`Drug Delivery Technology
`Second Edition
`Volume 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
`Majella E. Lane
`University of London
`London, UK
`
`informa
`healthcare
`New York London
`
`0001 Mylan Tech., Inc. v. Noven Pharma.,Inc.
`
`Noven Pharmaceuticals, Inc.
`EX2022
`
`IPR2018-00174
`
`
`
`Contents
`
`yv
`Preface
`Contributors xi
`
`PART I: USING MODIFIED-RELEASE FORMULATIONS TO
`MAINTAIN AND DEVELOP MARKETS
`
`1.
`
`The Modified-Release Drug Delivery Landscape: The Commercial
`Perspective
`J
`Stephen Perrett
`
`. The Modified-Release Drug Delivery Landscape: Academic
`Viewpoint
`17
`Juergen Siepmann and Florence Stepmann
`
`. The Modified-Release Drug Delivery Landscape: Advantages and
`Issues for Physicians and Patients 35
`Marco M. Anelli
`
`. The Modified-Release Drug Delivery Landscape: Drug Delivery
`Commercialization Strategies
`49
`Fintan Walton
`
`PART II: OCULAR TECHNOLOGIES
`
`5. Ophthalmic Drug Delivery
`59
`Pascal Furrer, Florence Delie, and Bernard Plazonnet
`
`8&5
`. Intraocular Implants for Controlled Drug Delivery
`Leila Bossy. Signe Erickson, Robert Gurny, and Florence Delie
`
`. Bioadhesive Ophthalmic Drug Inserts (BODI) for
`Veterinary Use
`107
`Pascal Furrer, Olivia Felt, and Robert Gurny
`
`. [on Exchange Resin Technology for Ophthalmic Applications
`Rajni Jani and Erin Rhone
`
`109
`
`0002
`
`Vu
`
`
`
`viii
`
`Contents
`
`PART IJ: INJECTION AND IMPLANT TECHNOLOGIES
`
`9.
`
`123
`Injections and Implants
`Majella E. Lane, Franklin W. Okumu, and Palani Balausubramanian
`
`10.
`
`11.
`
`Long-Acting Protein Formulation—-PLAD Technology
`Franklin W. Okumu
`
`£33
`
`Long-Term Controlled Delivery of Therapeutic Agents by the
`Osmotically Driven DUROS® Implant
`143
`Jeremy C. Wright and John Culwell
`
`. The SABER™Delivery System for Parenteral Administration 157
`Jeremy C. Wright, A. Neil Verity, and Franklin W. Okumu
`
`. Improving the Delivery of Complex Formulations Using the
`DepotOne® Needle
`159
`Kevin Maynard and Peter Crocker
`
`1771
`. ReGel Depot Technology
`Ramesh C. Rathi and Kirk D. Fowers
`
`15
`
`16
`
`17.
`
`18.
`
`19.
`
`The Atrigel® Drug Delivery System 183
`Eric J. Dadey
`
`Enhancing Drug Delivery by Chemical Modification 192
`Mimoun Ayoub, Christina Wedemeyer, and Torsten Wohr
`DepoFoam® Multivesicular Liposomes for the Sustained Release
`of Macromolecules
`207
`William J. Lambert and Kathy Los
`ALZAMER® Depot™Bioerodible Polymer Technology 235
`Guohua Chen and Gunjan Junnarkar
`
`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 Hadgraft, Majella E. Lane, and Adam C. Watkinson
`
`273
`ALZA Transdermal Drug Delivery Technologies
`Rama Padmanabhan, J. Bradley Phipps, Michel Cormier, Janet Tamada,
`Jay Audett, J. Richard Gyory, and Peter E. Daddona
`
`0003
`
`
`
`Contents
`
`ix
`
`22. Microneedles for Drug Delivery 295
`Mark R. Prausnitz, Harvinder S. Gill, and Jung-Hwan Park
`23. Transfersome®: Self-Optimizing and Self-Driven Drug-Carrier,
`for Localized and Transdermal Drug Delivery
`311
`Gregor Ceve
`
`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 Nanostructured Lipid Carriers
`349
`Eliana B. Souto, Rolf D. Petersen, and Rainer H. Miiller
`27. LidoSite*—Vyteris Iontophoretic Technology
`373
`Lakshmi Raghavan and Ashutosh Sharma
`
`383
`28. Nail Delivery
`Darren M. Green, Keith R. Brain, and Kenneth A. Walters
`
`29. Immediate Topical Drug Delivery Using Natural Nano-Injectors 395
`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
`427
`Alan Smith and Eric Tomlinson
`
`PART V: NASAL TECHNOLOGIES
`
`32. Nasal Drug Delivery 427
`Pradeep K. Karla, Deep Kwatra, Ripal Gaudana, and Ashim K. Mitra
`33. Controlled Particle Dispersion®: A Twenty-First-Century Nasal Drug
`Delivery Platform 451
`MareGiroux, Peter Hwang, and Ajay Prasad
`
`34. DirectHaler™ Nasal: Innovative Device and Delivery Method
`Troels Keldmann
`
`469
`
`PART VI: VAGINAL TECHNOLOGIES
`
`35. Intravaginal Drug Delivery Technologies
`A. David Woolfson
`
`0004
`
`487
`
`
`
`Contents
`
`36.
`
`37.
`
`38.
`
`39.
`
`Vaginal Rings for Controlled-Release Drug Delivery 499
`R. Kari Maicolm
`
`Phospholipids as Carriers for Vaginal Drug Delivery SJ
`MathewLeigh
`SITE RELEASE®,Vaginal Bioadhesive System 521
`Jennifer Gudeman, Daniel J. Thompson, and R. Saul Levinson
`
`Clindamycin Vaginal Insert 53/
`Janet A. Halliday and Steve Robertson
`
`40.
`
`Bioresponsive Vaginal Delivery Systems 539
`Patrick F. Kiser
`
`PART VII; PULMONARY TECHNOLOGIES
`
`41.
`
`42.
`
`Pulmonary Delivery of Drugs by Inhalation 553
`Paul B. Myrdal and B. Steven Angersbach
`AERx® Pulmonary Drug Delivery Systems
`David C. Cipolla 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
`. Adaptive Aerosol Delivery (AAD®) Technology
`Kurt Nikander and John Denyer
`
`603
`
`45.
`
`623
`Nebulizer Technologies
`Martin Knoch and Warren Finlay
`
`46.
`
`Formulation Challenges: Protein Powders for Inhalation
`Hak-Kim Chan
`
`623
`
`47.
`
`The Respimat®, a New Soft Mist™ Inhaler for Delivering Drugs
`to the Lungs
`637
`Herbert Wachtel and Achim Moser
`
`. Pressurized Metered Dose Inhalation Technology
`lan C. Ashurst
`
`647
`
`49.
`
`50.
`
`Dry Powder Inhalation Systems from Nektar Therapeutics
`Andrew R. Clark and Jeffry G. Weers
`Technosphere™/Insulin: Mimicking EndogenousInsulin Release
`Andrea Leone-Bay and Marshall Grant
`
`659
`
`673
`
`fndex
`
`681
`
`0005
`
`
`
`30
`
`DOTMatrix® 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 advancementin 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 manyfirsts 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 manyfacets of product development are eval-
`uated and the processis elucidated.
`
`WhyTransdermals?
`
`Systemic drug delivery via TDDSpresents 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 ofthe first pass liver metabolism resulting in lower required
`doses;
`easy discontinuation of dosing by simply removing the patch;
`
`405
`
`0006
`
`
`
`406
`
`Manteille
`
`~ 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.
`
`NDS
`
`Types of Transdermals—Evolutionary Steps
`
`|. 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 dueto 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 bloodlevels, in some cases over areas as large
`as 300cm’.
`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. Onthe other side of the membrane,thereis
`
`tN
`
`impermeable
`backing
`
`Liquid or sernisolid
`drug reservoir
`
`
`
`
`Rate-controtling
`
`membrane
`
`
` ReleaselinerSo Faceadhesive
`
`Figure 1 Reservoir transdermal system with face adhesive.
`
`0007
`
`
`
`DOT Matrix” Technology
`
`407
`
`a pressure sensitive adhesive (PSA) whichis, in turn, in contact with the
`disposable release liner.
`This type of TDDStypically 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 anchorthe rate controlling membrane to
`the occlusive backing, a perimeter is present in the system thatis 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 matrix systems: Solid matrix systems (Fig. 2) are no longer avail-
`able in the U.S. market but are worth mentioning dueto 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.
`in the evolu-
`Solid matrix systems, although an advancement
`tionary process in that they yielded reproducible dosing, encountered
`many problemssince 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 doorfor use
`of acrylic PSAs and hence they played a significant role in the evolu-
`tionary process.
`
`impermeable backing
`
`
`
`
` Perimeter adhesive Releaseliner Solid matrix
`
`Figure 2. Solid matrix transdermal system with perimeter adhesive,
`
`0008
`
`
`
`408
`
`Mantelle
`
`4. 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
`affinity for the drug and fluid vehicles in these solid matrices. Upon
`storage, almostall, 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.
`DIAsconstituted 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 machineslike
`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).
`5. DOT Matrix (Fig. 4): The latest evolutionary step in TDDS wasthe
`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
`
` 4
`
`Drug laden
`
`adhesive layer
`
`Releaseliner
`
`Figure 3. Drug-in-adhesive transdermal system.
`
`0009
`
`
`
`409
`
`DOT Matrix” Technology
`
`
`
`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 camethe recognition that rubber based PSAs
`have verylittle, if any, affinity for the drugs or vehicles and are essentially
`nonreactive. From the DIA systems camethe 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 PSAis uti-
`lized primarily for proper skin adhesion whereasthe acrylic’s PSA properties
`are allowed to be compromisedin order to achieve maximum drug and vehi-
`cle loading. The resulting product ts one with a delivery optimized thermo-
`dynamics matrix system, which, by design, delivers greater amounts of drug
`per unit area without the need forirritating chemical enhancers and provides
`the comfort and adhesion properties which today’s consumers demand.
`
`DEVELOPMENT OF TDDS SYSTEMS
`
`intellectual Property Considerations
`
`Intellectual property (IP) in the area of TDDShasseen 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 showsthat as recently as 1980 there was only one patent in
`
`0010
`
`
`
`20,000
`
`15,000
`
`10,000
`
`410
`
`25,000
`
`Mantelle
`
`21,618
`
`5,000
`
`1980
`
`1985
`
`1990
`
`1995
`
`2000
`
`2003
`
`2006
`
`Figure 5 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 planningto enter the field of the TDDSthere 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 ofthe strategies being utilized now include:
`
`Nw
`
`1.
`
`“Picture” claims:
`a.
`narrow composition windows,
`b.
`new methods of manufacturing.
`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 chemicalentities.
`
`0011
`
`
`
`DOT Matrix® Technology
`
`4il
`
`6. Novel polymeric systems/combinations:
`a.
`IP based on newly created PSA systemsor 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:
`
`ween
`
`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 approachis 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-B estradiol product in the
`market (Vivelle-Dot™) (Table 1) as well as the first ever TDDS todeliver
`methylphenidate (Daytrana™) at a rate of 80+ pg/cm?/hr (30mg from a
`37.5cm” patch over 9 hours) (Table 2). This delivery rate is achieved without
`the need forirritating chemical enhancers.
`Chemical enhancementconsists 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 TDDSthroughthe use of micro-needles,
`micro-protrusions, and other methods has been proposed for many years,
`but there are no commercial embodimentsto date. The IP field in this area is
`growing as fast as or faster than that of passive TDDSsince 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
`
`0012
`
`
`
`412
`
`Mantelle
`
`Table 1
`
`Based on Label Claim for 0.05 mg/day Dose
`
`Product
`
`Vivelle-Dot
`Vivelle
`Climara®
`Estraderm
`Mylan®
`Alora
`Esclim
`
`Patch size
`
`5.0 cm?
`14.5 cm?
`12.5 cm?
`18.0 cm*#
`23.7 cm”
`18.0 cm?
`22.0 cm?
`
`"Active area is cm’.
`Active area is 15.5cm?.
`“7-day patch; others are 3.5-day.
`
`Estradiol
`content
`
`%
`depletion
`
`0.8mg
`43mg
`3.9mg
`4.0mg
`1.9mg
`1.5mg
`10.0mg
`
`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 frequencyto create pores in the
`stratum corneum and hence reduce the barrier to hydrophilic drugs.
`
`Table 2
`
`Properties of Commercialized Transdermals
`
`Drug
`
`Molecular
`weight
`
`Daily TD
`dose
`
`Smallest
`patch
`size
`(cm?)
`
`In-vivo
`permeation
`rate (g/cm7/
`hr)
`
`5.5
`2.5
`0.33 mg/day
`303.35
`Scopolumine
`1.
`
`2.~—-Nitroglycerin 227.09 1.6 mg/16 hr 5.0 20.0
`
`
`
`
`3.
`Clonidine
`230.10
`0.1 mg/day
`a3
`1.19
`
`4.—_Estradiol 272.38 0.1 mg/day 10.0 42
`
`
`
`5.
`NETA
`340.45
`0.14 mg/day
`9.0
`0.65
`6.
`Ethiny! Estradiol
`296.40
`0.02 mg/day
`20.0
`0.042
`7.
`Norelgestromin
`327.47
`0.15 mg/day
`20.0
`0.31
`8.
`Nicotine
`162.23
`7.0 mg/day
`7.0
`42.0
`9.
`Testosterone
`288.42
`2.5 mg/day
`7.5
`14.0
`
`Fentanyl
`10.
`Lidocaine
`Il.
`12. Oxybutynin
`13. Methylphenidate
`14.
`Selegiline
`15.
`Buprenorphine
`
`336.50
`234.34
`357.49
`233.31
`187,28
`467.64
`
`0.6 mg/day
`21.33 mg/l2 hr
`3.9 mg/day
`12.0 mg/12 hr
`6.0 mg/day
`0.12 mg/day
`
`10.8
`=——:140.0
`39.0
`12.5
`20
`6.25
`
`2.5
`12.0
`4.16
`80.0
`12.5
`0.8
`
`0013
`
`
`
`DOT Matrix® Technology
`
`413
`
`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, 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
`powersource, costs, and the practicality of the systems for daily use. Once
`again, the hope is that these systems can be used to achieve therapeuticlevels
`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 somegeneral criteria
`which can help in the decision-making process whenselection of a passive
`system is required.
`
`1. Reservoir systems:
`a.
`volatile API—room temperature processing.
`b.
`expensive API—higheryields.
`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
`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
`smal] 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.
`
`b.
`
`b.
`
`c.
`
`.
`e.
`
`0014
`
`
`
`414
`
`Manitelle
`
`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 whilestill 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 weartime, respectively.
`
`Efficiency
`
`The binary adhesive system used in the DOT Matrix systems provides the
`formulator the ability to saturate the acrylic PSA without concern forits
`loss of PSA properties. As Table |
`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 manyfirsts, namely:
`|.
`the first two drug transdermal systems (CombiPatch®, Estalis®);
`2.
`the first, and still only, 17-B Estradiol product to deliver 0.10 mg/day
`from a patchsize of 10 cm? (Vivelle-Dot™, the smallest estrogen patch
`on the market);
`the first and only TDDSto deliver more than 45 wg/cm?/hr of any drug
`(Daytrana™delivers upwards of 80 pg/cm?/hr of methylphenidate),
`
`3.
`
`CONCLUSION
`
`Passive transdermal drug delivery is poised to become a moreprevalent 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 expandedthis frontier
`and set the standard for passive transdermal drug delivery. The number of
`
`0015
`
`
`
`DOTMatrix” 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
`
`