Controlled release for local delivery of drugs: barriers and models.

Controlled release systems are an effective means for local drug delivery. In local drug delivery, the major goal is to supply therapeutic levels of a drug agent at a physical site in the body for a prolonged period. A second goal is to reduce systemic toxicities, by avoiding the delivery of agents to non-target tissues remote from the site. Understanding the dynamics of drug transport in the vicinity of a local drug delivery device is helpful in achieving both of these goals. Here, we provide an overview of controlled release systems for local delivery and we review mathematical models of drug transport in tissue, which describe the local penetration of drugs into tissue and illustrate the factors - such as diffusion, convection, and elimination - that control drug dispersion and its ultimate fate. This review highlights the important role of controlled release science in development of reliable methods for local delivery, as well as the barriers to accomplishing effective delivery in the brain, blood vessels, mucosal epithelia, and the skin.

[1]  N. Nishimura,et al.  Real-Time Imaging of Perivascular Transport of Nanoparticles During Convection-Enhanced Delivery in the Rat Cortex , 2011, Annals of Biomedical Engineering.

[2]  Chelsea L. Ex-Lubeskie,et al.  Relationship between anisotropic diffusion properties and tissue morphology in porcine TMJ disc. , 2013, Osteoarthritis and cartilage.

[3]  R. Cone,et al.  Barrier properties of mucus. , 2009, Advanced drug delivery reviews.

[4]  Samir Mitragotri,et al.  Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[5]  Drug delivery: the heart of the matter. , 2008, Nature materials.

[6]  Russell O. Potts,et al.  Predicting Skin Permeability , 1992, Pharmaceutical Research.

[7]  N. Peppas,et al.  A simple equation for the description of solute release. III. Coupling of diffusion and relaxation , 1989 .

[8]  I. Fishbein,et al.  Biodegradable implant strategies for inhibition of restenosis , 1997 .

[9]  V. Place,et al.  Transdermal Delivery of Testosterone with TESTODERM™ to Provide a Normal Circadian Pattern of Testosterone , 1991, Annals of the New York Academy of Sciences.

[10]  J. Hilton,et al.  Polymeric controlled release of dexamethasone in normal rat brain , 1991 .

[11]  M F Armaly,et al.  The effect of pilocarpine Ocusert with different release rates on ocular pressure. , 1973, Investigative ophthalmology.

[12]  W. Mark Saltzman,et al.  Drugs released from polymers: diffusion and elimination in brain tissue , 1991 .

[13]  A. Verkman,et al.  Extracellular space volume measured by two-color pulsed dye infusion with microfiberoptic fluorescence photodetection. , 2009, Biophysical journal.

[14]  Robert Langer,et al.  Controlled release of macromolecules: Biological studies☆ , 1985 .

[15]  W. Saltzman,et al.  In vitro cytotoxicity and in vivo distribution after direct delivery of PEG-camptothecin conjugates to the rat brain. , 2004, Bioconjugate chemistry.

[16]  W. Saltzman,et al.  Convection-enhanced delivery of camptothecin-loaded polymer nanoparticles for treatment of intracranial tumors , 2011, Drug Delivery and Translational Research.

[17]  R. Levy,et al.  Controlled release of diphosphonate to inhibit bioprosthetic heart valve calcification: dose-response and mechanistic studies , 1986 .

[18]  T. Nagai Adhesive topical drug delivery system , 1985 .

[19]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[20]  Oliver Germershaus,et al.  Electrospun matrices for localized drug delivery: current technologies and selected biomedical applications. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[21]  John R Laird,et al.  Overview of New Technologies for Lower Extremity Revascularization , 2007, Circulation.

[22]  Yiyun Huang,et al.  Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma , 2013, Proceedings of the National Academy of Sciences.

[23]  L. Kalachev,et al.  Numerical Simulation of Local Pharmacokinetics of a Drug after Intravascular Delivery with an Eluting Stent , 2002, Journal of drug targeting.

[24]  A. Lethaby,et al.  Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. , 2015, The Cochrane database of systematic reviews.

[25]  Fung,et al.  Polymeric implants for cancer chemotherapy. , 1997, Advanced drug delivery reviews.

[26]  W. Mark Saltzman,et al.  Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA , 2009, Nature materials.

[27]  W. Saltzman,et al.  An electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness wounds. , 2013, Biomaterials.

[28]  A Deutch,et al.  Controlled release of dopamine from a polymeric brain implant: In vivo characterization , 1989, Annals of neurology.

[29]  Paul R. Carney,et al.  Voxelized Computational Model for Convection-Enhanced Delivery in the Rat Ventral Hippocampus: Comparison with In Vivo MR Experimental Studies , 2012, Annals of Biomedical Engineering.

[30]  J. Forrester,et al.  Kinetics of drug delivery to the arterial wall via polyurethane-coated removable nitinol stent: comparative study of two drugs. , 1995, Catheterization and cardiovascular diagnosis.

[31]  N. Peppas,et al.  A theory of molecular diffusion in the intestinal mucus , 1984 .

[32]  Isam Faik,et al.  Effects of diffusion coefficients and struts apposition using numerical simulations for drug eluting coronary stents. , 2007, Journal of biomechanical engineering.

[33]  W. Saltzman,et al.  Topical antibody delivery systems produce sustained levels in mucosal tissue and blood , 1998, Nature Biotechnology.

[34]  P F Morrison,et al.  Convection-enhanced delivery of macromolecules in the brain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  C. Nicholson,et al.  Extracellular space structure revealed by diffusion analysis , 1998, Trends in Neurosciences.

[36]  H. Quigley,et al.  Pilocarpine ocuserts. Long-term clinical trials and selected pharmacodynamics. , 1975, Archives of ophthalmology.

[37]  N. Peppas,et al.  Present and future applications of biomaterials in controlled drug delivery systems. , 1981, Biomaterials.

[38]  W. Olbricht,et al.  Fabrication and characterization of microfluidic probes for convection enhanced drug delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[39]  C. Nicholson Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum. , 1995, Biophysical journal.

[40]  N. Sjöberg,et al.  Clinical experience with the uterine progesterone system (Progestasert R). , 1976, Contraception.

[41]  Ann-Christine Albertsson,et al.  Recent developments in ring opening polymerization of lactones for biomedical applications. , 2003, Biomacromolecules.

[42]  F. Slack,et al.  Prevention of K-Ras- and Pten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles , 2011, Drug Delivery and Translational Research.

[43]  Benjamin C. Tang,et al.  Mucus-Penetrating Nanoparticles for Vaginal Drug Delivery Protect Against Herpes Simplex Virus , 2012, Science Translational Medicine.

[44]  Michael S. Roberts,et al.  Modeling the human skin barrier--towards a better understanding of dermal absorption. , 2013, Advanced drug delivery reviews.

[45]  Prasanta Chowdhury,et al.  Kinetic modeling on drug release from controlled drug delivery systems. , 2010, Acta poloniae pharmaceutica.

[46]  Yen Cu,et al.  Mathematical modeling of molecular diffusion through mucus. , 2009, Advanced drug delivery reviews.

[47]  D. Kamei,et al.  Modeling Mass Transfer from Carmustine-Loaded Polymeric Implants for Malignant Gliomas , 2014, Journal of laboratory automation.

[48]  E. Edelman,et al.  Mechanisms of transmural heparin transport in the rat abdominal aorta after local vascular delivery. , 1995, Circulation research.

[49]  E. R. Cooper,et al.  Diffusion apparatus for skin penetration , 1984 .

[50]  G. Grassi,et al.  Mathematical modeling of simultaneous drug release and in vivo absorption. , 2011, International journal of pharmaceutics.

[51]  W. Mark Saltzman,et al.  Distribution of nerve growth factor following direct delivery to brain interstitium , 1995, Brain Research.

[52]  C. Beaulieu,et al.  The basis of anisotropic water diffusion in the nervous system – a technical review , 2002, NMR in biomedicine.

[53]  A. Biglan,et al.  Transdermal Nicotine for Smoking Cessation: Six-Month Results From Two Multicenter Controlled Clinical Trials , 1991 .

[54]  W. Mark Saltzman,et al.  Drug Delivery: Engineering Principles for Drug Therapy , 2001 .

[55]  B. Møllgaard,et al.  Dermal drug delivery — Improvement by choice of vehicle or drug derivative☆ , 1985 .

[56]  M E McCauley,et al.  Effect of transdermally administered scopolamine in preventing motion sickness. , 1979, Aviation, space, and environmental medicine.

[57]  K. Whaley,et al.  Antigen-releasing polymer rings and microspheres stimulate mucosal immunity in the vagina. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[58]  R. Braatz,et al.  Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution , 2012, Computer methods in biomechanics and biomedical engineering.

[59]  E. Edelman,et al.  Computational simulations of local vascular heparin deposition and distribution. , 1996, The American journal of physiology.

[60]  W. Saltzman,et al.  Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[61]  W. Saltzman,et al.  Pharmacokinetics of the Carmustine Implant , 2002, Clinical pharmacokinetics.

[62]  A. Fisher,et al.  Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. , 2001, JAMA.

[63]  A. Ludwig,et al.  The use of mucoadhesive polymers in ocular drug delivery. , 2005, Advanced drug delivery reviews.

[64]  N. Johnson,et al.  Controlled delivery of heparin-binding EGF-like growth factor yields fast and comprehensive wound healing. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[65]  C. Beaulieu,et al.  Determinants of anisotropic water diffusion in nerves , 1994, Magnetic resonance in medicine.

[66]  Nikolaos A. Peppas,et al.  Solute and penetrant diffusion in swellable polymers. I. Mathematical modeling , 1986 .

[67]  Patrick W Serruys,et al.  Coronary-artery stents. , 2006, The New England journal of medicine.

[68]  J. Siepmann,et al.  Mathematical modeling of bioerodible, polymeric drug delivery systems. , 2001, Advanced drug delivery reviews.

[69]  Paolo Zunino,et al.  Multidimensional Pharmacokinetic Models Applied to the Design of Drug-Eluting Stents , 2004 .

[70]  S. Mitragotri,et al.  Current status and future potential of transdermal drug delivery , 2004, Nature Reviews Drug Discovery.

[71]  W. Saltzman,et al.  Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. , 1998, Cancer research.

[72]  E. Edelman,et al.  Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery , 2001, Circulation.

[73]  W. Saltzman,et al.  Parameter estimation methodology in a model of hydrophobic drug release from a polymer coating. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[74]  V. Odlind,et al.  Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. , 1994, Contraception.

[75]  J. Hershman,et al.  Biologic effects of transdermal estradiol. , 1986 .

[76]  Mu-Yi Hua,et al.  Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain , 2010, Proceedings of the National Academy of Sciences.

[77]  Samir Mitragotri,et al.  Mathematical models of skin permeability: an overview. , 2011, International journal of pharmaceutics.

[78]  F Joffre,et al.  Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. , 1987, The New England journal of medicine.

[79]  Nicholas A. Peppas,et al.  Solute and penetrant diffusion in swellable polymers. II. Verification of theoretical models , 1986 .

[80]  L. M. Sanders,et al.  Controlled delivery of an LHRH analogue from biodegradable injectable microspheres , 1985 .

[81]  W. Mark Saltzman,et al.  Controlled growth factor delivery induces differential neurite outgrowth in three-dimensional cell cultures , 1993 .

[82]  H. Merkle,et al.  Release kinetics of polymeric laminates for transdermal delivery: Experimental evaluation and physical modelling , 1985 .

[83]  W. Saltzman,et al.  Controlled delivery of antibodies against leukocyte adhesion molecules from polymer matrices , 1996 .

[84]  N. B. Graham,et al.  Vaginal pessaries from crystalline/rubbery hydrogels for the delivery of prostaglandin E2 , 1984 .

[85]  N. Peppas,et al.  Mechanisms of solute release from porous hydrophilic polymers , 1983 .

[86]  K. Shakesheff,et al.  Polymeric systems for controlled drug release. , 1999, Chemical reviews.

[87]  Yuri Dancik,et al.  Mathematical and pharmacokinetic modelling of epidermal and dermal transport processes. , 2013, Advanced drug delivery reviews.

[88]  L. Bahamondes,et al.  Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years. , 2002, Contraception.

[89]  C. Murphy,et al.  Reduction in Wound Bioburden using a Silver‐Loaded Dissolvable Microfilm Construct , 2014, Advanced healthcare materials.

[90]  Anders Axelsson,et al.  The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review. , 2011, International journal of pharmaceutics.

[91]  R. Langer,et al.  Formulation and Delivery of Proteins and Peptides. Design and Development Strategies. , 1995 .

[92]  A. Tzafriri,et al.  Strut Position, Blood Flow, and Drug Deposition: Implications for Single and Overlapping Drug-Eluting Stents , 2005, Circulation.

[93]  J. Heller Polymers for controlled parenteral delivery of peptides and proteins , 1993 .

[94]  Yen Cu,et al.  In vivo distribution of surface-modified PLGA nanoparticles following intravaginal delivery. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[95]  David S. Jones,et al.  Mucoadhesive polymeric platforms for controlled drug delivery. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[96]  P. Castle,et al.  Long-term vaginal antibody delivery: delivery systems and biodistribution. , 2000, Biotechnology and bioengineering.

[97]  Robert Langer,et al.  Transdermal drug delivery , 2008, Nature Biotechnology.

[98]  C. G. Pitt,et al.  The controlled parenteral delivery of polypeptides and proteins , 1990 .

[99]  W. Saltzman,et al.  Gene expression and mucosal immune responses after vaginal DNA immunization in mice using a controlled delivery matrix. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[100]  K. Lehmann,et al.  Transdermal fentanyl: clinical pharmacology. , 1992, Journal of pain and symptom management.

[101]  G Dubini,et al.  Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix , 2008, Computer methods in biomechanics and biomedical engineering.

[102]  L. Brannon-Peppas,et al.  Water diffusion and sorption in amorphous macromolecular systems and foods , 1994 .

[103]  V D Calhoun,et al.  A finite element model for predicting the distribution of drugs delivered intracranially to the brain. , 1997, American journal of physiology. Regulatory, integrative and comparative physiology.

[104]  R. Gurny,et al.  Ocular therapy with nanoparticulate systems for controlled drug delivery , 1985 .

[105]  Benjamin C. Tang,et al.  Vaginal Delivery of Paclitaxel via Nanoparticles with Non‐Mucoadhesive Surfaces Suppresses Cervical Tumor Growth , 2014, Advanced healthcare materials.

[106]  E. Edelman,et al.  Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[107]  J. Boateng,et al.  Wound healing dressings and drug delivery systems: a review. , 2008, Journal of pharmaceutical sciences.

[108]  W. Good Transder®-Nitro Controlled Delivery of Nitroglycerin via the Transdermal Route , 1983 .

[109]  A. Domb,et al.  Polymeric carriers for regional drug therapy. , 1995, Molecular medicine today.

[110]  Li Yan,et al.  Controlled release of epidermal growth factor from hydrogels accelerates wound healing in diabetic rats. , 2012, Journal of the American Podiatric Medical Association (Print).

[111]  W. Mark Saltzman,et al.  Chemotherapeutic Drugs Released from Polymers: Distribution of 1,3-bis(2-chloroethyl)-l-nitrosourea in the Rat Brain , 1996, Pharmaceutical Research.

[112]  A. Fleming,et al.  Conjugation to increase treatment volume during local therapy: a case study with PEGylated camptothecin. , 2007, Bioconjugate chemistry.

[113]  Giuseppe Pontrelli,et al.  Mathematical modelling of NABD release from endoluminal gel paved stent , 2009, Comput. Biol. Chem..

[114]  F Litvack,et al.  Localized Arterial Wall Drug Delivery From a Polymer‐Coated Removable Metallic Stent: Kinetics, Distribution, and Bioactivity of Forskolin , 1994, Circulation.

[115]  M. Leider Goodman & Gilman's The Pharmacological Basis of Therapeutics , 1985 .

[116]  R. Langer,et al.  Transport rates of proteins in porous materials with known microgeometry. , 1989, Biophysical journal.

[117]  W. Saltzman,et al.  Simultaneous delivery of an active protein and neutralizing antibody: creation of separated regions of biological activity. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[118]  W. Saltzman,et al.  Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants. , 1995, The Journal of pharmacology and experimental therapeutics.

[119]  C. Nicholson,et al.  Diffusion of albumins in rat cortical slices and relevance to volume transmission , 1996, Neuroscience.

[120]  Francesco Migliavacca,et al.  Drug release from coronary eluting stents: A multidomain approach. , 2010, Journal of biomechanics.