Modified-Release
`Drug Delivery Technology
`Second Edition
`VolDDie 2
`
`edited by
`Michael J. Rathbone
`InterAg
`Hamilton, New Zealand
`Jonathan Hadgraft
`University of London
`London. UK
`Michael S. Roberts
`University of Queensland
`Brisbane, Australia
`Majeiia E. Lane
`University of London
`London, UK
`
`informa
`
`healthcare
`
`NewVwh ionbom
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`0001
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`.
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`Pharma.,
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`MYLAN - EXHIBIT 1041
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`

`

`Contents
`
`v
`Preface
`Contributors xi
`
`PART I: USING MODIFIED-RELEASE FORMULATIONS TO
`MAINTAIN AND DEVELOP MARKETS
`
`1 . The Modified-Release Drug Delivery Landscape: The Commercial
`Perspective 1
`Stephen Perrett
`2. The Modified-Release Drug Delivery Landscape: Academic
`Viewpoim 17
`Juergen Siepmann and Florence Siepmami
`3. The Modified-Release Drug Delivery Landscape: Advantages and
`Issues for Physicians and Patients 35
`Marco M. Anelli
`4. The Modified-Release Drug Delivery Landscape: Drug Delivery
`Commercialization Strategies 49
`Fmtan Walton
`
`PART II: OCULAR TECHNOLOGIES
`
`5. Ophthalmic Drug Delivery 59
`Pascal Furrer, Florence Delie, and Bernard Plazonnet
`6. Intraocular Implants for Controlled Drug Delivery 55
`Leila Bossy, Signe Erickson, Robert Gurny, and Florence Delie
`7. Bioadhesive Ophthalmic Drug Inserts (BODI) for
`Veterinary Use 101
`Pascal Furrer, Olivia Felt, and Robert Gurny
`8. Ion Exchange Resin Technology for Ophthalmic Applications 109
`Rajni Jani and Erin Rhone
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`via
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`Contents
`
`PART III; INJECTION AND IMPLANT TECHNOLOGIES
`
`IS!
`
`9. Injections and Implants 123
`Majella E. Lane, Franklin W. Okumu, and Palani Bahusuhramanian
`10. Long-Acting Protein Formulation—PL AD Technology 133
`Franklin W. Okumu
`11. Long-Term Controlled Delivery of Therapeutic Agents by the
`Osmotically Driven DUROS® Implant 143
`Jeremy C. Wright and John Culwell
`Delivery System for Parenteral Administration
`TM
`12. The SABER
`Jeremy C. Wright, A. Neil Verity, and Franklin W. Okumu
`13. Improving the Delivery of Complex Formulations Using the
`DepotOne® Needle 159
`Kevin Maynard and Peter Crocker
`14. ReGel Depot Technology 171
`Ramesh C. Rat hi and Kirk D. Powers
`15. The Atrigel® Drug Delivery System 183
`Eric J. Dadey
`16. Enhancing Drug Delivery by Chemical Modification 191
`Mimoun Ayouh, Christina Wedemeyer, and Torsten Wohr
`17. DepoFoam® Multivesicular Liposomes for the Sustained Release
`of Macromolecules 207
`William J. Lambert and Kathy Los
`18. ALZAMLR® Depot1 M Bioerodible Polymer Technology 215
`Guohua Chen and Gunjan Junnarkar
`19. Pegylated Liposome Delivery of Chemotherapeutic Agents:
`Rationale and Clinical Benefit 227
`Francis J. Martin
`
`PART IV: DERMAL AND TRANSDERMAL TECHNOLOGIES
`
`20. Dermal and Transdermal Drug Delivery 263
`Jonathan Had graft, Majella E. Lane, and Adam C. Watkinson
`21. ALZA Transdermal Drug Delivery Technologies 273
`Rama Padmanahhan, J. Bradley Phipps, Michel Cormier, Janet Tamada,
`Jay Audett, J. Richard Gyory, and Peter E. Daddona
`
`0003
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`Contents
`
`ix
`
`22. Microneedles for Drug Delivery 295
`Mark R. Prausniti, Ha winder S. Gill, and Jung-Hwan Park
`23. Transfersome®: Self-Optimizing and Self-Driven Drug-Carrier,
`for Localized and Transdermal Drug Delivery 311
`Gregor Cevc
`24. Advances in Wound Healing 325
`Michael Walker and Steven Percival
`25. Ultrasound-Mediated Transdermal Drug Delivery 339
`Samir Mitragotri and Joseph Kost
`26. Lipid Nanoparticles with Solid Matrix for Dermal Delivery: Solid Lipid
`Nanoparticles and Na no structured Lipid Carriers 349
`Eliana B. Souto, Rolf D. Petersen, and Rainer H. Muller
`27. LidoSite®—Vyteris lontophoretic Technology 373
`Lakshmi Raghavan and Ashutosh Sharma
`28. Nail Delivery 383
`Darren M. Green, Keith R. Brain, and Kenneth A. Walters
`29, Immediate Topical Drug Delivery Using Natural Nano-Injectors 595
`Tamar Lotan
`30. DOT Matrix® Technology 405
`Juan A. Mantelle
`31. The PassPort™ System: A New Transdermal Patch for Water-Soluble
`Drugs, Proteins, and Carbohydrates 417
`Alan Smith and Eric Tomlinson
`
`FART V: NASAL TECHNOLOGIES
`
`32. Nasal Drug Delivery 427
`Pradeep K. Karia, Deep Kwatra. Ripal Gaudana. and Ashim K. Mitra
`33. Controlled Particle Dispersion®: A Twenty-First-Century Nasal Drug
`Delivery Platform 451
`Marc Giroux, Peter Hwang, and Ajay Prasad
`34. DirectHaler™ Nasal; Innovative Device and Delivery Method 469
`Troels Keldmann
`PART VI: VAGINAL TECHNOLOGIES
`
`35, Intravaginal Drug Delivery Technologies 481
`A. David Woolfson
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`Contents
`
`36. Vagina] Rings for Controlled-Release Drug Delivery 499
`R. Karl Malcolm
`37, Phospholipids as Carriers for Vaginal Drug Delivery 511
`Mathew Leigh
`38. SITE RELEASE®, Vaginal Bioadhesive System 527
`Jennifer Gudeman, Daniel J. Thompson, and R. Saul Lev ins on
`39. Clindamycin Vaginal Insert 53/
`Janet A. Haiti day and Steve Robertson
`40. Bio responsive Vaginal Delivery Systems 539
`Patrick F. Kiser
`
`PART VII: PULMONARY TECHNOLOGIES
`
`41. Pulmonary Delivery of Drugs by Inhalation 55J
`Paul B. Myrdal and B. Steven Anger shock
`42. AERx® Pulmonary Drug Delivery Systems 563
`David C. Cipolla and Eric Johansson
`43. Formulation Challenges of Powders for the Delivery of Small
`Molecular Weight Molecules as Aerosols 573
`Anthony J. Hickey and Heidi M. Man sour
`44. Adaptive Aerosol Delivery (AAD®) Technology 603
`Kurt Nikander and John Denyer
`45. Nebulizer Technologies 613
`Martin Knoch and Warren Finlay
`46. Formulation Challenges: Protein Powders for Inhalation 623
`Hak-Kim Chan
`47. The Respimat®, a New Soft Mist™ Inhaler for Delivering Drugs
`to the Lungs 637
`Herbert Wachtel and Achim Moser
`48. Pressurized Metered Dose Inhalation Technology 647
`Ian C. Ashurst
`49. Dry Powder Inhalation Systems from Nektar Therapeutics 659
`Andrew R. Clark and Jeffry G. Weers
`50. Technosphere®/Insulin: Mimicking Endogenous Insulin Release tf73
`Andrea Leone-Bay and Marshall Grant
`
`Index 6HI
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`30
`DOT Matrix® Technology
`
`Juan A. Mantelle
`Noven Pharmaceuticals, Inc., Miami, Florida, U.S.A.
`
`BACKGROUND
`Introduction
`The concept of delivering drugs through the skin for systemic activity has
`been around throughout recorded history. Only during the last 30 years,
`however, has there been meaningful advancement in the area, fueled by the
`recognition of
`the potential benefits of transdermal drug delivery.
`Transdermal drug delivery systems (TDDS) either have been or are being
`developed in practically every known therapeutic category.
`This chapter is focused on how the evolution of transdermal systems
`led to the development of DOT Matrix* technology by Noven Pharma­
`ceuticals, Inc., and how the implementation of this technology has resulted
`in many firsts in TDDS technology. In order to properly explain the DOT
`Matrix story, the "state" of transdermals is presented as a series of decision­
`making processes where the many facets of product development are eval­
`uated and the process is elucidated.
`
`Why Transdermals?
`Systemic drug delivery via TDDS presents several opportunities and benefits
`as compared to traditional oral delivery. As compared to pills, TDDS, or
`patches, offer the following advantages, among others:
`1. avoidance of the first pass liver metabolism resulting in lower required
`doses;
`2. easy discontinuation of dosing by simply removing the patch;
`
`405
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`3. providing steady drug delivery and, consequently, steady blood levels
`for the dosing duration;
`4. multiple-day dosing potential;
`5.
`increased compliance;
`6. control over the duration of dosing;
`7.
`life cycle extension opportunities for older molecules at lower costs with
`lower risks.
`
`Types of Transdermals—Evolutionary Steps
`
`1. Creams, ointments, plasters and salves: As the first in the evolutionary
`process for systemic transdermal drug delivery, these types of TDDS
`have been around for centuries. Over the years, these types of TDDS
`have taken on many different configurations, from the simple grinding
`of plants and roots into a paste to more sophisticated and elegant
`emulsions, hydrogels, and ointments. Although efficacious when used
`properly, they have several drawbacks. First, they typically require large
`surface areas to achieve the therapeutic doses required due to their lack
`of occlusion. Secondly, dosing can be erratic since the patient must
`spread the preparation over the required surface area of the skin in
`order to achieve the target blood levels, in some cases over areas as large
`as 300 cm2.
`2. Reservoir systems: Reservoir TDDS {Fig. 1) typically consist of a drug
`containing reservoir or gel held between an outer occlusive layer and a
`rate controlling membrane. On the other side of the membrane, there is
`
`Liquid or semisolid
`drug reservoir
`
`Impermeable
`backing
`
`Rate-controlling
`membrane
`
`Release liner
`
`Face adhesive
`
`Figure 1 Reservoir transdermal system with face adhesive.
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`a pressure sensitive adhesive (PSA) which is, in turn, in contact with the
`disposable release liner.
`This type of TDDS typically utilizes rubber-based PSAs as they
`are more permeable and inert to the drug and the vehicles utilized in the
`reservoir. In order to properly anchor the rate controlling membrane to
`the occlusive backing, a perimeter is present in the system that is not in
`direct contact with the reservoir components. As can be expected, this
`perimeter or border absorbs drug and vehicle until it equilibrates with
`storage time.
`These systems constitute an advance in the transdermal evolu­
`tionary process in that their surface area, and consequently their delivery
`and dosing, is more reproducible and they require lesser surface areas
`due to their occlusive nature. The primary drawback to these systems
`has been the types of delivery vehicles (enhancers or solubilizers) used
`which have a tendency to be irritating. ]n addition, the adhesive prop­
`erties can be compromised by these vehicle,'drug combinations.
`Solid matrix systems: Solid matrix systems {Fig. 2) are no longer avail­
`able in the U.S. market but are worth mentioning due to their role in the
`evolutionary process. In 1980s, they were very prevalent in the nitro­
`glycerin market. The principle behind these systems was to provide a
`"solid reservoir" with no need for a rate controlling membrane. The
`PSA could then be kept remote from the drug-containing solid matrix
`and thus prevent the deterioration of the adhesive properties with
`storage time.
`Solid matrix systems, although an advancement in the evolu­
`tionary process in that they yielded reproducible dosing, encountered
`many problems since the solid matrix tended to ooze and detach from
`the occlusive backing. As such, their use slowly declined resulting in
`their removal from the market. However, they opened the door for use
`of acrylic PSAs and hence they played a significant role in the evolu­
`tionary process.
`
`tmpermeabfe backing
`
`T
`
`^^^1
`
`Release liner
`
`Solid matrix
`
`Perimeter adhesive
`
`Figure 2 Solid matrix transdermal system with perimeter adhesive.
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`Drug-in-adhesive systems'. Drug-in-adhesive (DIA) TDDS (Fig. 3) evolved
`almost by mistake although many would argue that it was an inevitable
`outcome. Some of the first commercial embodiments resulted from
`placing acrylic PSAs on the face of matrix systems and noticing their
`afllnity for the drug and fluid vehicles in these solid matrices. Upon
`storage, almost all, if not all of the drug, was absorbed by these acrylics
`leaving the solid matrix practically devoid of drug and vehicles.
`DIA systems are comprised of an occlusive backing, the drug and exci-
`pient containing PSA layer, and a disposable release liner. The PSA layer
`can be rubber based (e.g., polyisobutylene, silicone, natural rubber) or
`acrylic based.
`DIAs constituted a significant advance in the evolutionary process
`in that the drug and vehicles are incorporated directly into the PSA and
`as such, for most designs there is no need for the perimeter or border. In
`addition, these units can be made on continuous motion machines like
`adhesive coaters. Dosing is reproducible, and the adhesives are designed
`with the drug and vehicles already incorporated so the adhesive proper­
`ties typically do not deteriorate upon storage.
`The primary drawback of these systems comes from the need to
`balance drug and vehicle loading, solubility with the adhesive properties.
`The compromise, almost invariably, is that the TDDS ends up being
`larger in order to accomplish the aforementioned balance (i.e., less drug
`and vehicle loading per unit area).
`DOT Matrix (Fig. 4): The latest evolutionary step in TDDS was the
`development of the DOT Matrix system in the mid-1990s by Noven
`Pharmaceuticals, Inc. Structurally similar to the DIA systems that
`preceded it, in that it consists of an occlusive backing, a drug and
`vehicle-containing PSA layer and a disposable release liner, that is
`where the similarities end. DOT Matrix technology incorporates the
`learnings from all of its predecessors into a TDDS that solves the
`
`Backing
`
`Release liner
`
`Figure 3 Drug-in-adhesive transdermal system.
`
`s
`
`Drug laden
`adhesive layer
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`DOT Matrix Technology
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`409
`
`CflSltcr.trntwi tjaty in itr.r/Ui:
`for tn$h rfvUic.'y ofhchswy
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`^
`
`-
`
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`yfi
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`vi
`
`i-~ O
`O T"
`
`«
`
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`
`Figure 4 Circular image is the surface of the drug;adhesive layer of a DOT
`Matrix™ patch photographed with a scanning electron microscope.
`
`patch design dilemma of achieving a Comfortable (non-irritating).
`Adherent, Reproducible and Small transdermal system (a combination
`of physician/end-user preferred properties referred to by the acronym
`CARS).
`From the reservoir systems came the recognition that rubber based PSAs
`have very little, if any, affinity for the drugs or vehicles and are essentially
`nonreactive. From the DIA systems came the use of acrylic PSAs with their
`potential for drug and vehicle solvation. From experimentation came the
`recognition that these two types of PSAs (rubber based and acrylic) are
`essentially nonmiscible and as such can be utilized jointly to serve distinctly
`separate functions within the finished product. The rubber based PSA is uti­
`lized primarily for proper skin adhesion whereas the acrylic's PSA properties
`are allowed to be compromised in order to achieve maximum drug und vehi­
`cle loading. The resulting product is one with a delivery optimized thermo­
`dynamics matrix system, which, by design, delivers greater amounts of drug
`per unit area without the need for irritating chemical enhancers and provides
`the comfort and adhesion properties which today's consumers demand.
`
`DEVELOPMENT OF TDDS SYSTEMS
`tntellectual Property Considerations
`Intellectual property (IP) in the area of TDDS has seen a proliferation in the
`number of U.S. patents as well as in the number of companies which are
`including the word "transdermal" in their patent specifications as well as the
`claims. Figure 5 shows that as recently as 1980 there was only one patent in
`
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`25,000 t-
`
`20,000 -
`
`15,000 -
`
`10,000 -
`
`5,000 -
`
`Mantelle
`
`21,618
`
`14,777
`
`8,206
`
`0
`
`1
`3
`1980
`
`i
`
`60 26
`1985
`
`2,435
`532
`H Ll
`1995
`
`740
`
`168
`1990
`
`•
`
`,048
`l
`
`2000
`
`.537
`
`,988
`
`2003
`
`i
`
`2006
`
`i
`
`Figure S U.S. patents incorporating the word "transdermal" in the specification or
`claims.
`
`the United States with the word transdermal in the claims while there were
`three which included it in the specification. By the middle of 2006, these
`numbers had grown to 1988 and 21,618, respectively.
`For those planning lo enter the field of the TDDS there are, as can be
`surmised from the above, many IP obstacles, Gone are the days when IP
`would be granted for general polymer classes with multiple drugs. Hence,
`some of the strategies being utilized now include:
`1. "Picture" claims:
`a. narrow composition windows,
`b. new methods of manufacturingK
`2. Expiring patents:
`a. making older technology new again by utilizing advances in PSA
`technology.
`3. New chemical entities (NCEs):
`a. patenting these NCEs in TDDS.
`4. Pharmacokinetic-based IP:
`a.
`IP based on the specific blood levels achieved and the duration of
`delivery.
`5. Novel skin permeation enhancers:
`a. IP based on the discovery of new combinations of enhancers or
`surprising results with known chemical entities.
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`6. Novel polymeric systems combinations:
`a.
`IP based on newly created PSA systems or surprising results from
`combinations of known systems.
`
`Formulation Considerations
`Overcoming the resistance of the stratum corneum to the passage of drug
`into the systemic circulation remains the primary barrier to TDDS devel­
`opment. As such, many different modalities can be utilized to achieve thisj
`namely:
`1. enhanced drug solubilization
`2. chemical enhancement
`3. mechanical enhancement
`4. electrical enhancement
`5.
`thermal enhancement
`Enhanced drug solubilization traditionally has come from utilizing the
`base form of a given API. This approach is not without its own drawbacks
`since the base form is typically more unstable to atmospheric influences such
`as light, oxygen, and moisture. Another known option is the use of pro­
`drugs that are lipophilic as presented to the skin but are then converted to
`the parent molecule in the system {e.g., norethindrone acetate, which con­
`verts readily to norethindrone.) Enhanced drug solubilization is achieved in
`the DOT Matrix® TDDS by modifying the Hildebrand solubility parameter
`of the acrylic PSA to achieve saturation at a target level and thus maximize
`the thermodynamic driving force in the system. The net result of this
`approach has been the creation of the smallest 17-p estradiol product in the
`market (Vivcllc-Dot™) (Table I) as well as the first ever TDDS to deliver
`methylpbenidate (Daytrana™) at a rate of 80 + jig/em'/hr (30 mg from a
`37.5 cm2 patch over 9 hours) (Table 2). This delivery rate is achieved without
`the need for irritating chemical enhancers.
`Chemical enhancement consists of utilizing vehicles which either flu-
`idize or bridge the stratum corneum. As such, most of these vehicles have
`been shown to be irritating to the skin so their use has been limited to a
`handful of molecules (e.g., ethanol, triacetin, low molecular weight alcohols,
`fatty acids, fatty acid esters, and fatty acid alcohols).
`Mechanical enhancement of TDDS through the use of micro-needles,
`micro'protrusions, and other methods has been proposed for many years,
`but there are no commercial embodiments to date. The IP field in this area is
`growing as fast as or faster than that of passive TDDS since this approach
`appears to offer a methodology which bypasses the stratum corneum barrier
`by effectively creating a mechanical hole through it. Hollow as well as solid
`needles, micro-blades, drug-laden needles, etc. are just some of the proposed
`
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`Table 1 Bused on Label Cliiim for 0.05 mg. day Dose
`
`Product
`
`Vivelle-Dot
`Vivelle
`Climara0
`Estraderm
`Mylanc
`Alora
`Escltm
`
`Patch size
`
`5.0 cm2
`14.5 cm2
`12.5 cm2
`18,0 cm2"
`23.7 cm2b
`!8.0 cm2
`22.0 cm2
`
`Estradiol
`content
`
`%
`depletion
`
`0,8 mg
`4.3mg
`3.9mg
`4.0ing
`L9nig
`l.Smg
`lO.Omg
`
`22.4
`4.0
`9,0
`4.4
`18.0
`) 1.6
`1.8
`
`"Active area is cm2.
`bAciive area is 15.5cm:.
`*7-day patch; others are 3.5-d;ty.
`
`embodiments which are in developmenl today with the promise of larger
`molecules, including smaller peptides and proteins now being considered
`suitable candidates.
`Alternative modes of mechanical enhancement have been developed
`which utilize heat, electrical current or radio frequency to create pores in the
`stratum corneum and hence reduce the barrier to hydrophilic drugs.
`
`Table 2 Properties of Commercialized Transdermals
`
`Drug
`
`Scopolamine
`Nitroglycerin
`Clonidine
`Estradiol
`NETA
`Ethinyl Estradiol
`Norclgestromin
`Nicotine
`Testosterone
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`
`10. Fentanyl
`11. Lidocaine
`12. Oxybutynin
`13. Methylphenidate
`14. Selegiline
`15. Buprenorphine
`
`Molecular
`weight
`
`Daily TD
`dose
`
`Smallest
`patch
`size
`(cm2)
`
`I n-vivo
`permeation
`rate (g. cm2
`hr)
`
`303.35
`227.09
`230.10
`272.38
`340.45
`296.40
`327.47
`162.23
`288.42
`
`336,50
`234.34
`357.49
`233.31
`187.28
`467.64
`
`0.33 mg/day
`1.6 mg/16 hr
`0.1 mg/duy
`0.1 mg/day
`0.14 mg/day
`0.02 mg/day
`0.15 mg/day
`7,0 mg/day
`2.5 mg/day
`
`2.5
`5.0
`3.5
`10.0
`9.0
`20.0
`20.0
`7,0
`7.5
`
`0.6 mg/day
`21.33 mg/12 hr
`3.9 mg/day
`12.0 mg/12 hr
`6.0 mg/day
`0.12 mg/day
`
`10.0
`140,0
`39.0
`12.5
`20
`6.25
`
`5,5
`20.0
`1.19
`.42
`0.65
`0.042
`0.31
`42.0
`14,0
`
`2.5
`12.0
`4.16
`80.0
`12.5
`0.8
`
`0013
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`Although the way in which the pores are created is obviously different from
`the micro-needles or micro-blades, the result is similar in that the stratum
`corneum's permeability barrier is compromised to achieve the required drug
`permeation.
`Electrical enhancement, othenvise referred to as Iontophoresis, utilizes
`charged molecules with an electrical source to achieve permeation through
`the stratum corneum. Although these systems have been proposed for over
`20 years, their commercial success has been limited by the buikiness of the
`power source, costs, and the practicality of the systems for daily use. Once
`again, the hope is that these systems can be used to achieve therapeutic levels
`of larger molecules or higher doses.
`Thermal enhancement is a more recent development wherein an
`external heat source is applied to the patch resulting permeation enhance­
`ment which can be tailored to provide a sharp peak, if needed, or simply a
`sustained, yet higher delivery rate.
`
`Which Types of TDDS to Use and When?
`With all of the available options for TDDS development, which option is
`best suited to a particular molecule? To follow are some general criteria
`which can help in the decision-making process when selection of a passive
`system is required.
`L Reservoir systems:
`a. volatile API—room temperature processing.
`b. expensive API—higher yields.
`c. difficult to solubilize API—reservoir can accommodate larger
`vehicle loading.
`2. Traditional DIA systems;
`a.
`inexpensive API—need higher drug loading to achieve the target
`delivery rates;
`low doses/smaller molecules—where larger patch sizes are not
`problematic.
`3. DOT Matrix® systems
`a. expensive API -highly efficient delivery via the customized poly­
`meric systems;
`thermodynamic driving
`b. higher doses/larger molecules^—higher
`force results in an enhanced ability to deliver these;
`c. volatile API
`ustomized solvent system enables differential vola-
`tilization resulting in lesser drug loss during processing
`d. small size—for applications where a discreet patch is required
`e. customizable wear properties—wear properties can be optimized,
`via the selection and customization of the PSA system used.
`
`b.
`
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`THE DOT MATRIX EXPERIENCE
`Adhesives
`The DOT Matrix systems, by virtue of the blend of rubber based (silicone)
`PSAs with the acrylic PSAs afibrds the formulator several unique opportu­
`nities. The first and probably most remarkable feature is the fact that the
`acrylic PSA can be tailored, via modification of the reactive moiety, to
`achieve the desired solubility potential for the API while still maintaining
`the integrity of the polymeric system. Second, by altering the ratio of the
`two PSAs, one can also significantly alter the total delivery as well as the
`shape of the pharmacokinetic curve. Furthermore, by adjusting the func­
`tionality and molecular weight of these PSAs, stability and wear properties
`can be tailored to each API and intended wear time, respectively.
`
`Efficiency
`The binary adhesive system used in the DOT Matrix systems provides the
`formulator the ability to saturate the acrylic PSA without concern for its
`loss of PSA properties. As Table I illustrates, the attainment of higher
`drug concentrations permits a higher depletion rate for the given wear per­
`iod, resulting in less drug being discarded at the end of the dosing period.
`
`Firsts
`DOT Matrix has, in the years since its creation provided the transdermal
`market with many firsts, namely:
`L
`the first two drug transdermal systems (CombiPatch®, Estalis®);
`2.
`the first, and still only, 17-P Estradiol product to deliver 0. lOmg day
`from a patch size of 10 cm2 (Vivelle-Dot™, the smallest estrogen patch
`on the market);
`the first and only TDDS to deliver more than 45 fig/cm2/hr of any drug
`(Dayliana™ delivers upwards of 80 ^ig/cm2 hr of methylphcnidatc).
`
`3.
`
`CONCLUSION
`Passive transdermal drug delivery is poised to become a more prevalent ther­
`apeutic choice as the technology has progressed to the point where larger
`molecules and larger doses in almost all therapeutic categories are in
`advanced development. With this added exposure to the general population
`comes the responsibility of the pharmaceutical companies to make these
`patches more esthetically appealing, flexible, and adhesive for the intended
`dose duration. The DOT Matrix system has already expanded this frontier
`and set the standard for passive transdermal drug delivery. The number of
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`ACTEST00225158
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`DOT Matrix Technology
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`415
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`molecules that are contemplated in the various therapeutic categories for
`this system continues to expand as the PSA technology and consequent ver­
`satility has progressed to better suit the needs of the formulator. Acrylic
`PSAs with various reactant moieties in a wide range of concentrations
`have progressed the solubilization potential of these systems significantly
`and further advancement is occurring almost daily. Future developments
`will be more challenging, but the DOT Matrix systems are continuing to
`expand the horizon of APIs that can be delivered transdermally.
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`0016
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`ACTEST00225159
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