Controlled Release 50 years later:
`Responsive Intelligence and Delivery by Design
`
`Nicholas A Peppas
`Fletcher S. Pratt Chair in Engineering
`Laboratories for Biomaterials, Drug Delivery, Bionanotechnology and Molecular Recognition
`Departments of Chemical Engineering and Biomedical Engineering, and College of Pharmacy
`The University of Texas at Austin
`
`1
`
`
`Responsive Intelligence and Delivery by Design
`
`Nicholas A Peppas
`Fletcher S. Pratt Chair in Engineering
`Laboratories for Biomaterials, Drug Delivery, Bionanotechnology and Molecular Recognition
`Departments of Chemical Engineering and Biomedical Engineering, and College of Pharmacy
`The University of Texas at Austin
`
`1
`
`
`
`When I read the latest issues of (cid:16894)Science(cid:16895) or
`(cid:16894)Nature Biotechnology(cid:16895), (cid:16894)Nature Materials(cid:16895) or
`(cid:16894)Nature Drug Discovery(cid:16895)…
`
`I see the same statement repeated again and again
`
`(cid:16894)and this work will have important applications in
`drug delivery(cid:16895)
`
`I smile and I cannot but think of the very early days of the field when …
`drug delivery was not popular,
`pharmaceutical companies were not that interested in new (cid:16894)systems(cid:16895)…
`drug delivery projects did not attract NIH or NSF grants and …
`did not buy you tenure
`
`How much have we changed in the last 25 years….
`
`2
`
`
`
`The Early Days of (cid:16894)Controlled Release(cid:16895) (1960-85):
`Setting the Foundations, Mechanisms, (cid:16894)Devices(cid:16895)
`and Release Profiles
`
`Diffusion in Controlled Release Systems
`
`•
`
`•
`
`Controlled Release Systems Function Because a Bioactive
`Agent Diffuses Through a Polymer Carrier
`
`Drug (Peptide, Protein) Diffusion Through Polymer Carrier
`is the Main Mechanism of Controlled Release
`
`3
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Pioneers and Imaginative Solutions
`
`•
`
`• Over the past 65 years approaches have been developed for incorporation of
`drugs in solid polymers and slowing down their release
`Prof. Takeru Higuchi (Univ Wisconsin the Univ Kansas) presented a seminal
`contribution in 1961. Its classical equation became the standard of design of drug
`delivery systems in the 1960s to 1980s
`•T. Higuchi, J.Pharm.Sci., 50, 874-875 (1961)
`
`•
`
`In the next years, other pioneers followed such as Anthony Simonelli,
`Ted Roseman and Bill Higuchi
`
`4
`
`
`
`A Milestone in Drug Delivery:
`Takeru Higuchi 1961
`
`T. Higuchi, J.Pharm.Sci., 50, 874-875 (1961)
`
`Exact Solution of the Higuchi Problem
`
`5
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Pioneers and Imaginative Solutions
`
`• Other major contributions were made by engineers and medical doctors
`in the 1960s
`• Prof. Judah Folkman (Harvard Medical School) published a pioneering
`paper in 1964
`J. Folkman and D.M. Long, The use of silicone rubber as a carrier
`for prolonged drug therapy, J.Surg.Res., 4, 139-142 (1964)
`
`6
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Pioneers and Imaginative Solutions
`Enter ALZA in 1967!
`
`Rational Design of Drug Delivery Systems
`• Dr Alejandro Zaffaroni previously of Synthex
`started ALZA in 1967
`• He attracted the cream of the chemical and
`pharmaceutical field including
`Alan Michaels of MIT, Richard Baker, Kumar
`Chandrasekaran, Felix Theeuwes, Jorge Heller
`
`•
`
`Alejandro Zaffaroni
`
`Felix Theuwees
`
`Alan Michaels
`
`Kumar Chandrasekaran
`
`Pat Wong
`
`7
`
`
`
`The ALZA Consultants
`Rational Design of Drug Delivery Systems
`
`Alejandro Zaffaroni
`Exceptional Consultants, inspiring leaders and pioneers of the field
`
`Tak Higuchi
`
`Don Paul
`
`Judah Folkman
`
`Hal Hopfenberg
`
`Allan Hoffman
`
`8
`
`
`
`ALZA(cid:16891)s Contributions to Technology:
`Membrane and Osmotic
`Controlled Release Devices
`
`•
`
`•
`
`Such Devices Include Systems for:
`- Ocular Therapy
`-
`Contraception
`-
`Transdermal Applications
`- Other Uses
`A wonderful (cid:16894)lesson(cid:16895) in engineering applications!
`
`9
`
`
`
`Ocular Therapy
`Ocusert®
`
`(cid:131)
`
`(cid:131)
`
`(cid:131)
`
`Historical Reservoir
`System Made of
`Ethylene-Vinyl Acetate
`(EVAc) Copolymer
`
`It was Available in Two
`Different Loadings 20
`(cid:541)(cid:74)(cid:18)(cid:75)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:23)(cid:19)(cid:3)(cid:541)(cid:74)(cid:18)(cid:75)
`
`Active Agent:
`Pilocarpine
`
`10
`
`
`
`Contraception
`Progestasert®
`
`(cid:131) Historical
`Reservoir
`System Made
`of EVAc
`Copolymer
`
`(cid:131) Release Rate
`of 65 (cid:541)(cid:74)(cid:18)(cid:71)(cid:68)(cid:92)(cid:3)
`for a Year
`
`(cid:131)
`
`Active Agent:
`Progesterone
`
`11
`
`
`
`Transdermal Systems
`Delivery of Scopolamine, Nitroglycerine, etc.
`
`12
`
`
`
`The next Quest:
`Improved Release Profiles
`Chemical engineers, pharmaceutical scientists
`redefine the field
`
`Constant D1P
`•
`• One-Dimensional Diffusion
`•
`Constant Boundaries (No Swelling)
`
`13
`
`
`
`Drug Delivery Based on Simple Design Equations
`Becomes more Complex and More Exact
`
`•
`•
`•
`
`Constant D1P
`One-Dimensional Diffusion
`Constant Boundaries (No Swelling)
`
`Fujita Analysis
`(cid:62)
`(cid:62)
`Di (cid:32)(cid:32) Dio exp -(cid:69)2 co (cid:16) ci
`Ji (cid:32)(cid:32) (cid:16)Di 1+ (cid:119) ln (cid:74) i
`(cid:170)(cid:3)
`(cid:119) ln xi
`(cid:172)(cid:3)(cid:171)(cid:3)
`
`(cid:186)(cid:3)
`(cid:188)(cid:3)(cid:187)(cid:3)
`
`(cid:64)
`(cid:64)
`
`dci
`dz
`
`(Influence of Diluent
`Concentration, ci )
`
`14
`
`
`
`Models to Describe Drug Release from
`Controlled Release Systems
`
`Equations can be Used to Design New Systems by Selecting the Optimal
`Geometry, Method of Formulation, and Size.
`
`1. R.W. Baker and H.K. Lonsdale, in Controlled Release of Biologically
`Active Agents, A.C. Tanquarry and R.E. Lacey, eds., p.15, Plenum Press,
`New York, NY, 1974.
`2. P.I. Lee, J. Membr. Sci., 7, 255 (1980).
`3. N.A. Peppas, Chapter 7 in Controlled Drug Bioavailability, Vol. 1., Drug
`Product Design and Performance, V.F. Smolen and L.A. Ball, editors, p.
`274, Wiley, New York, 1984.
`4. N.A. Peppas, in Medical Applications of Controlled Release Technology,
`Vol. 2, R.S. Langer and D. Wise, editors, p. 169, CRC Press, Boca Raton,
`Florida, 1984.
`
`15
`
`
`
`DIFFUSION-CONTROLLED
`
`Matrix Systems
`Membrane Reservoirs
`
`CHEMICALLY-ACTIVATED
`
`Biodegradable Polymers
`Pendant Chain Chemistry
`
`CONTROLLED
`RELEASE
`
`SOLVENT-ACTIVATED
`
`Swellable Gels
`Osmotic Systems
`
`PULSATILE
`
`pH- or Temperature- Sensitive
`Electric or Ultrasonic
`Multi-Compartmental
`
`Mechanistic Classification of Drug Delivery Systems Introduced
`By R. S. Langer and N. A. Peppas in 1979
`
`16
`
`
`
`A Milestone in Drug Delivery 1980
`
`Ping I Lee (1948- )
`ChE from NTU, Taipei
`Industrial career at Ciba Giegy,
`Smith Kline
`Now Professor of Pharmacy at the
`University of Toronto
`
`17
`
`
`
`Designing Advanced Delivery Systems
`
`Harold Hopfenberg
`(1938- ) NCSU
`Fundamental contributions
`in swellable and biodegradable
`delivery systems
`
`18
`
`
`
`Notable Contributions of
`Robert Langer (MIT)
`
`Robert Langer of MIT and Nicholas
`Peppas of UT first set the
`principles for the development
`of successful pharmaceutical
`delivery systems in 1977
`and various biomaterials-based medical devices in the
`1980s to now.
`
`19
`
`
`
`Protein Delivery Systems
`
`Robert Langer of MIT developed the first class of protein delivery
`systems with contributions to new biomaterials, drug delivery systems,
`tissue engineering, stem cells, chemotherapy and bionanotechnology
`
`Bob Langer and Judah Folkman in 1974
`
`20
`
`
`
`Peptide Release From Porous Polymers
`
`Preparation of Ethylene-Vinyl Acetate (EVAc)
`Systems (Langer, 1976-83)
`Ron Siegel, Elezar Edelman, Mark Saltzman
`
`21
`
`
`
`Kinetics of Release for Bovine Serum Albumin (BSA)
`from EVAc Matrices at Various Drug Loadings and
`Particle Sizes. Abscissa is Square Root of Time.
`Ordinate is Cumulative Fraction of Incorporated BSA
`that is Released.
`Loading = 0.10, particle size range = 150-(cid:20)(cid:27)(cid:19)(cid:541)(cid:80)
`Loading = 0.10, particle size range = 300-(cid:20)(cid:21)(cid:24)(cid:541)(cid:80)
`Loading = 0.30, particle size range = 150-(cid:20)(cid:27)(cid:19)(cid:541)(cid:80)
`Loading = 0.30, particle size range = 300-(cid:20)(cid:21)(cid:24)(cid:541)(cid:80)
`Loading = 0.50, particle size range = 150-(cid:20)(cid:27)(cid:19)(cid:541)(cid:80)
`
`22
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Pioneers and Imaginative Solutions
`In Europe numerous pharmaceutical scientists were leading the field
`•
`• Prominent among them Francis Puisieux in Paris, Bob Davis of
`Nottingham, and Prof Peter Speiser in Zurich (numerous associates: J.
`Kreuter, R. Gurny, P. Couvreur)
`• Peter Speiser…
`• Father of pharmaceutical nanotechnology!
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`Reviews
`Regular articles
`•Nanoparticles: a New Colloidal Drg
`Delivery System
`•J.J. Marty, R.C. Oppenheim and P. Speiser
`•Pharm Acta Helv, 53, 17 (1978)
`
`•Nanoparticles and Nanocapsules:
`•New Dosage Forms in the Nanometer Size Range
`•J. Kreuter
`•Pharm Acta Helv, 53, 33 (1978)
`
`1978
`
`1982
`
`1986
`
`1990
`
`1994
`
`1998
`
`2002
`
`23
`
`
`
`Nanoparticles in Drug Delivery
`
`As drug carriers in nanomedicine
`
`Liposomes (Alec
`Bangham, UK 1961)
`Frank Szoka, G. Gregoriadis,
`D. Papahadjopoulos
`
`Lipid nanoemulsions
`
`Polymeric Nanospheres
`P Couvreur, R Muller, many others
`
`Polymeric Micelles &
`Decorated Structures
`Kazunori Kataoka many others
`
`Dendrimers
`Jean Frechet, Ruth Duncan
`Don Tomalia
`
`24
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Pioneers and Imaginative Solutions
`
`Japanese research advances the field
`•
`• Prof Hitoshi Sezaki, Hiroshi Maeda and Tsuneji Nagai
`Pioneers of the field
`• Earliest mucoadhesive delivery systems developed in Japan in 1970
`
`• A new generation followed with Kazunori Kataoka, Teruo Okano,
`Mitsuru Hashida, Yuichi Sugiyama and so many others
`• Emphasis on advanced drug dynamics and biological studies
`
`25
`
`
`
`Rational Design of Drug Delivery Systems
`N. A. Peppas and associates (1978-2000)
`
`26
`
`
`
`Rational Design of Drug Delivery Systems
`Brannon-Peppas, Peppas and associates
`
`27
`
`
`
`Heuristic (?) Design of Drug Delivery Systems
`R. Kosrmeyer, P. Ritger and N.A. Peppas
`
`28
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Some personal thoughts
`Early days of controlled release at Purdue
`
`• Development of the design standards of drug delivery systems
`Richard Korsmeyer (1979-1982), now VP of Pfizer
`
`29
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Some personal thoughts
`Early days of controlled release at Purdue
`
`• Development of the design standards of drug delivery systems
`
`30
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Some personal thoughts
`
`Bob Langer, Ping Lee, the speaker and a few other engineers came to the field in 1975
`•
`• My interaction with all pharmaceutical engineers, especially the European and Japanese
`pharmaceutical scientists has been scientifically rewarding
`Public thanks are due to my colleagues at the Universities of Paris-Sud, Lille, Lyon,
`Grenoble, Geneva, Parma, Pavia, Naples, Trieste, Ferrara, Computense (Madrid), Santiago
`de Compostela, Barcelona, Athens, Ljubliana, Marmara (Istanbul), Haceteppe (Ankara),
`Berlin (Free University), Nottingham and Hoshi (Tokyo)
`
`•
`
`31
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Some personal thoughts
`Work with the Universities of Pavia and Parma (1983-present)
`
`Work over the last 27 years with Aldo LaManna, Paolo Colombo, Ubaldo Conte,
`Carla Caramella, Ruggero Bettini
`
`32
`
`
`
`The Evolution of Controlled Drug Delivery Devices and Systems:
`Some personal thoughts
`Work with the University of Parma
`
`Lauretta Maggi
`
`Elena Losi
`
`Ruggero Bettini
`
`33
`
`
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