –OH, therefore, therefore it is likely that these groups would
interact with the functional groups of the hydrophilic polymers and drug. These interactions
between the drug and components of the adhesive matrix would result in a greater affinity with the
patch components than with the skin, therefore the drug tends to favor the patch components than
diffusing towards the skin.
48
15% RTG + 20% OA 5% K17+10% RTG+12% OA 5% VA64+10% RTG+12% OA
Cumulative Amount Released (µg/cm2) 700
600
500
400
300
200
100
0
0 5 10 15 20 25 30 35 40 45 50
Time (hours)
formulations using Duro-Tak 87-6908 (n=4) with standard deviations. The RTG content for 15%
RTG+12% OA
15% RTG+20% OA 5% K17+10% RTG+12% OA 5% VA64+10%RTG+12%OA
400
Cumulative Amount Released (ug)
350
300
250
200
150
100
50
0
0 5 10 15 20 25
Time (h)
formulations using Duro-Tak 87-2074 (n=4) with standard deviations. The RTG content for 15%
RTG+12% OA
49
We were also able to compare the cumulative amount permeated of our rotigotine formulations to
the marketed rotigotine patch, the Neupro® patch. When comparing our formulations to the
Neupro® patch, the marketed patch had a quicker release than our formulations in the first 8 hours
of the experiment (Fig. 3.11). After 48 hours, 100% of RTG had released from the Neupro® patch,
46.23% from the 15% RTG + 20% OA patch, 55.87% from the 5% K17 + 10% RTG + 12% OA
patch, and 39.29% from the 5% K17 + 10% RTG + 12% OA patch. Overall, the marketed product
had a greater amount permeated compared to our formulations. Though it is observed that as the
release slows down, the cumulative amount released from the Neupro® patch is similar to the 15%
RTG+20% OA formulation at the 48-hour time point. It should be noted that the components of
the Neupro® rotigotine patch are different from our formulations. According to the Neupro® patch
monograph, the adhesive layer consists of a silicone adhesive as well as contains Povidone K90,
sodium metabisulphite, ascorbyl palmitate, and DL α tocopherol, whereas our formulations are
based on the PIB adhesive. The slow release of our patches may be attributed to the presence of
oleic acid in our formulations. FTIR was utilized to investigate the presence of intermolecular
interactions of the components found in the transdermal patches. The IR spectra for oleic acid is
characterized by a strong OH/CH broad band around 2900 cm-1 and a strong carbonyl stretching
band centered at 1708 cm-1 (Fig. 3.12). The IR spectra of a transdermal patch containing 15%
RTG+20% OA cast with the PIB adhesive is presented in Figure 3.13. The spectra demonstrate
that the carbonyl band is shifted to the 1739cm-1 region, suggesting an intermolecular hydrogen
bonding between the carboxylic group of oleic acid and the hydroxyl group of rotigotine.
Therefore, this interaction between the oleic acid and rotigotine may reduce the diffusion
coefficient of rotigotine, thereby slowing down its release. The interaction between oleic acid and
rotigotine may also be the reason as to why oleic acid appears to be an efficient rotigotine
crystallization inhibitor.
50
Neupro Patch 15% RTG + 20% OA 5% K17+10% RTG+12% OA 5% VA64+10% RTG+12% OA
Cumulative Amount Permeated 700

600
500
400
(µg/cm2)
300
200
100
0
0 5 10 15 20 25 30 35 40 45 50
Time (hours)
Figure 3.11 Comparison of the cumulative drug permeated (µg) of rotigotine for marketed
Neupro® patch and various transdermal patch formulations using Duro-Tak 87-6908 (n=4) with
standard deviations. The RTG content for 15% RTG+20% OA was 11.8 mg, 7.8 mg for 5%
K17+10% RTG+12% OA and 5% VA64+10% RTG+12% OA and 4.5 mg for the Neupro® patch
Figure 3.12 FT-IR spectra of oleic acid
Figure 3.13 FT-IR spectra of a transdermal patch containing 15% RTG+20% OA
51
3.3.8 In vitro Skin Permeation Studies for Diclofenac Patches
Similar to what was seen with the patches containing rotigotine, it was found that the order of
cumulative amount of diclofenac permeated was 15% DCF+20% OA > 5% K17+10% DCF+12%
OA > 5% VA64+10% DCF+12% OA (Fig. 3.14). Similar to what was observed in the dissolution
testing results, the cumulative skin permeation for diclofenac was significantly greater than the
rotigotine patches for all formulations. Again, this is likely due to the reasons state above where
diclofenac has a greater affinity to the skin than to the patch components. Therefore, the drug will
favor the skin over the patch components. Another factor that may contribute to these findings is
the conditions used for the permeation studies. The receptor medium used for rotigotine was
acetate buffer pH 4.5. Rotigotine’s solubility and lipophilicity are pH dependent.30 At neutral pH,
rotigotine is in its neutral form and is poorly water-soluble and lipophilic. However, at more acidic
pH, rotigotine is in its protonated form, where its solubility increases but its lipophilicity decreases.
It is also known that lipophilic compounds have an increased solubility in the intercellular domains
and can permeated through the skin more easily. In addition, as mentioned previously, factors such
as molecular weight, log P, drug loading and the area of application are parameters that play an
important role in drug permeation through the SC. However, the molecular weight and log P of
diclofenac and rotigotine are quite similar, and the drug loading and area were identical for both
patches. Therefore, the difference in the amount permeated for both drugs may be attributed
rotigotine’s reduced lipophilicity at an acidic pH and the possibility of diclofenac intermolecular
interactions, minimizing its affinity to the patch components, thereby increasing its permeation
rate.
52
15% DCF + 20% OA 5% K17+10% DCF+12% OA 5% VA64+10% DCF+12% OA
Cumulative Amount Permeated 3000
2500
2000
1500
(µg/cm2)
1000
500
0
0 10 20 30 40 50 60
Time (hours)
Figure 3.14 Cumulative drug permeated (µg/cm2) of diclofenac in various transdermal patch
DCF+20% OA was 11.8 mg, 7.8 mg for 5% K17+10% DCF+12% OA and 5% VA64+10%
DCF+12% OA
3.3.9 Conclusion
The formulations that exhibited promising results from the adhesive slide testing were prepared
into patches and subjected to long-term physical stability studies. In addition, their performance
was evaluated using dissolution testing and skin permeation studies. For rotigotine, all
formulations prepared with the PIB adhesive were physically stable for up to 8.5 months, while
those prepared with the acrylate copolymer adhesive were physically stable for up to 5 months. In
additional, rotigotine dissolution profiles illustrated that patches prepared with the acrylate
copolymer adhesive had a greater cumulative amount released than those prepared with the PIB
adhesive. However, when it came to the skin permeation studies, rotigotine patches prepared with
the PIB adhesive had a greater cumulative amount permeated. In addition, it was found that the
selection of adhesive is important in determining the resulting drug release profile. The near zero-
order release profile from the PIB patches demonstrated that the drug released at a constant rate,
something that is especially desirable for therapeutic treatment of a chronic disease. Meanwhile,
53
the diclofenac patches were only physically stable for up to 2-5 months. Compared to the rotigotine
patches, the diclofenac patches had a significantly great cumulative amount released and
permeated.
54
Chapter 4
Mathematical Modeling of the Rotigotine Drug Release from the
Microreservoirs
4.1 Introduction
Mathematical modeling of drug delivery is an important tool that offers many advantages such as
speeding up product development and further understanding the mechanisms controlling drug
release from a particular delivery system.32,33 In Chapter 3, the results presented from the
dissolution testing for the rotigotine patches prepared with the acrylate copolymer adhesive
illustrated that they generate a first-order release profile, which is expected for traditional matrix-
type transdermal patches. On the other hand, rotigotine patches prepared with the PIB adhesive
unexpectedly generated a near zero-order release profile. The difference in release profiles may be
due to the fact that patches prepared with the PIB adhesive displayed the presence of
microreservoirs, while those prepared with the acrylate adhesive did not. Therefore, it was
hypothesized that for the PIB patches, rotigotine is dissolved at a higher concentration in the oleic
acid-rich droplets and must first diffuse through the oleic-acid rich reservoir phase before diffusing
through the adhesive matrix. The adhesive matrix consequently acts as a rate limiting membrane
giving rise to an apparent constant release rate. Since the analysis of this type of microreservoir
system has not been previously reported in literature, there are no existing models that accurately
describe its drug release behavior. Therefore, it would be advantageous to analyze its release
behavior using a mathematical model to gain further understanding on the overall mechanism
governing the drug release from the microreservoirs.
55
4.2.1 Predicting the total amount release with considerations of m∞
The model considers the following assumptions:
1. The system is a diffusion-controlled drug delivery system
2. The drug release rate from the microreservoir is constant with respect to time
3. The drug release rate from the microreservoir is uniform across the population
4. The payload of each microreservoir is proportional to the microreservoir radius
5. The microreservoirs are spherical
For this model, we considered a parameter that varies according to a distribution: the total payload
of a microreservoir (m∞), i.e. the amount of drug in the microreservoir, while still ignoring the
initial burst effect. This parameter will vary between particles and can be described by some
distribution. Since the release rate is constant, the time to release the entire payload (t∞) is directly
determined by m∞ and the release rate. Determining the distribution for m∞ is possible since the
size of the microreservoirs is directly correlated to the total payload of a microreservoir (i.e. the
larger the microreservoir, the higher the payload and vice versa). Therefore, we measured the
diameter of various microreservoir sizes from microscope images using the ImageJ software and
their respective histograms were plotted to allow us to determine the distribution that would be
most suitable (Fig. 4.1). From the histograms, it appeared that the size of the microreservoirs
followed a gamma distribution. To confirm the distribution, Q-Q plots were plotted to compare
the experimental data with gamma and normal distribution (Fig. 4.2). The linearity of the points
displayed in the gamma distribution Q-Q plot suggests that they fit a gamma distribution well,
while the points for the normal distribution follow a nonlinear pattern, suggested they are not
normally distributed. Therefore, a gamma distribution was used to describe the microreservoir
sizes going forward for the modeling.

56
70
60
50
40
Frequency
30
20
10
0
0 10 20 30 40 50 60
Microreservoir Diameter (µm)
Figure 4.1 Histogram of microreservoir sizes for 15% RTG + 20% OA formulation (n = 371)
57
(a) 60
50
40
Quantiles of Input Sample

30
20
10
-10
-5 0 5 10 15 20 25 30 35 40 45
Quantiles of Normal Distribution
(b) 60
50
Quantiles of Input Sample
40
30
20
10
0
0 10 20 30 40 50 60
Quantiles of Gamma Distribution
Figure 4.2 Q-Q Plot of Sample Data versus Distribution (a) Normal distribution (b) gamma
distribution
The conceptual basis and development of the model was heavily adapted from Dappert, Thies,
Donbrow and Gross22,32,33. First, we assumed that the release profile of each individual
microreservoir depends only on the payload of their respective microreservoir. The amount of drug
released and the release rate from an individual microreservoir is described as the following:
89 𝑚∞
𝑏𝑡 𝑡 < /8(<;89 )
𝑏 𝑡 <
: 𝑏
𝑚(𝑡; 𝑚4 ) = 5 89 and = 5 𝑚∞ Equation 4.1
𝑚4 𝑡 ≥ : /< 0 𝑡 ≥
𝑏
58
where 𝑚(𝑡; 𝑚4 ) is the amount of drug released with respect to time, t, given some parameter, in
this case drug payload (𝑚4 ); and 𝑏 is the release rate. The fractional release, which also only
depends on the payload, 𝑚4 , and can therefore be expressed as:
:< 89 : 89
89
𝑡 < : /8 ∗ (<;89 ) 89
𝑡 < :
∗(
𝑚 𝑡; 𝑚4 ) = @ 89
and /<
=@ 89
Equation 4.2
1 𝑡 ≥ :
0 𝑡 ≥ :
where 𝑚∗ (𝑡; 𝑚4 ) is the fractional amount released. Dappert and Thies had demonstrated in their
work that the fractional release rates and amount released from the population, which has
individual release functions varying according to some physical parameter can be expressed as:
/B ∗(<) 4
/<
= ∫H 𝜓(𝛼 )𝑔(𝑡; 𝛼 )𝑑𝛼 Equation 4.3
< 4
𝑀∗ (𝑡) = ∫H ∫H 𝜓(𝛼 )𝑔(𝑡; 𝛼 ) 𝑑𝛼 𝑑𝑡 Equation 4.4
where:
/8 ∗(<;J)
𝑔(𝑡; 𝛼 ) = /<
Equation 4.5
𝛼 is some physical parameter; 𝜓(𝛼 ) is a probability distribution for the physical parameter, in this
case a gamma distribution; and M*(t) is the fractional amount released from the population. From
Eq. 4.3 and 4.4 we can re-express the above fractional release rate and amount released as the total
release rate and amount as the following:
/B(<) 4
/<
= 𝑁 ∫H 𝑚4 (𝛼 )𝜓(𝛼 )𝑔(𝑡; 𝛼 )𝑑𝛼 Equation 4.6
< 4
𝑀(𝑡) = 𝑁 ∫H ∫H 𝑚4 (𝛼 )𝜓(𝛼 )𝑔(𝑡; 𝛼 ) 𝑑𝛼 𝑑𝑡 Equation 4.7
where N is the number of microreservoirs in the system. For our system, the radius of the
microreservoir is the physical parameter that varies across the population, which is directly
correlated to the payload (𝑚4 ), thus, substituting 𝛼 for r, we will have:
/B(<) 4
/<
= 𝑁 ∫H 𝑚4 (𝑟)𝜓(𝑟)𝑔(𝑡; 𝑟)𝑑𝑟 Equation 4.8
59
< 4
𝑀(𝑡) = 𝑁 ∫H ∫H 𝑚4 (𝑟)𝜓(𝑟)𝑔(𝑡; 𝑟) 𝑑𝑟 𝑑𝑡 Equation 4.9
where r is the radius of the microreservoir. Since the empirical data that was measured between
varying microreservoirs was their diameter and not the amount released, the physical parameter
that will vary is the radius. However, since the release profiles are dependent on 𝑚4 , this term will
be expressed in terms of the microreservoir radius, based on the volume of density to obtain 𝑚4 .
Therefore, substituting our fractional release rate from Eq. 4.2 into Eq. 4.8, we get:
/B(<) 4
/<
= 𝑁 ∫H 𝑚4 (𝑟)𝜓(𝑟)𝑔(𝑡; 𝑟)𝑑𝑟
V ]N^QTR_` Ya
4 <\
𝑁 ∫H 𝜌N4Q3R𝜋𝑟 T 𝜓(𝑟) UWNXQYRZ[Y ]N^Q R_` Y c 𝑑𝑟
:
= Equation 4.10
H < b T a
:
(/Y
⎡: iV
`g hX j ⎤
4 4 T ⎢
= 𝑁 ∫H 𝜌N Q3R𝜋𝑟 𝜓(𝑟) ⎢
a]N^Q R_` Y
Y
ZW ⎥
T (/Y ⎥ 𝑑𝑟 Equation 4.11
H
⎢ `l hX j ⎥
iV
⎣ Y
ZW ⎦
4 b
= 𝑁 ∫b 𝜌N4Q3R𝜋𝑟 T 𝜓(𝑟) p]N^ R_` Yq 𝑑𝑟 + 𝑁 ∫H 𝜌N4Q3R𝜋𝑟 T 𝜓(𝑟) (0) 𝑑𝑟 Equation 4.12
:
QT
4
= 𝑁 ∫b 𝑏 𝜓(𝑟) 𝑑𝑟 Equation 4.13
u/T
<:
where b = sX t , N4Q3R𝜋𝑟 T is the volume for a sphere and 𝜌 is the density, hence multiplying these
_]
Y
two terms will give 𝑚4 . The population release rate can therefore be described as:
< 4
𝑀(𝑡) = 𝑁 ∫H ∫b 𝑏 𝜓(𝑟) 𝑑𝑟 𝑑𝑡 Equation 4.14
Figure 4.3, 4.4 and 4.5 demonstrates the measured and predicted amount released for the various
prepared formulations with estimated parameters and the coefficient of determination R2 for the
fitting presented in Table 4.1. The data was fitted by integrating Eq. 4.14, and a linear offset (a0)
was added to account for the burst effect using MATLAB (R2018b). Therefore, the unknown
60
parameters that needed to be estimated were: N, the offset (a0), and b. Optimization of these
parameters were done to minimize the squared error from the experimental data. The gamma
distribution parameters scale (k) and shape (θ) were estimated using the maximum likelihood
estimates from the empirical data. Figure 4.3 illustrates that the initial release appears to be fairly
linear but gradually becomes non-linear at larger times. This is not surprising when one considers
the relative time scale in question. It is well known that one can take the initial section of a first-
order release curve and expand its time scale, at sufficiently large extent of expansion the
resulting release profile will appear to be zero-order or constant rate. In the present case, the
form of the release function is reasonable for our system, since the distribution applied was a
gamma distribution, which is in the exponential family, it is therefore expected that the
population release will also have an exponential form on a global time scale. However, at the
limited local time scale, the population release profile will appear to approach a steady-state rate
of drug release.
61
Figure 4.3 Measured and predicted amount released of RTG for 15% RTG + 20% OA patch at
different time scales
62
Figure 4.4 Measured and predicted amount released of RTG for 5% K17 + 10% RTG + 20% OA
patch at different time scales
63
Figure 4.5 Measured and predicted amount released of RTG for 5% VA64 + 10% RTG + 20%
OA patch at different time scales
64
Table 4.1 Estimated parameters and R2 of fitted data
Formulation b (µg/h) N a0 (µg) R2
15% RTG + 20% OA 36.262e-6 1.894e6 670.444 0.93390
5% K17 + 10% RTG + 20% OA 14.307e-6 3.074e6 682.607 0.99644
5% VA64 + 10% RTG + 20% OA 61.296e-6 0.868e6 481.431 0.99977
4.2.2 Conclusion
The mathematical model developed describing the rotigotine drug release from the
microreservoirs allowed us to gain a better understanding of the drug release behaviour. We
considered the total payload of a single microreservoir (m∞) as a parameter that varies according
to the distribution of microreservoir size, while ignoring the initial burst effect. The distribution
for m∞ was determined by measuring the diameter of various microreservoir sizes from
microscope images using the ImageJ software. From the diameter measurement, we were able to
plot their respective histograms and confirm with Q-Q plots that the data fit a gamma
distribution. Following this, a population release rate equation was developed (Eq. 4.14) and
experimental data fitted by integrating Eq. 4.14 using MATLAB, which illustrated that the initial
release appears to be fairly linear at short local time scale but gradually becomes non-linear at
large global time scale.
65
Chapter 5
Summary and Future Directions
5.1 Summary
The main objectives of this research were to formulate a supersaturated drug-in-adhesive patch
stable at room temperature by incorporating effective crystallization inhibitors and to compare the
performance based on two different pressure-sensitive adhesives. From this research, we were able
to identify effective crystallization inhibitors for rotigotine. In addition, an unexpected formation
of microreservoirs in patches prepared with the PIB adhesive revealed that the selection of
adhesive is important in determining the resulting drug release profile. Modeling the drug release
from the microreservoir allowed us to further understand the mechanisms controlling the drug
release.
In Chapter 2, various additives that were commonly used as anti-nucleant polymers were evaluated
for their potential to inhibit rotigotine crystallization using a slide crystallization technique that
minimized the amount of materials required. Although PLM was more tedious and required more
time to operate compared to other common techniques such as XRD or DSC, this method has a
higher sensitivity for the detection of crystallization, which was critically important for our project.
Two different pressure-sensitive adhesives were selected, which were a polyisobutylene and
acrylate copolymer adhesive. However, due to the hydrophobic nature of PIB, the range of
additives that could be incorporated in the adhesive was limited. From the various additives that
were evaluated, only Plasdone K17, Kollidon® VA64 and oleic acid were found to be suitable
additives in the inhibition of rotigotine crystallization in both adhesives.
66
The studies in Chapter 3 focused on the evaluation of the physical stability and performance of the
transdermal patches prepared from the identified crystallization inhibitors. After identifying oleic
acid, Kollidon® VA64, and Plasdone K17 as suitable additives in inhibiting rotigotine
crystallization, transdermal patches were prepared and subjected to long-term physical stability
testing (40°C ± 2°C/75% RH ± 5%). The rotigotine patches prepared with PIB adhesive were
physically stable for up to 6.5-8.5 months, while those prepared with the acrylate copolymer
adhesive were physically stable for up to 5 months. The diclofenac patches were physically stable
up to 2-5 months. Dissolution testing was carried out in a modified USP Apparatus 6 which
allowed us to characterize the drug release properties of our patches. Results obtained from the
dissolution testing of our rotigotine patches demonstrated that the cumulative drug release was
significantly faster from those prepared with the acrylate copolymer. In addition, it was observed
that the drug release profiles were different in their characteristic shape for rotigotine patches based
on either polyisobutylene or acrylate copolymer adhesives, suggesting the underlying release
mechanisms are different depending on the adhesive being used. The observed difference in release
profiles may be attributed to the presence of microreservoirs in the patches prepared with the PIB
adhesive. The near zero-order release profile from the PIB patches demonstrated that the drug
released at a constant rate, something that is especially desirable for therapeutic treatment of a
chronic disease. Lastly, the amount released and permeated was significantly higher for the
diclofenac patches compared to the rotigotine patches.
Chapter 4 focused on the mathematical modeling of rotigotine drug release from the
microreservoirs. Since this particular system has not been previously reported in literature,
mathematical modeling would enable us to gain a greater understanding of the mechanism
67
controlling drug release from the microreservoirs. Various mathematical models and their
applicability were explored to find one that best describes the microreservoir system.
For our model, we assumed the following:
1. The system is a diffusion-controlled drug delivery system
2. The drug release rate from the microreservoir is constant with respect to time
3. The drug release rate from the microreservoir is uniform across the population
4. The payload of each microreservoir is proportional to the microreservoir radius
5. The microreservoirs are spherical
The model considered a parameter that varied according to a gamma distribution, this parameter
being the total payload of a microreservoir (m∞), i.e. the total amount of drug in the microreservoir.
This model appeared to sufficiently predict the amount released of drug when compared to the
experimental data collected. However, an improvement that could be made is to modify the 3rd
assumption and allow the release rate to vary according to a distribution different from that of m∞.
In reality, the release rate should vary depending on the location of the reservoir (i.e. the further it
is from the outermost layer of the adhesive, the slower the release rate). In this case, if there are
several layers of microreservoirs throughout adhesive layer, this microreservoir layer closest to the
outermost layer of the adhesive will have the largest release rate. Taking this distribution into
consideration would give a more accurate representation of the drug release from our system.
5.2 Future Directions
The work presented in this thesis primarily focused on the development and characterization of a
room temperature stable rotigotine transdermal patch. Additives that were able to inhibit rotigotine
crystallization were identified. The suitable transdermal components were then selected to produce
a DIA transdermal patch system. Dissolution testing of the rotigotine patches prepared with the
68
PIB adhesive exhibited an unexpected drug release profile, which prompt our interest to further
understand the mechanism controlling the drug release from the microreservoirs by using
mathematical modeling. However, there a few recommendations to build upon the current
findings:
1. Further investigation of a larger spectrum of potential additives that can inhibit
crystallization of rotigotine in a DIA transdermal patch. Identifying more anti-nucleant
agents and their mode of crystallization inhibition would allow us to gain a more in depth
understanding of the mechanism that governs the inhibition and crystal growth. In addition,
one could take the identified anti-nucleant agents and compare the inhibitory effects they
have on other drugs with similar physical and chemical properties as rotigotine to confirm
the mechanism of crystallization inhibition. Thus, by gaining a deeper understanding of the
mechanism at which the anti-nucleant agents are able to inhibit crystallization efficiently,
the formulation development process can be accelerated by selecting additives based on
their physicochemical properties.
2. Improve the permeation rate of the current rotigotine formulations by varying the drug
loading and additives used in the transdermal patch. In Chapter 3, a comparison study was
done with the marketed Neupro® rotigotine patch using skin permeation studies. The
results demonstrated that the release from our prepared rotigotine patches using the PIB
adhesive is much slower in the first 8 hours compared to the marketed patch. However, the
patches containing 15% RTG + 20% OA the cumulative amount release at the 48-hour time
point were similar to the Neupro® patch. Formulation development with the PIB adhesive
was quite challenging due to the hydrophobic nature of PIB, therefore drug loading and
additives used were limited. However, if the drug loading can be increased by incorporating
69
additional solubilizers, the release rate would likely increase and could possibly achieve
bioequivalence to the marketed product.
3. The mathematical modeling of rotigotine from the microreservoirs could be improved by
taking into consideration that the release rate from each microresevoir will vary depending
on its location in the adhesive later and to account for this distribution should give a more
accurate representation of the drug release of our system.
70
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Investigation of The Stabilization of Supersaturated Drug-in-Adhesive Transdermal Drug Delivery Systems - Minthi Bui

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Investigation of The Stabilization of Supersaturated Drug-in-Adhesive Transdermal Drug Delivery Systems - Minthi Bui

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Investigation of the Stabilization of Supersaturated Drug-in-

Adhesive Transdermal Drug Delivery Systems

A thesis submitted in conformity with the requirements

© Copyright by Minhthi Bui [2019]

to improve the resulting systemic bioavailability. Supersaturation is an attractive enhancement

bioavailability due to spontaneous crystallization. Stabilization of such systems using additives is

mechanisms governing drug release from our systems.

Figure 1.2 Schematic representation of transdermal drug-in-adhesive-type patches…………….. 4

Figure 1.3 Schematic representation of cross-section of human skin…………………………….. 7

Figure 1.4 “Brick and mortar” structure of the stratum corneum………………………………… 8

Figure 1.5 Permeation pathways through the skin………………………………………………... 9

Figure 1.6 Representation of a stable, unstable and metastable solution………………………... 12

Figure 1.7 Crystal formation of the rotigotine Neupro® patch………………………………….. 13

Figure 3.12 FT-IR spectra of oleic acid …………………………………………………………. 51

lidocaine, nitroglycerin, and oxybutynin (Table 1.1).23

1.1.2 Types of transdermal patches

1. It should be non-irritating to the skin.

2. It should be easily removed after its intended use.

are commonly used as backing films.

reformulating the reservoir patch into a drug-in-adhesive design.23

Figure 1.1 Schematic representation of transdermal reservoir-type patch1

drawback of DIA patches is that formulation development can be quite challenging.23

Table 1.1 List of transdermal patches approved by the US FDA 2, 23

Estradiol (Estraderm®) Menopausal symptoms Reservoir 1986

Fentanyl (Duragesic®) Chronic pain Reservoir/DIA 1990

Nicotine (Habitrol®) Smoking cessation Matrix 1990

Nicotine (Nicoderm®) Smoking cessation Reservoir 1991

Estradiol (Vivelle®) Menopausal symptoms DIA 1994

Nitroglycerin (Nitro-Dur®) Angina pectoris DIA 1995

Nitroglycerin (Minitran®) Angina pectoria DIA 1996

Estradiol (Alora®) Menopausal symptoms DIA 1996

Estradiol with norethidrone

Buprenorphine (Butrans®) Chronic pain DIA 2010

Estradiol (Minivelle®) Menopausal symptoms DIA 2012

substances from entering the body.

1.1.3 Structure of the skin

('( ) '* ) /'

penetration enhancement methods, thereby improving the topical bioavailability of transdermal

be achieved using a supersaturated system.29

Figure 1.3 Schematic representation of cross-section of human skin29

permeation enhancers.29 The transappendageal pathway involves the permeation of a drug

1.1.4 Physical and Chemical Enhancement Strategies

electroporation, microneedle-based devices, and sonophoresis.6 Iontophoresis and electroporation

molecules to penetrate across the skin primarily by electrophoresis.4,26 Electroporation is another

holes into the skin to deliver the desired drug.4

have the following criteria to be a viable candidate6:

1. It should be non-irritating to the skin and be non-toxic and non-allergenic;

2. It should have a rapid but reproducible and predictable effect;

3. It should not have any pharmacological activity;

of endogenous materials from the body);

5. Once removed, a quick recovery of skin properties is expected;

7. It should be compatible with drugs and other excipients in the formulation;

8. It should be pharmaceutically acceptable.

1.1.5 Passive Enhancement

Passive permeation enhancement utilizing supersaturating systems may be a more desirable

enhancers.38 Optimized formulations based on the principle of supersaturation have been

demonstrated to improve permeation and topical availability.7,8,34 Applying the concept of

patch.9,41 A supersaturated system implies that the concentration of a chemical compound in

Figure 1.6 Representation of a stable, unstable and metastable solution10

highlights the importance of formulating a room temperature stable transdermal product.

Therefore, to develop a supersaturated system for effective transdermal enhancement, it is crucial

to ensure the system is physically stable.34-37

Figure 1.7 Crystal formation of the rotigotine Neupro® patch25