Design of Controlled Release Drug Delivery Systems This page intentionally left blank Design of Controlled Release Drug Delivery Systems Xiaoling Li, Ph.D Bhaskara R Jasti, Ph.D Department of Pharmaceutics and Medicinal Chemistry Thomas J Long School of Pharmacy and Health Sciences University of the Pacific Stockton, California McGraw-Hill New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto Copyright © 2006 by The McGraw-Hill Companies, Inc All rights reserved Manufactured in the United States of America Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher 0-07-158883-3 The material in this eBook also appears in the print version of this title: 0-07-141759-1 All trademarks are trademarks of their respective owners 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This page intentionally left blank For more information about this title, click here Contents Contributors Preface xi ix Chapter Application of Pharmacokinetics and Pharmacodynamics in the Design of Controlled Delivery Systems James A Uchizono Chapter Physiological and Biochemical Barriers to Drug Delivery Amit Kokate, Venugopal P Marasanapalle, Bhaskara R Jasti, and Xiaoling Li 41 Chapter Prodrugs as Drug Delivery Systems Anant Shanbhag, Noymi Yam, and Bhaskara Jasti 75 Chapter Diffusion-Controlled Drug Delivery Systems Puchun Liu, Tzuchi “Rob” Ju, and Yihong Qiu 107 Chapter Dissolution Controlled Drug Delivery Systems Zeren Wang and Rama A Shmeis 139 Chapter Gastric Retentive Dosage Forms Amir H Shojaei and Bret Berner 173 Chapter Osmotic Controlled Drug Delivery Systems Sastry Srikond, Phanidhar Kotamraj, and Brian Barclay 203 Chapter Device Controlled Delivery of Powders Rudi Mueller-Walz 231 Chapter Biodegradable Polymeric Delivery Systems Harish Ravivarapu, Ravichandran Mahalingam, and Bhaskara R Jasti 271 Chapter 10 Carrier- and Vector-Mediated Delivery Systems for Biological Macromolecules Jae Hyung Park, Jin-Seok Kim, and Ick Chan Kwon 305 vii viii Contents Chapter 11 Physical Targeting Approaches to Drug Delivery Xin Guo 339 Chapter 12 Ligand-Based Targeting Approaches to Drug Delivery Andrea Wamsley 375 Chapter 13 Programmable Drug Delivery Systems Shiladitya Bhattacharya, Appala Raju Sagi, Manjusha Gutta, Rajasekhar Chiruvella, and Ramesh R Boinpally Index 429 405 Contributors Engineering Fellow, ALZA Corporation, a Johnson & Johnson Company, Mountain View, Calif (CHAP 7) Brian Barclay, PE (MSChE) Bret Berner, Ph.D Vice President, Depomed, Inc., Menlo Park, Calif (CHAP 6) Ph.D Candidate, Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (CHAP 13) Shiladitya Bhattacharya, M Pharm Ramesh R Boinpally, Ph.D Research Investigator, OSI Pharmaceuticals, Boulder, Colo (CHAP 13) College of Pharmaceutical Sciences, Kakatiya University, Warangal, India (CHAP 13) Rajasekhar Chiruvella, M Pharm Xin Guo, Ph.D Assistant Professor, Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (CHAP 11) Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (CHAP 13) Manjusha Gutta, M.S Associate Professor, Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (EDITOR, CHAPS 2, 3, 9) Bhaskara R Jasti, Ph.D Tzuchi “Rob” Ju, Ph.D Group Leader, Abbott Laboratories, North Chicago, Ill (CHAP 4) Jin-Seok Kim, Ph.D Associate Professor, College of Pharmacy, Sookmyung Women’s University, Seoul, South Korea (CHAP 10) Ph.D Candidate, Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (CHAP 2) Amit Kokate, M.S Phanidhar Kotamraj, M Pharm Ph.D Candidate, Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif (CHAP 7) Principal Research Scientist, Biomedical Research Center, Korea Institute of Science and Technology, Seoul, South Korea (CHAP 10) Ick Chan Kwon, Ph.D ix Copyright © 2006 by The McGraw-Hill Companies, Inc Click here for terms of use Programmable Drug Delivery Systems Patient Analyzer pump module 423 Glucose analyzer Process controller Glucose Insulin Infusion pump module Saline Buffer Figure 13.4 Block diagram of Biostator operation through attractive and repulsive forces and hydrogen bonding to yield different phases The interchange between these phases is marked by abrupt swelling or shrinking of the matrix Thus these polymers can respond to changes in environmental pH and act accordingly with desired release characteristics.33 Alterations in pH also can be responsible for the increase in solubility of loaded active agents Glucose oxidase immobilized on sepharose beads were incorporated into ethyl vinyl acetate matrices along with insulin in the solid form Glucose from blood enters these matrices, gets oxidized to glucuronic acid, and the decrease in pH increases the solubility of insulin, which diffuses out The insulin in this case was modified by the addition of three extra lysine residues that ensured an isoelectric point of pH 7.4 for the molecule.33 In a similar design, the decrease in pH was linked to polymer degradation, which causes release of the drug Insulin was immobilized in a pH-sensitive bioerodible polymer made from ethylidene-2,4,8,10-tetraoxaspirol(5,5)undecane and N-methyldiethanolamine, which was further coated with a hydrogel containing immobilized glucose oxidase In this case, however, it was later observed that degradation of the polymer was not hydronium ion–specific but depended on the constitution of the buffering system.39 pH-dependent polymer relaxation also has been explored for pulsatile insulin delivery Hydrogels made of 2-hydroxyethylacrylate, 424 Chapter Thirteen N,N-dimethylaminoethyl methacrylate, and 4-trimethylsilyl styrene and loaded with insulin and glucose oxidase show swelling at low pH caused by the oxidation of glucose, thereby releasing insulin.33 Binding and competitive binding of marker molecules, present in the environment of the delivery system, act as feedback control to the release of drugs from the system A delivery system for naltrexone, a long-acting opioid antagonist, was designed to release the drug from a matrix system triggered by the presence of morphine in the blood The drug is dispersed in a bioerodible polymer matrix coated with a lipid layer that prevents water entry into the matrix, thereby preventing drug release The delivery system is placed in a dialysis bag which also contains a lipase conjugated to morphine-antimorphine complex The enzyme is reversibly activated by the presence of free morphine in the dialysis bag as the antibody competitively binds to the free morphine and releases the active enzyme The active enzyme degrades the lipid layer, thereby “turning on” naltrexone delivery.33 Insulin can be derivatized by glycosylation, and the glycosylated product is bound to concavalin A and coated with hydrophilic nylon to form microcapsules When free glucose levels in the blood increases, free glucose displaces glycosylated insulin from the concavalin complex The release rate depends on the polymer coatings or the matrix materials and the relative affinity of the glycosylation units on insulin toward concavalin A compared with glucose.41, 42 In temperature-sensing systems, phase changes owing to changes in temperature cause polymers such as N-isopropylpolyacrylamide to swell and shrink, restricting or releasing the entrapped components.43–46 Biodegradable hydrogels cross-linked with hyaluronic acid serve as inflammation-sensing systems At sites of inflammation leukocytes and macrophages produce hydroxyl radicals, which specifically break down the hyaluronic acid cross-linking, thus aiding in drug release at the site of inflammation.47, 48 13.4 Current Systems and Future Potential Biomicroelectronic and microfabricated systems are actively targeted by many investigators and companies, as evident by efforts from MicroCHIPS to commercialize an electronically activated drug delivery microchip, ChipRx, to introduce systems that integrate silicon and electroactive polymer technologies for controlled delivery and iMEDD to develop nanoporous membranes and micromachined particles for a variety of drug delivery applications An implantable biosensor, which is in the early stages of development and is being developed by ChipRX, can be used in on-demand therapy The system is the size of a matchstick Programmable Drug Delivery Systems 425 Products that are currently under development for commercialization are external and implantable microchips for the delivery of proteins, hormones, pain medications, and other pharmaceutical compounds Microchips can be developed as a “pharmacy on a chip” because different drugs can be placed in different reservoirs of the same microchip, and the release could be achieved by applying the electrical potential to a specific reservoir Two major impediments to successful commercialization of bio-MEMS devices have been evaluation of these systems and their packaging It is estimated that packaging constitutes of up to 80 percent of the device final cost Packaging is a particularly challenging task if the device is to be implanted, where hermeticity and biocompatibility are of paramount importance Careful considerations in the design and engineering of the systems at several different levels (material, device, system, testing, and packaging) are critical to the success of the final product It is reasonable to recognize that bio-MEMS are a promising field in drug delivery research However, it encompasses a tremendously enabling array of techniques that provide new approaches for solving outstanding problems in drug delivery Some of the current programmable drug delivery systems that employ polymer-based programmable release include Covera-HS, Verelan PM, Cardizem LA, Innopran XL, Uniphyl, and naproxen sodium extended release formulation from Andrx Pharmaceuticals Covera-HS releases verapamil to hours after ingestion This lag time is introduced and controlled by a soluble membrane coating between the drug core and the outer semipermeable membrane Water from the gastrointestinal tract enters the tablet, dissolves the soluble coating causing the osmotic layer to expand, which pushes the drug layer, releasing the drug through a precision laser-drilled orifice in the outer membrane at a constant rate The biologically inert components of the delivery system remain intact during GI transit and are eliminated in the feces as an insoluble shell The sodium naproxen extended release formulation from Andrx Pharmaceuticals contains a portion of the drug for initial burst release and another portion in the form of a sustained release matrix Plasma levels of the drug are detected within 30 minutes of dosing, with peak plasma levels occurring at about hours after dosing The major drawbacks in current polymer-based programmable drug delivery systems arise from biological variations among individuals, and hence these systems may exhibit variations in in vitro models Food effects in the gastrointestinal tract often lead to altered release patterns and result in a deviation from predicted plasma drug concentrations The implantable systems may suffer from biofouling, i.e., growth of cells and tissues over the surface of the implant This often hampers their release kinetics and performance Some closed-loop systems have been 426 Chapter Thirteen successfully applied and the sensors give predictable results when incorporated in ex-vivo systems (e.g., Biostator) 13.5 Conclusions To conclude, it is time for all pharmaceutical technologists to reevaluate the potential of programmable systems for drug delivery, which are still in the developmental stage The key considerations in the design of these systems are their biocompatibility and the toxicity of the polymerbased devices, response time and sensitivity to the stimulus and markers, the ability to maintain desired levels of the drugs, and the routine formulation issues regarding dosage design, sterility, shelf life, and reproducibility The immense pharmacological benefit from these systems should make this an important and rewarding area for future research References Reinberg, A., and Smolensky, M H Circadian changes of drug disposition in man Clin Pharmacokinet 7:401–420, 1982 Petit, E., Milano, G., Levi, F., et al Circadian rhythm-varying plasma concentration of 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system (TES): I Concept and design J Drug Target 2:35–44, 1994 29 Thiel, W J., Barr, I., and Kleinig, M In vitro and in vivo testing of a single dose vaccination system Int Symp Control Rel Bioact Mater., 1994 30 Cardamone, M., Lofthouse, S A., Lucas, J C., et al In vitro testing of a pulsatile delivery system and its in vivo application for immunisation against tetanus toxoid J Contr Rel 47:205–219, 1997 31 Iskakov, R M., Kikuchi, A., and Okano, T Time-programmed pulsatile release of dextran from calcium-alginate gel beads coated with carboxy-n-propylacrylamide copolymers J Contr Rel 80:57–68, 2002 32 Sharma, V K Process for the pulsatile delivery of diltiazem HCL and product produced thereby, U.S Patent 5,914,134, 1999 33 Wise, D L Handbook of Pharmaceutical Controlled Release Technology New York: Marcel Dekker, 2000, pp 65–89 34 Clemens, A H., Chang, P H., and Myers, R W The development of Biostator, a glucose controlled insulin infusion system (GCIIS) Horm Metab Res 7:23–33, 1977 35 Fogt, E J., Dodd, L M., Jenning, E M., and Clemens, A H Development and evaluation of a glucose analyzer for a glucose controlled insulin infusion system (Biostator) Clin Chem 24:1366–1372, 1978 36 Lysy, Y., Globus, M., and Chowers, I Control of hypoglycemia by the Biostator Isr J Med Sci 20:727–728, 1984 37 Blanco, E E., and Samadani, R Automatic blood monitoring for medication delivery method and apparatus, U.S Patent 5109850, 1992 38 Palti, Y Implantable drug delivery pump, U.S Patent 5,474,552 39 Ng, S Y., and Heller, J Block copolymers based on poly(ortho esters) containing amine groups, U.S Patent 6667371, 2003 40 Kitano, S., Koyama, Y., Kataoka, K., et al A novel drug delivery system utilizing a glucose responsive polymer complex between poly (vinyl alcohol) and poly(N-vinyl-2pyrrolidone) with a phenylboronic acid moiety J Contr Rel 19:161–170, 1992 428 Chapter Thirteen 41 Shiino, D., Murata, Y., Kubo, A., et al Amine containing phenylboronic acid gel for glucose-responsive insulin release under physiological pH J Contr Rel 37:269–276, 1995 42 Sung Wan Kim, Chaul Min Paii, Kimiko Makino, et al Self-regulated glycosylated insulin delivery J Contr Rel 11:193–201, 1990 43 Liu, X.-M., Wang, L S., Wang, L., et al The effect of salt and pH on the phasetransition behaviors of temperature-sensitive copolymers based on N-isopropylacrylamide Biomaterials 25:5659–5666, 2004 44 Motonaga, T., and Shibayama, M Studies on pH and temperature dependence of the dynamics and heterogeneities in poly(N-isopropylacrylamide-co-sodium acrylate) gels Polymer 42:8925–8934, 2001 45 Mi, K Y., Yong, K S., Young, M L., and Chong, S C Effect of polymer complex formation on the cloud-point of poly(N-isopropylacrylamide) (PNIPAAm) in the poly(NIPAAm-co-acrylic acid): polyelectrolyte complex between poly(acrylic acid) and poly(l-lysine) Polymer 39:3703–3708, 1998 46 Akerman, S., Viinikka, P., Svarfvar, B., et al Drug permeation through a temperaturesensitive poly(N-isopropylacrylamide) grafted poly(vinylidene fluoride) membrane Int J Pharm 164:29–36, 1998 47 Nobuhiko Yui, Teruo Okano, and Yasuhisa Sakurai Inflammation responsive degradation of cross-linked hyaluronic acid gels J Contr Rel 22:105–116, 1992 48 Nobuhiko Yui, Jun Nihira, Teruo Okano, and Yasuhisa Sakurai Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid J Contr Rel 25:133–143, 1993 Index Absorption: cornea, 55, 56, 57 enhancers, 66, 67, 68, 308 GI, 42–52, 66, 164, 185, 307–312 nasal, 61, 63, 67, ocular, 57, 58, rate constant, skin, 52, 55, 61, 67, 128 Active targeting, 97, 349, 351, 375, 377, 392 Aerosols, 235, 236 Albumin, 56, 62, 258, 273, 296, 314, 383 Alginate, 161, 164, 165 Amino acids, 51, 60 Amorphous, 155, 169 Antibody, 377, 379, 380, 381, 384, 385, 386, 387, 391, 395, 397, 398, 424 Antibody-targeted chemotherapy, 385 Antigen, 379, 380, 384, 385, 387, 395 Area under the curve (AUC), 5, 30, 393 Artificial muscle valves, 410 Barriers, 30, 41–68, 340, 341, 343, 351, 367, 369 enzymatical, 42, 310–312 diffusional, 307–310 physiological, 30, 66 Bile salts, 316 Binders, 160, 161 Bioadhesives: applications, 193 polymers, 191 microparticles, 174 systems, 67, Bioavailability, 5, 20–21, 48, 50, 51, 52, 57, 58, 63, 67, 158, 164 Biodegradable polymers/systems: degradation, 287 design principles, 280 diffusion controlled, 280 drug loading, 281 erosion controlled, 286 future potential, 299 implants, 297 ionic interactions, 285 method of preparation, 291 microparticles, 293 molecular weight effects, 284, 288, 290 nanoparticles, 296 polymers, 273 porosity effects, 283 rationale, 272 size effects, 281 solvent effects, 291 systems, 272 Biofouling, 425 Bio-MEM, 425 Biomembrane, 340–343, 357, 364, 366 Biotin, 381 Blood brain barrier, 77, 297, 298, 367 Blood supply, 47, 61, 63, 65 Bowman’s membrane, 55 Brain, 16, 51, 297, 330 Buccal mucosa, 58, 59, 60, 61 Buffer solution, 159, 160 Cadherins, 380, 395 Capsules, 158, 179, 217, 218, 224, 245, Carbohydrate, 47, 98, 189, 377, 380, 383, 386, 387, 388, 389 Cardizem LA, 425 Cellular targeting, 375, 377 Chitosan, 66, 67, 328–329 429 Copyright © 2006 by The McGraw-Hill Companies, Inc Click here for terms of use 430 Index Choroid, 56, 57 ChipRX, 424 Chronopharmakokinetics, 406 Bupivacane, 407 cortisol, 406 fluorouracil, 407 ketoprofen, 407 ranitidine, 407 terbutaline, 407 vindesine, 407 Clearance: definition, at steady state, 30 Closed loop system, 408, 409, 410, 416, 420, 422, 425 biosensor feedback, 410 biostator, 421, 426 concavalin, 424 ethylidene-2,4,8,10tetraoxaspirol(5,5)undecane, 423 glucose controlled insulin infusion system, 421 glucose oxidase, 421, 423, 424 2-hydroxyethacrylate, 423 insulin, 421, 424 lipase, 424 morphine, 424 naltrexone, 424 N-isopropylpoly acrylamide, 424 N-methyldiethanolamine, 423 trigger mechanisms, 422 Coating agents, for tablets, 160 Coatings, 140, 143, 150, 157, 159, 160, 165 Colloidal, 159, 315, 365, 378, 379, 386, 387, 395 Complement system, 358 Compression coating, of tablets, 162 Concentration of drug: Cp,max, 4, 21, 27–29 in plasma (Cp), 1, 2, 5, 7, 13–15, 29–31 site of absorption, 13, 20 steady state, 19, 25–29 Conjectiva, 55, 56, 57, 58 Controlled-release products: coated systems, 140, 143, 144, 149, 150, 152, 155, 156, 157, 158, 159, 162, 163, 164, 167, 168 definition of, 205 oral, 168 (See also Modified-release products) Cornea, 56, 57, Corneal epithelium, 55, 57 Corneal endothelium, 55, 57 Covera HS, 425 Critical micelle concentration, 343, 353 Crystalline, 54, 55, 147, 155, 169 Degradation, 51, 57, 58, 61, 63, 64, 65, 66, 158 Device controlled delivery: programmable, 405–426 pulmonary, 231 Degradation controlled delivery systems, 286 Dendrimers, 96 Diffusion, 236, 237, 238 barrier, 57, 108, 120 concentration gradient, 141 diffusion coefficient, 141, 144, 145, 149, 152 diffusion controlled systems, 280 Fick’s laws of, 141, 144, 238 Fickian, 148, 154 flux, 141, 144 Hixson-Crowell cubic root law, 142, 149 lag time in, 164 Noyes-Whitney equation, 141 permeability, 156 sink condition, 150 Dissociation constants, 142 Dissolution, 142–156, 162–169 DNA, 318–330, 345, 347, 368 Dosage form(s): capsule, 158 controlled release, 152, 158, 324–327 gastrointestinal retentive, 173–195 tablet, 143, 144, 147, 157, 158,160, 161, 162, 163, 164, 165, 166, 168 Dose, 155, 158, 159, 166, 167, 168 Drug loading, 353, 359, 360, 366 Drug release, 342, 346, 354, 361, 362, 396 Dry-powder inhaler (DPI), 232–261, 242 active device, 243, 252, 265 multiple dose, 248–252 passive device, 242–243 single dose, 245–248 Dry-powder delivery, 235 Ehrlich, Paul, 376 Electrical responsive systems, 416 Electroporation, 67, 128, Elimination rate constant (K), Emulsions, 214, 294, 324 Index Endocytosis, 98, 307, 342, 381, 382, 383, 385, 390, 393, 394, 395, 396 Endosome, 324, 342, 345, 355, 357, 368, 395, 396 Enhanced permeation and retention effect (EPR effect), 96, 344, 350, 351, 356, 393 Enteric coated, 66, 143, 145, 152, 157, 159, 160, 179 Enzymatic degradation, 51 Enzymes, 49, 50, 51, 52, 53, 54, 55, 57, 63, 64, 66, 67 Epidermis, 52, 93, 261, 262, 264 Erodible polymer, 146, 225, 274, 423 Erosion: bulk erosion, 287 erosion controlled systems, 286 surface erosion, 287 Excipients, 143, 147, 152, 156, 158, 166, 297 Extended-release products: embedded in matrix systems, 146, 154 oral, 156 Extracellular matrix, 355, 366 Extravasation, 351, 367 Fatty acids, 47, 49, 53, 54, 93, 116, 175 Fenestrae, 343 Fick’s laws, 93, 109, 141, 144, 238 Fickian diffusion, 148, 154, 280 Film coatings, 157, 159, 160–164, 167 First-pass effect, 48, 50, 52, 58, 63, 65, 77, 94, 123 Floating dosage forms, 175, 185 Flux, 128, 141, 144 Folic acid, 351, 381, 382, 386, 389 Gastric emptying, 52, 66, 177, 178 Gastric retentive delivery system, 173–195 Gastrointestinal, 5, 42, absorption, 157, 159, 168 effect of food, 52 pH, 44, 48, 152, 157, 159 physiology, 48, 49, 50, 51 Gene delivery, 318 Gene therapy, 378, 390 Glass transition temperature (Tg), 258, 281 Glycoproteins, 45, 49, 62, 190, 309, 380, 382 Granules, 53, 60, 158, 159, 164 431 Half-life, 6, 25 (Fig 1.17) Hormone, 66, 124, 273, 382, 408 Hydrodynalically balanced system, 187 Hydrogen bonding, 47, 54, 55, 309 Hydrophilic polymeric matrix system, 140, 143, 147, 153, 166 Hydrophobic interaction, 309, 354, 357, 360, 368 Hydroxypropyl methylcellulose (HPMC), 160–165, 167, 169 phthalate, 159 iMEDD, 424 Immediate release dosage forms, 143, 156, 158, 160, 164, 168, 169 Immunogenicity, 375, 383, 392, 397, 398 Impaction, 235, 236, 237 Implants, 131, 132, 227, 411 biodegradable, 132, 297, Inhaler: metered-dose, 232 dry powders, 232 Innopran XL, 425 Insulin, 408 Integrins, 380, 381, 389, 395 Intermolecular bonds, 54 Intraocular, 57 Intravenous, 341, 342, 345, 356, 360, 363, 366, 367 bolus injection, 5, 8, 26, infusion, 12, 32, 123, 155, 205, 406 Intravaginal, 131, In vivo, 150, 156, 164, 181, 319, 324, 343, 392 Ionic strength, 120, 122, 160, 281, 323 Ionization: constants, 145, 152 of weak acids, 142 of weak bases, 142 Iontophoresis, 67 Iris, 55, 56 Keratinized, 43, 58, 61 Kinetics, 140, 143, 150, 166, 375, 392 drug release, 167, 194 Kupffer cell, 344, 345, 357 LADME, 4–7 Lens, 56, 68 Ligand, 308, 313, 320, 379 Ligand-based targeting, 375, 376, 378, 392, 393, 395, 396, 398 Link model, 432 Index Lipidic colloid, 356–366 Lipids, 46, 47, 53, 54, 55, 60, 62, 316–317 Liposomes, 67, 68, 356–366, 377, 380, 386, 387, 389, 390 cationic, 357, 365–366 cleavable lipids, 363, 369 conventional, 344, 357–358 gel phase, 362–363 lipoplex, 355, 365–366, 368 liquid crystalline, 362–363 long circulating, 358 melting temperature, 362 triggerable, 351, 361–365 Long-circulating, 296, 353, 356, 358, 368, 369 Low-density lipoprotein, 383, 390, 391 Lung, 63, 64, 65, 68, 232, 235, 241–242 deposition efficiency, 239 Macrophage, 54, 261, 344, 357, 363, 388, 395 Manufacture, 115, 157, 166, 273, 298 Mathematical models, 146 Matrix systems, 140, 143, 146–148, 152–154, 165–169 Membrane, 42, 45, 46, 47, 49–55, 59, 60, 62, 63, 106, 108, 112, 120, 127, 193, Membrane controlled drug delivery systems, 140, 143, 158 Membrane destabilization, 345, 346, 364, 369 Metered-dose inhaler, 232 Micelles, 377, 386 Microchips, 425 Micronized powders, 153 Microparticles, 377 biodegradable, 293 Micropump, 168 Microspheres, 158, 314, 328, 367, 417 Migrating motor complex (MMC), 176 Milling, 257 Minimum effective concentration (MEC), 1, 2, 9, 10, 25, 31, 32 Minimum toxic concentration (MTC), 1, 2, 9, 10, 25, 31, 32 Modified-release products: delayed-release, 140, 143, 152, 157, 159, 160 (See also Delayed-release products; Enteric coatings) drug release rate in, 140, 145, 149, 150, 152–154, 160, 163, 164, 166–168 extended-release, 156, 165 (See also Extended-release products) Modified-release products (Cont.): repeat action, 140, 151, 157 targeted release, 152 Molecular weight, 149, 151, 159, 160, 166, 167, 169 Mononuclear phagocyte system (MPS), 341, 344, 353, 357, 358, 363 Mucoadhesive, 160 Delivery systems, 173, 189 Mucociliary clearance, 62, 63 Mucus, 60, 62, 64, 65, 66, 189 turnover rate, 192 Mucosa, 42, 45, 46, 47, 49, 58, 61, 65, 132, 174, 193, 261, 262, 308 N-(2-hydroxypropyl) methacrylamide (HPMA), 385, 386, 388, 390, 397 Nanoparticles, 317, 377 biodegradable, 296 Nanosphere, 366–369 PLGA, 367, 368 Nasal delivery, 61, 62, 63, 90 Needle-free injection, 233, 234, 235, 261 Non-keratinized, 58, 60, 65 Open loop systems, 408,409, ADHD, 418 electrical responsive systems, 416 microchips, 409, 425 microfabricated systems, 409 microinjection, 410 micropumps, 409, 411 polymer based systems, 416–420 Opsonin, 341, 344 Oral administration route, 32, 189, 306, delayed-release products for, 152, 157, 159, 160 extended-release products for, 156, 165 Organ targeting, 375, 377 Osmosis, 206 Osmotic pressure, 203 Osmotic pump drug delivery system, 203 barrier layer formers, 215 classification of, 220 core ingradients, 219 delivery of liquid active agents, 217, 221 disintegrants, 219 elementary osmotic pump, 222 emulsifying agents, 214 flow promoting layer, 217, 219, 224, 225 flux regulating agents, 214 Higuchi-Leeper pump, 215–216 marketed products, 226 mechanical permeability, 208 Index Osmotic pump drug delivery system (Cont.): mechanism of release, 206 oral delivery systems, 222 osmotic components, 213 osmotic pressure, 203, 207–211 osmotic pump, 207 patient compliance, 205 plasticizer, 215 porous particle carriers, 218 Push-Pull pump, 222, 223 release kinetics, 207, 209, reflection coefficient, 208 rationale for design, 205 Rose-Nelson pump, 215 semipermeable membrane, 203, 212, 213–214 surfactants, 219 Van’t Hoff ’s equation, 203, 206 Paracelluar transport, 60, 307, 308, 317, Passive targeting, 375, 376, 377, 392, 393 Payload, 340–342, 349, 351, 353 PEGylation, 348, 349, Pellets, 158, 159, 164, 167 Penetration enhancer, 66, 67, 68, 127, Peptides, 49, 57, 63, 64, 67, 306, 377, 381, 386, 389, 395 Permeability, 47, 57, 58, 60, 61, 63, 64, 67, 156 pH, 44, 48, 57, 60, 62, 66, 152, 157, 159, 160, 161 pH-sensitive, 363–365 Phagocytosis, 395 Pharmacodynamics, 1–3, 8–11, 32–35 Pharmacokinetics, 1–39 convolution, 15 disposition, 13–15 compartmental, 8, 11–25 ideal characteristics for drug delivery, 29–32 input, 11–13 linear, 8, 11–25 liposomal delivery, 34 multiple-dose input, 25–29 noncompartmental, nonlinear, 8–9 polymeric drug delivery, 34 protein and peptide delivery, 33 single-dose input, 16–25 transdermal delivery, 34 Photodynamic therapy, 390 Physical targeting, 340–369 433 Pinocytosis, 351, 395 pKa (dissociation constant), 142, 143, 144 Poly (amino acid), 278, 386, 387, 388, 397 Polyamides, 383 Polyanhydrides, 279, 383 Polyesters, 274, 383 Polyethylene glycol (PEG), 152, 166, 316, 348, 358, 387, 389, 390, 397 Polylactones, 277 Polymer-drug conjugate, 346, 347, 349–351 Polymeric micelle, 340, 343, 347, 351–354 Polymer-protein conjugate, 342, 346, 347, 349 Polymerization, 160 Polymers, 377, 378, 383, 385, 387, 389, 390, 393, 395, 397 biodegradable (see Biodegradable polymers) copolymer, 347–353, 356, 367–369 natural, 160, 165, 328–329 nonerodible, 146 polyethylene, 152, 166 (See also individual polymers) Polyorthoesters, 279 Polyphosphazenes, 278 Polyplex, 346, 347, 355–356 Polysaccharides, 67, 97, 213, 273, 296, 306, 386, 387, alginate, 161, 164, 165 pectin, 67 Porosity, of powders, 143, 165 Powders, 231 micronized, 153 particle size of, 149, 150, 153, 154, 156, 165 Power injection, 261 Precorneal fluid drainage, 55, 57 Prodrugs, 51, 57, 58, 67, 68 ADEPT, 95 amides, 82 buccal delivery, 94 carrier, 99 definition, 76 dendrimers, 98 esters, 79 GDEPT, 95 LEAPT, 98 linker, 99 MDEPT, 96 nasal delivery, 90 ocular delivery, 91 oral delivery, 94 434 Index Prodrugs (Cont.): parenteral delivery, 92 salts, 84 soft drugs, 77 transdermal delivery, 93 VDEPT, 95 Programmable implantable medication system (PIMS), 411, 412, 421 command system, 411 electrophoretic pump, 414 implantable programmable infusion pump, 412 microminiature drug delivery device, 411 power system, 411 silicon micropumps, 413 telemetry system, 411 Protein, 24, 33, 46, 47, 260, 310, 383, 397 Proteins (delivery of proteins and peptides), 63, 64, 68 nasal, 63 pulmonary, 63, 64 Proteoglycan, 345, 355, 366, Pseudo steady state, 111, 153 Pulmonary delivery, 63–65, 232 optimal particle size, 239, 240 Pulsatile release, 12, 24, 30, 35, 140, 216, 409 Quasi-steady-state, 145 Radioimmunotherapeutics, 385 Receptors, 9, 61, 312, 379 Rectal administration route: advantages of, 48, 51, 52, 67 limitations, 47, 67 suppositories for, 67 Rectum: physiology of, 42, 43, 44, 47, 48, mechanism of absorption, 47–48 factors affecting absorption, 47, 48, 52, 67 Release kinetics: square root of time, 154, 167 zero order, 140, 153, 154 Renal clearance, 343 Reservoir system, 120, 127, 155, 205 Respiratory tract, 235, 240 alveolar, 240 bronchioles, 241 Retentive delivery systems, 173 expanding systems, 182 expanding hydrogels, 183 Retentive delivery systems (Cont.): gas-generating expanding membrane, 183, 184 expandable compressed systems, 184 floating, 185, 186 sinking dosage forms, 185, 186 Reticuloendothelial system (RES), 295, 296, 341, 383, 387 Reynolds number, 237 Riboflavin, 185, 381, 382 Sclera, 55, 56, 57, 132 Sedimentation, 177, 235, 236, 237 Selectins, 380, 387, 389, 395 Self-administration, 234 Skin, 52–55 permeability, 55 structure of epidermis, 52 Solubility: aqueous, 85, 88, 91, 99, 154–156, 161, 166–168 organic, 160 pH dependent, 160, 161, 163, 194, 255, 257, 292, 294, (See also Dissolution) Spray-drying, 3, 24, 25, 257, 259, 261 Steady-state, 141, 145, 153 Steric stabilization, 345, 359, 369 Stokes-Einstein equation, 238 Stokes law, 237 Stokes number, 236 Stroma, 55, 56, 57 Subcellular targeting, 375, 378 Sugar coatings, 157, 161 Supercritical fluids, 260 Suppositories, 4, 67 Sustained release, 88, 131, 160, 194, 258, 261, 272, 273, 358, 366–368, 410, 425 Tablets: binders for, 160, 161 coated particles in, 158, 162, 163, 168 coating agents for, 160 colorants for, 157 compression-coated, 162 core, in extended release, 158, 159, 161, 162, 165, 168 enteric-coated, 143, 144, 160 film-coated, 160, 161 fluid-bed coating of, 161–163 layered, 168 sugar-coated, 161 Index Targeted enzyme prodrug therapy, 375, 391, 392 Targeting drug delivery, 143, 273, 329, 339–369, 375–398 Tears, 55, 56, 57, 58 normal volume of, 56 Therapeutic window, 2, 25, 32, 146, 205, 235, 243, 253 Tight junctions, 30, 57, 60, 62, 64, 308, 312, 377 Thermosensitive, 346, 362 Tissue penetration, 367 Transcellular transport/absorption, 79, 309 Transferrin, 320, 382, 386, 390 Triggered release, 343, 346, 351, 361, 362, 365, 369 435 Vasculature, 56, 320, 343, 345, 350, 356 Viscosity, 49, 66, 132, 143, 149, 151, 152, 154, 160, 161, 164, 166, 167, 211, 236, 309 Vitamins, 47, 313, 314, 377, 381 Vitreous, 56, 57 Volume of distribution, 6, 23–25 Water, 46, 49, 52, 57, 60, 62, 119, 147, 151, 153, 160, 161, 189, 193, 204, 212, 215, 217, 221, 287, Water soluble polymers, 140, 143, 148, 152, 154, 159, 161, 166, 167–169 Weak acid, 142, 143, 145, 361 Weak base, 142, 361 Uniphyl, 425 Vaccines, 51, 263, 264, 278, 297, 314, 344 Vagina, 34, 65, 131, 306 factors affecting absorption, 65, 66 physiology of, 65, 66 Zero-order input, 10, 11, 12, 17, 18 Zero-order release, 13, 115, 120, 127, 140, 152, 153, 154, 165, 206, 291, 406 Zeta potential, 323, 330, 355, 366–368 This page intentionally left blank ABOUT THE EDITORS XIAOLING LI, PH.D., is a professor and chair of the Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California Professor Li received his Ph.D degree from the University of Utah and had his postdoctoral training at Ciba-Geigy (now Novartis) His research interest areas are design and synthesis of novel polymers for pharmaceutical and biomedical applications, targeted drug delivery, and transport of drugs across biological barriers He holds two patents, has published more than 30 papers, and had more than 70 presentations at national and international conferences He serves as a consultant for various pharmaceutical and biotechnology companies BHASKARA R JASTI, PH.D is an associate professor in the Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California Prior to joining the University of the Pacific, he worked as a staff scientist at Cygnus Therapeutics Systems and as an assistant professor at Wayne State University in the Departments of Pharmacy and Internal Medicine, where he also acted as an assistant director of pharmacology core His current research interests are identifying the barriers for drug delivery and the design of targeted and mucosal drug delivery systems Dr Jasti has published more than 30 papers and presented more than 60 papers at various national and international meetings Copyright © 2006 by The McGraw-Hill Companies, Inc Click here for terms of use .. .Design of Controlled Release Drug Delivery Systems This page intentionally left blank Design of Controlled Release Drug Delivery Systems Xiaoling Li, Ph.D Bhaskara R Jasti, Ph.D Department of. .. (1.54) 1.7 Applications of Pharmacokinetics in the Design of Controlled Release Delivery Systems 1.7.1 Design challenges for controlled release delivery systems Of the many design goals that need... to designing a successful controlled release delivery system While some controlled Achievement of a sufficient input flux of drug 30 Chapter One release delivery systems face even greater design