Mooilion-Holoaso
`Ilnnn Ilolivony Toonnolonv
`Second Edition
`
`Unlnno 2
`
`edited by
`
`Michael J. Rathbone
`InterAg
`Hamilton. New Zealand
`
`Jonathan Hadgraft
`Unnrarsfiy of London
`London, UK
`
`Michael S. Roberts
`Universr'ly of Queensland
`Brisbane. Australia
`
`Majella E. Lane
`Univemfly of London
`London. UK
`
`informa
`healthcare
`New York London
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2022
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`IPR2018-00174
`
`

`

`Contents
`
`Preface
`
`v
`
`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 Ferret:
`
`. The Modified-Release Drug Delivery Landscape: Academic
`Viewpoint
`17
`
`Juergen Siepmorm and Florence Siepmmm
`
`. The Modified-Release Drug Delivery Landscape: Advantages and
`Issues for Physicians and Patients 35
`Marco M . Anefli
`
`. The Modified-Release Drug Delivery Landscape: Drug Delivery
`
`Commercialization Strategies
`
`49
`
`F into)? Wainm
`
`PART II: OCULAR TECHNOLOGIES
`
`5.
`
`59
`Ophthalmic Drug Delivery
`Pascal Furrer, FIorence Deh'e. and Ben-lord Pimomzet
`
`85
`Intraocular Implants for Controlled Drug Delivery
`Leila Bossy. Signe Erickson. Robert Gm'ny. and Florence Defie
`
`Bioadhesive Ophthalmic Drug Inserts (BODI) for
`Veterinary Use
`101
`Pascat Fun-er, Olivia Feh. and Robert Gnrny
`
`8.
`
`[on Exchange Resin Technology for Ophthalmic Applications
`Rojm' Joni and Erin Rhone
`
`109
`
`0002
`
`VIC
`
`

`

`viii
`
`Contents
`
`PART III: INJECTION AND IMPLANT TECHNOLOGIES
`
`9.
`
`123
`Injections and Implants
`Majella E. Lane, Frankiin W. Okumu, and Paiani Baiausubramanian
`
`10.
`
`Long-Acting Protein Formulation—PLAD Technology
`Franklin W. Okumu
`
`133
`
`11.
`
`12.
`
`13.
`
`Long-Term Controlled Delivery of Therapeutic Agents by the
`Osmotically Driven DUROS® Implant
`143
`Jeremy C. Wright and John Cuiweil
`
`The SABERTM Delivery System for Parenteral Administration 151
`Jeremy C. Wright, A. Neil Verity, and Frankiin W. Okumu
`
`Improving the Delivery of Complex Formulations Using the
`DepotOne® Needle
`159
`Kevin Maynard and Peter Cracker
`
`14.
`
`171
`ReGel Depot Technology
`Romesh C. Rathi and Kirk D. Fowers
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`The Atrigel® Drug Delivery System I83
`Eric J. Dadey
`
`Enhancing Drug Delivery by Chemical Modification 191
`Mimoun Ayoub, Christina Wedemeyer, and Torsten Wri'hr
`
`DepoFoam® Multivesicular Liposomes for the Sustained Release
`of Macromolecules
`207
`
`Wiiiiam J. Lambert and Kathy Los
`
`ALZAMER® DepotTM Bioerodible Polymer Technology 215
`Guohua Chen and Ganja»: Junnorkar
`
`Pegylated Liposome Delivery of Chemotherapeutic Agents:
`Rationale and Clinical Benefit 227
`
`Francis J. Martin
`
`PART IV: DERMAL AND TRANSDERMAL TECHNOLOGIES
`
`20.
`
`21.
`
`263
`Dermal and Transdermal Drug Delivery
`Jonathan Hadgroft, Majelia E. Lane. and Adam C. Watkinson
`
`273
`ALZA Transdermal Drug Delivery Technologies
`Roma Padmanabhan, J. Bi-adiey Phipps. Michel Cormier, Janet Tornado.
`Jay Auden, J. Richard Gyory, and Peter E. Daddona
`
`0003
`
`

`

`Contents
`
`ix
`
`22.
`
`Microneedles for Drug Delivery 295
`Mark R. Prausnirz, Harvinder S. Gm, and Jung-finer: 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 Kosr
`
`26.
`
`Lipid Nanoparticles with Solid Matrix for Dermal Delivery: Solid Lipid
`Nanoparticles and Nanostructured Lipid Carriers
`349
`Eh’ana B. Sonia. Rolf D. Petersen, and Rainer H. Mailer
`
`27.
`
`LidoSite®—Vyteris Iontophoretic Technology
`Lakshmi Raghavan and Ashmosh Sharmn
`
`373
`
`28.
`
`383
`Nail Delivery
`Darren M. Green. Keith R. Brain, and Kenneth A. Walters
`
`29.
`
`Immediate Topical Drug Delivery Using Natural Nam-Injectors 395
`Tamar Loren
`
`30.
`
`DOT Matrix® Technology 405
`Juan A. Mamefle
`
`31.
`
`The PassportTM System: A New Transdermal Patch for Water-Soluble
`Drugs. Proteins, and Carbohydrates
`417
`Alan Smith and Eric Tomh'nsan
`
`PART V: NASAL TECHNOLOGIES
`
`32.
`
`33.
`
`Nasal Drug Delivery 427
`Pradeep K. Karla, Deep Kwan'a, Ripe! Gandana. and Ashim K. Mitre
`
`Controlled Particle Dispersion®2 A Twenty—First-Century Nasal Drug
`Delivery Platform 451
`Mare Giroux. Peter Huang, and Ajay Prasad
`
`34.
`
`Directl-[alerTM Nasal: Innovative Device and Delivery Method
`Troels Keldmann
`
`469
`
`PART VI: VAGINAL TECHNOLOGIES
`
`35. Intravaginal Drug Delivery Technologies 48]
`A. David Woolfscm
`
`0004
`
`

`

`.1:
`
`Contents
`
`36. Vagina] Rings for Controlled-Release Drug Delivery 499
`R. Kari Malcolm
`
`37. Phospholipids as Carriers for Vaginal Drug. Delivery 511
`Mathew Leigh
`
`38. SITE RELEASE®, Vaginal Bioadhesive System 521
`Jennifer Gudemon, Daniel J. Thompson, and R. Saul Levinson
`
`39. Clindamycin Vaginal Insert 53]
`Janet A. Hailiday and Steve Robertson
`
`40. Bioresponsive Vaginal Delivery Systems 539
`Patrick F. Kiser
`
`PART VII: PULMONARY TECHNOLOGIES
`
`41. Pulmonary Delivery of Drugs by Inhalation 553
`Pan! 8. Myrdal and 8. Steven Angersbach
`
`42. AERx® Pulmonary Drug Delivery Systems
`David C. Cl'pofla and Eric Johansson
`
`563
`
`43. Formulation Challenges of Powders for the Delivery of Small
`Molecular Weight Molecules as Aerosols
`573
`Anthony J. Hickey and Heidi M. Mansour
`
`44. Adaptive Aerosol Delivery (AAD®) Technology
`Km? Nikander and John Denyer
`
`603
`
`613
`45. Nebulizer Technologies
`Martin Knock and Warren Finlay
`
`46. Formulation Challenges: Protein Powders for Inhalation
`Halt-Kim Chan
`
`623
`
`47. The Respimat®, a New Soft MistTM Inhaler for Delivering Drugs
`to the Lungs
`637
`Herbert Wachtel and Achim Maser
`
`48. Pressurized Metered Dose Inhalation Technology
`Ian C. Arthur's!“
`
`647
`
`49. Dry Powder Inhalation Systems from Nektar Therapeutics
`Andrew R. Cfork and Jefiry G. Wears
`
`659
`
`50. Technosphere'gflnsulill: Mimicking Endogenous Insulin Release
`Andrea Leone-Bay and Marshall Gram
`
`673
`
`Index 68!
`
`0005
`
`

`

`30
`
`DOT Matrix® Technology
`
`Juan A. Mantelle
`
`Noven Pharmaceuticals, inc, Miami, Florida, USA.
`
`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 DDT 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 Transderrnals?
`
`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.
`
`2.
`
`avoidance of the first pass liver metabolism resulting in lower required
`doses;
`easy discontinuation of closing by simply removing the patch;
`
`405
`
`0006
`
`

`

`406
`
`H99?
`
`Mantcfle
`
`providing steady drug delivery and, consequently, steady blood levels
`for the dosing duration;
`multiple-day dosing potential;
`increased compliance;
`control over the duration of dosing;
`life cycle extension opportunities for older molecules at lower costs with
`lower risks.
`
`Types of Transdermals—Evolutionary Steps
`
`1.
`
`go
`
`Creams. or'emrems, plasters and selves: 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.
`
`Reservoir sysrems: Reservoir TDDS (Fig. I) typically consist of a drug
`containing reservoir or gel held between an outer occlusive layer and a
`rate controlling membrane. 011 the other side of the membrane, there is
`
`lmpermeable
`backing
`Liquid or semisolid
`
`drug reservoir
`
`
`
`
`_
`Rate-controlllng
`membrane
`
`
` Release liner/ F303 flthSiVB
`
`
`
`Figure 1 Reservoir transdermal system with face adhesive.
`
`0007
`
`

`

`DOT zlfietrix‘t Technology
`
`407
`
`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. In addition, the adhesive prop-
`erties can be compromised by these vehicle-“drug combinations.
`3. Solid man-ix systems: Solid matrix systems (Fig. 2) are no longer avail-
`able in the US. market but are worth mentioning due to their role in the
`evolutionary process. In l9805, 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.
`in the evolu-
`Solid matrix systems, although an advancement
`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.
`
`
`
`Impermeable backing
`
`
`
`
`[I'll/WWW]
`l/M
`
`
`
`
`
`
`Perimeter adhesive
`
`Release liner
`Solid matrix
`
`Figure 2 Solid matrix transdermal system with perimeter adhesive.
`
`0008
`
`

`

`403
`
`Mantelle
`
`4. Drug-in-acfltesive systems: Drug-in-adhesive (D! A) 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
`affinity 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 line r. 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 loadingli'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).
`5. DOT Matrix (Fig. 4): The latest evolutionary step in TDDS was the
`development of the DOT Matrix system in the mid-19905 by Noven
`Pharmaceuticals, Inc. Structurally similar to the BIA 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 thal solves the
`
`
`
`Backing
`
`WW
`
`
`
`
`t__4___
`/
`Drug laden
`
`adhesive layer
`
`Release liner
`
`Figure 3 Drug-in-adhesive transdermal system.
`
`0009
`
`

`

`nor Marrixm Technology
`
`409
`
`
`
`Figure 4 Circular image is the surface of the drugv’adhesive layer of a DOT
`MatrixTM 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 physicianfend-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 BIA systems came the use of acrylic PSAs with their
`potential for drug and vehicle salvation. 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 and 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 preperties which today‘s consumers demand.
`
`DEVELOPMENT OF TDDS SYSTEMS
`
`Intellectual Property Considerations
`
`Intellectual property (IP) in the area ofTDDS 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 1930 there was only one patent in
`
`0010
`
`

`

`4M
`
`25.000
`
`Mantelle
`
`20.000
`
`15.000
`
`10,000
`
`5,000
`
`1980
`
`1935
`
`1990
`
`1995
`
`2000
`
`2003
`
`2006
`
`Figure 5 U.S. patents incorporating the word “transderrnal” in the specification or
`claims.
`
`the United States with the word transden'nal 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 to enter the field of the TDDS there are, as can be
`surmised from the above, many [P 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:
`
`[\J
`
`narrow composition windows,
`a.
`new methods of manufacturing.
`b.
`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 1P:
`
`a. W based on the specific blood levels achieved and the duration of
`delivery.
`5. Novel skin permeation enhancers:
`:1.
`IP based on the discovery of new combinations of enhancers or
`surprising results with known chemical entities.
`
`0011
`
`

`

`DOT Mam'xm Technology
`
`4”
`
`6. Novel polymeric systemslcombinations:
`a.
`[P 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 this,
`namely:
`
`newn—
`
`enhanced drug solubilization
`chemical enhancement
`
`mechanical enhancement
`
`electrical enhancement
`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 lip0philic as presented to the skin but are then converted to
`the parent molecule in the system (cg, norethindrone acetate, which con-
`verts readily to norethindrone.) Enhanced drug solubilization is achieved in
`the DOT MatrixG' 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-B estradiol product in the
`market (Vivellc-Dotm) (Table l) as well as the first ever TDDS to deliver
`methylphenidate (Daytrananfl at a rate of 80+ugllcmzl‘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. arejust some of the proposed
`
`0012
`
`

`

`412
`
`Manta”:
`
`Table '1
`
`Based on Label Claim for 0.05 lug-flay Dose
`
`Product
`
`Patch size
`
`content
`
`depletion
`
`Estradiol
`
`%
`
`Vivelle-Dot
`Vivelle
`Climara"
`Estraderm
`Mylan“
`Alora
`Esclim
`
`5.0 cm2
`14.5 cm2
`12.5 cm2
`18.0 c1112“
`23.7 cm2b
`18.0 cm2
`22.0 cm:
`
`0.8mg
`4.3mg
`3.9mg
`4-0mg
`1.9mg
`1.5mg
`10.0mg
`
`“Active area is cmz.
`hActive area is 15.5cm1.
`
`“7-day patch; others are 15-day.
`
`22.4
`4.0
`9.0
`4.4
`18.0
`11.6
`1.8
`
`embodiments which are in development 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
`Norelgestromin
`Nicotine
`Testosterone
`
`1 .
`2.
`3.
`4.
`5.
`
`6.
`7.
`8.
`9.
`
`10.
`1 l.
`
`Fentanyl
`Lidocaine
`
`12. Oxybutynin
`13. Methylphenidate
`14.
`Sclegiline
`15.
`Buprenorphine
`
`Molecular
`
`weight
`
`303.35
`227.09
`230.10
`272.38
`340.45
`
`296.40
`322.47
`[62.23
`288.42
`
`336.50
`234.34
`
`352.49
`233.31
`187.23
`462.64
`
`Daily TD
`dose
`
`0.33 mgfday
`1-6 mgflfi hr
`0.1 mgfday
`0.1 trig/day
`0.14 mg/day
`0.02 nag/day
`0.15 mgfday
`7.0 mglfday
`
`2.5 mgfday
`
`0.6 mgllday
`21.33 rag/12 hr
`3.9 mglfday
`12.0 mg/ 12 hr
`
`6.0 mg/day
`0.12 mgfday
`
`Smallest
`
`In—vivo
`
`patch
`size
`
`(arr-2)
`
`permeation
`rate (gfcmzi'
`hr)
`
`2.5
`5.0
`3.5
`10.0
`9.0
`20.0
`20.0
`7.0
`
`7.5
`
`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
`
`

`

`DOT Mamirm' Technology
`
`43
`
`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
`co rneurn’s permeability barrier is compromised to achieve the required drug
`permeation.
`Electrical enhancement, otherwise 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 bulkiness 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.
`
`b-
`
`b.
`
`c.
`
`I. Reservoir Systems:
`a.
`volatile API—room temperature processing.
`b.
`expensive Al’Iihigher yields.
`c.
`difficult
`to solubilize APl—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
`higher doses/larger molecules—higher
`force results in an enhanced ability to deliver these;
`volatile API—customized solvent system enables differential vola-
`tilization resulting in lesser drug loss during processing
`small size—for applications where a discreet patch is required
`customizable wear properties—wear properties can be optimized,
`via the selection and customization of the PSA system used.
`
`d.
`9
`
`0014
`
`

`

`4M
`
`Manta”:
`
`THE DOT MATRIX EXPERIENCE
`
`Adhesives
`
`The DOT Matrix systems, by virtue of the blend of rubber based (silicone)
`PSAs with the acrylic PSAs affords 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 PSAs1 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 1
`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
`
`in the years since its creation provided the transdermal
`DOT Matrix has,
`market with many firsts, namely:
`
`i.
`2.
`
`3.
`
`the first two drug transdermal systems (CombiPatch®, Estalis®);
`the first, and still only, 17-13 Estradiol product to deliver 0.10mgjday
`from a patch size of 10 cm2 (Vivelle-Dotm, the smallest estrogen patch
`on the market);
`the first and only TDDS to deliver more than 45 ug/cmzlhr of any drug
`(DaytranaTM delivers upwards of 30 pg_.t'cm2.-'hr ol' methylphenidate).
`
`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
`
`0015
`
`

`

`DOT Matrix; Technology
`
`415
`
`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.
`
`0016
`
`