Contents

Preface Contributors

1. Controlled Release of Bioactive Agents from Lactide/ Glycolide Polymers Danny H. Lewis

2. Polyanhydrides as Drug Del ivery Systems Mark Chasin, Abraham Domb, Eyal Ron, Edith Mathiowitz, Kam Leong, Cato Laurencin, Henry Brem, Stuart Grossman, and Robert Langer

3. Poly-ε-Caprolactone and Its Copolymers Colin G. Pitt

4. Poly(ortho esters) Jorge Heller, Randall V. Sparer, and Gaylen M. Zentner

5. Polyphosphazenes as New Biomedical and Bioactive Materials Harry R. Allcock

6. Pseudopoly(amino acids) Joachim Kohn

iii vii

1

43

71

121

163

195

V

vi

7. Natural Polymers as D r u g Del ivery Systems Simon Bogdansky

8. Liposomes Vila K. Nassander, Gert Storm, Pierre A. M. Peeters, and Daan J. A. Crommelin

Index

Contents

231

261

339

Index

Abate, 90 Ace tonit rile, 205 n-Acetylhydroxyproline, 203 a-Acetylmethadol, 87 Aclarubicin, 21, 250 Actinomycin D , 297, 304 Adriamycin, 21-22, 233, 243-

250, 303 Alanine, 211 Albumin, 232, 240, 262, 282 Albuterol, 299 Alkaline phosphatase, 59, 61 Alkylcyanoacrylate, 262 Alzheimer's disease, 55 Ames mutagenicity, 110 Amino acid ester, 174-176 Aminolipids, 276 2-Aminopicoline, 179 Amino-4-picoline, 177 Amphotericin B , 285, 309 Ampicillin, 22 Anesthetics, 15 Angiogenesis, 55, 57 Antibacterial agents, 177 Antibiotics, 15, 22, 233

Antibody, 27 Anticancer agents, 15 Antigens, 25, 27-28, 307 Antimony trifluoride, 2 Ascorbic acid, 280 Aseptic processing, 12-13 Aspartic acid, 212 Aspergillus, 286 Atropine, 298 Autocatalytic degradation, 97 Autoradiography, 52-54

Baboons, 17 B C N U , 50, 53, 55, 59, 66 Benzocaine, 179 Benzyl penicillin, 298 Bethanechol, 55-56, 58 Biocompatibility, 65 Biodegradation, 14, 81, 85, 97 Biomedical membranes, 182 Biscarboxyphenoxy propane, 44 Bisphenol A , 223 Bleomycin, 239, 249-250, 300

339

340

Block copolymers , 84 B lood , 8 Bone , 239 Bovine growth hormone, 30, 60,

63 B r a i n , 53-55, 66 Breast c a n c e r , 245 p_-Bromoaniline, 65 Bruce l lo s i s , 287 Bu lk eros ion , 5, 97 B u t y l £-aminobenzoate , 179 Buty la ted h y d r o x y t o l u e n e , 280 B u t y l h y d r o x y a n i s o l e , 280 Y - B u t y r o l a c t o n e , 122

Cadmium acetate, 44 Ca lc i ton in , 25 C a n d i d a , 286 C a n d i d i a s i s , 285 C a p r o n o r , 71. 79, 94, 110-112 n - C a r boxy an h y d r i d e s , 196. 205 C a r b o x y f l u o r e s c e i n , 275, 277,

298, 303 p_-Carboxyphenoxyalkanoic a c i d ,

49 Carc inoma, 57 Carmust ine (see B C N U ) Car t i l age , 61, 239 Case in microspheres , 248 Catecholamine, 172-173 Catt le s y n c h r o n i z a t i o n , 14 C C N U , 21 Ce l lu lose , 232-233 Cellulose acetate b u t y r a t e , 84-

85 Cellulose propionate , 84 C e r v i c a l c a p , 238 Chemoembolism, 244-245 Chemoembolization, 21 C h i t i n , 233 Chloramphenico l , 22 Ch lor ine d iox ide , 24 C h l o r o f o r m , 64 Ch loroproca ine , 179 Chloropromazine , 90-91

Index

C h l o r o q u i n e , 297 Chola te , 269 Cho le s t ero l , 264-265, 277, 279-

280, 285, 288, 301, 310 Cholesterolhemisuccinate , 261 C h o n d r o g e n i c s t imulat ing p r o ­

te ins , 56, 61 C i s p l a t i n , 185, 290, 300 Cl in ica l t r ia l s , 17-18 Code ine , 87 Co l lagen , 232-234

dimensional s tab i l i ty , 234 mechanical s t r e n g t h , 234 t issue i r r i t a t i o n , 234

Complement, 282 Compress ion molding , 10, 50,

52, 63, 87, 208 C o n j u n c t i v i t i s , 233 Contact ang le s , 167-168, 183 Contact lenses , 184 Cont inuous- f low reactors , 172 Contracept ive hormones, 2 C o n t r a c e p t i v e s , 6, 9, 11, 28 C o p p e r , 63 C o r n e a , 55, 65 C o r n e a l sh i e lds , 236 Cor t i cos t ero ids , 242, 299, 308 C o r t i s o n e , 56 Cort i sone acetate, 54 Cromoglycate , 299 C r y o p r e s e r v a t i o n , 278 C r y o p r o t e c t a n t s , 277 C y a n o g e n bromide, 219 C y a n o g e n hal ide , 218 C y c l a z o c i n e , 18 C y c l o b e n z a p r i n e h y d r o c h l o r i d e ,

145, 149, 153, 155 Cyc lophosphamide , 285 Cytos ine arab inos ide , 90, 298,

300

Denta l , 2 Deoxycholate , 269, 285 Desami no tyros ine , 220 Devonorges t re l , 143

Index

Dexamethasone, 237 Dexon, 13 Dextran, 232-233 Dextran acetate, 7 Diabetes, 57, 60 Dibucaine, 24 Dicetylphosphate, 310 Dideoxykanamycin, 23 Differential scanning colorim-

etry (DSC) , 3 Diffusion, 17, 26, 88 Diffusion coefficients, 86 Diketene acetal, 122-123, 127 4-Dimethylaminopyridine, 45 Dimiristoy lphosphatidy (choline t

286 Dimiristoy lphosphatidylglycerol,

286 Dioleoylphosphatidic acid, 266 Diphenol, 218 l,6-Diphenyl-l,3,5-hexatriene,

276 Diphosgene, 45 Diquat, 12 Distearoylphosphatidylcholine,

288 Dopamine, 172-173, 177 Doxorubicin, 233, 243, 247,

250, 272, 290-294 DuPont, 2

Earth metal oxides, 44 Ehrlich ascites carcinoma, 244,

250 ELISA, 30 Endothal, 12 Endothelial cells, 65 Enzymatic degradation, 105 Enzymes, 56 Epinephrine, 172 Epirubicin, 244 Epoxyhydrodienes, 279 Erythrocytes, 301 Erythromycin, 235 Erythromycin estolate, 235

341

Estradiol, 238 Estradiol benzoate, 16 Estrogen, 14, 27 Estrus, 26 Ethinyl estradiol, 16, 87 Ethylene oxide, 13 Ethylene vinyl acetate, 65, 88 Ethyl oleate, 94 Extrusion, 87

Fabrication, 87 Fibers, 11, 87, 232 Fibrinogen, 282 Fibrinogen microspheres, 250 Fibroblasts, 103 Fibronectin, 282 Films, 232, 234 Fluidized bed coating, 8-9 5-Fluorouracil, 90, 238-239, 243,

249-250 Flurbiprofen, 237 Fluridone, 12, 90 Formulations, 45

compression molding, 10, 45, 50, 52, 63, 87, 208

"hot melt" microencapsulation, 46

injection molding, 10, 11, 45 microsphere preparation by

solvent removal, 46 Fracture, 2 FSH, 14 Fumaric acid, 49 Fur , 24

p-Galactosidase, 60, 62 Gamma irradiation, 13 Ganglioside, 282 Gelatin, 232, 240 Gelatin microspheres, 248-250 Gelfoam, 66 Gel permeation chromatography,

44, 151

342 Index

Gentamicin , 22, 234-235, 237, 246, 309

Giant cel ls , 103 Glass transi t ion temperature , 83 Glaucoma, 233, 235 Glioblastoma, 66 Glucose , 58 Glucose-6-phosphate d e h y d r o ­

genase. 172-173 G l u t a r i c d ia ldehyde , 172 Glutathione , 298 G n R H , 27 Good Manufac tur ing Pract i ces ,

12, 31 Growth hormone, 30 Growth promoter , 14

S - H C G , 28 H e p a r i n , 168-170 Hepatic c a n c e r , 245 Hepatocytes , 282 H e r b i c i d e s , 12, 88, 90 H e r n i o r r h a p h y , 2 1 ,6-Hexanediol , 126, 129, 144,

152-153, 155-156 Histamine, 300 H o r s e , 17 Humid i ty , 3 Hya luron ic a c i d , 232-233 H y d r i l l a , 90 H y d r o c o r t i s o n e , 24 Hydrocort i sone acetate, 24 H y d r o g e l s , 183, 187-188, 232-

233 H y d r o p e r o x i d e s , 279 u ) -Hydroxybutyr i c a c i d , 122 2 0 - H y d r o x y e c d y s o n e . 97 H y d r o x y p h o s p h a z e n e s , 175 H y d r o x y p r o l i n e , 202, 205, 208

Immunization, 27 Immunoglobulins, 282 Implants, 10

India i n k , 301 Indomethacin, 233 Inflammation, 65-66 Infrared s p e c t r o s c o p y , 63 Inherent v i s cos i ty , 13 Injection mold ing , 10-11, 50, 65,

151-152 Insect hormones, 24 Insecticide, 90 Insu l in , 29, 56-60, 242 Interferon , 30, 93 Intraepithelial cerv ica l d y s p l a s i a ,

238 Intraocular lenses , 184 Inul in , 232-233, 305

Juveni le hormone, 24

K i d n e y , 185 Kinet i c s , 47 Krebs c y c l e , 5

L a t e x , 301 L a u r y l a lcohol , 2 Leishmaniasis , 282 L e v o n o r g e s t r e l , 11, 16. 88. 94. 96

110-112, 142, 144, 146 Lewis l u n g carc inoma, 21 L H R H analog , 97, 100 ( D - T r p 6 , d e s - G l y 1 0 ] L H R H d i ­

ethylamide , 97 L H R H polypept ide , 14, 25-27 Lidoca ine , 24 Ligament recons truc t ion , 2 L i g h t - s c a t t e r i n g , 274 L i p o p r o t e i n s , 282, 288 L i s t er io s i s , 287 Local anesthet ics , 179 L y p r e s s i n , 25 L - l y s i n e , 196 L y s i n e , 211

Index

L y s o p h o s p h o l i p i d s , 272

Macrophages , 8, 103 Magnesium h y d r o x i d e , 140 Magnetic albumin microspheres ,

246-247 Magneti te , 246 Mammary adenocarcinoma, 247 M D P - B 3 0 , 29 Mechanical s t r e n g t h , 11 M e d i s o r b , 2 M e d r o x y p r o g e s t e r o n e , 234 Meglumine antimoniate, 284 Melatonin , 24-25 Melt rheometers , 11 M e l t - s p i n n i n g , 87 Meper id ine , 87 Meshes , 232 Metaproterenol , 299 L - M e t h a d o n e , 18-20, 87, 92-93 Methoprene , 24 Methotrexate , 290, 308 Methylene c h l o r i d e , 46-47, 50,

213 Methy lpredniso lone , 24 Microcapsu les , 6, 8-9 , 85, 87,

90, 92-93, 98-99 Microf lu id ized bed coa t ing , 19 M i c r o s p h e r e s , 6, 8-10, 16-17,

19-25, 28-29, 87, 91, 93, 232, 240-249

Milk, 28 Misonidazole , 22 Mitomycin C , 21, 243-245, 249 Molecular weight , 44-45, 47 M o n k e y s , 99 Monocytes , 8 Monoslalogangl ioside, 288 M o r p h i n e , 19, 97 Muramyl d ipept ide , 28-29 M u r a m y l t r i p e p t i d e , 313 Mutagen ic , 65 Mycobacter ium, 287

313

Nafarel in acetate, 26 Naloxone, 18 Nal trexone , 18-19, 87, 93-94,

97-99, 122 Nanopart ic les , 240 N a p r o x e n , 175 Narcotic antagonis ts , 2, 15, 18,

92 Narcot ics , 86 j j -Ni troacetani l ide , 135 E - N i t r o a n i l i n e , 49, 65, 207, 208 N i t ro furanto in , 91 Noregestimate, 16 Norep inephr ine , 172 N o r e t h i n d r o n e , 87. 141-142 Norethis terone , 6, 9-10, 14-18,

122 N o r g e s t r e l , 15, 87, 242

O c u l a r i n s e r t s , 232, 234-235 O p s o n i n s , 288 O x y t o c i n , 298

n - P a l i m t o y l h y d r o x y p r o l i n e , 206 Papa in , 240 Papaverine h y d r o c h l o r i d e , 233 P C P P r S A , 59 Pentaery thr i to l , 123, 128-129 Periodontal d isease , 14, 23 Permeabi l i ty , 86, 103 Perox idat ion , 279 Petroleum e t h e r , 46-47 Phagocytos i s . 102 Pharmacokinetic s tudies , 94 Phase separat ion , 8-9 , 22 Phat idy lchol ine , 264 L-Pheny la lan ine mustard (mel-

p h a l a n ) , 175 p_-Phenylenediamine, 65 Phosgene , 45 Phosphat idy lcho l ine , 261, 266,

270, 275, 277, 279

34U Index

Phosphatidylglycerol, 261, 279 Phosphatidyl inositol, 288 Phosphat idy lr ine , 261, 310 Phospholipids, 279, 310 Phthalic acid, 154 Phthalic anhydride, 133, 144-

145, 148, 153-155 Pilocarpine, 234-235, 237 n-Pivalohydroxyproline, 203 Plasma extenders, 187 Platinum antitumor agents, 185 Pluronic F68, 88 Poly(acryl) starch, 232 Poly (n-acylhydroxyproline

ester), 202, 204, 207, 209

Polylbis(methoxyethoxyeihoxy)-phosphazene) "MEEP", 184

Poly [ bis( methy lamino )phospha-zene], 186

Poly (bis-(£-methylphenoxy) -phosphazene], 169

Poly(bisphenol A carbonate), 213

Poly( bisphenol A iminocar-bonate), 213, 224

Poly [ bis (phenoxy) phosphazene 1, 170

Polycaprolactone, 12 Poly-c-Caprolactone:

anionic polymerization, 73 biodegradable packaging, 71 biodegradation, 81, 97 blends, 84 cationic polymerization, 75 coordination polymerization,

77 crystallinity, 81, 102-103, 105 glass transition temperature,

81 heat of fusion, 81 melting point, 81 monomer synthesis, 72 permeability, 86 physical properties, 84 radical polymerization, 80

[ Poly - c- Caprolactone ] solubility, 82 synthesis, 72 tensile strength, 84 toxicology, 110

Poly<carboxyphenoxy acetic acid), 51

PolyI(£-carboxyphenoxy) alkanel, 47

Poly(carboxyphenoxy) hexane, 62, 64

Poly(carboxyphenoxy) methane, 62, 64

Poly ( carboxyphenoxyoctanoic acid), 51

Poly(carboxyphenoxy) propane, 62

Poly (carboxyphenoxypropane-sebacic acid), 47, 54, 64-66

Poly(carboxyphenoxyvaleric acid), 51

Polycytidylic acid, 30 Poly(diphenoxyphosphazene),

169 Polyesters, 71 Polyester-urethanes, 84 Polyether ether ketone, 210-211 Polyglactin, 8 Poly (glutamic acid), 196 Poly(hydroxyethyl methacrylate),

65 Poly(hydroxyproline esters), 208 Poly(iminocarbonates), 212-215,

218-219, 221-223, 225 Polyisoprene, 4 Polyisosinic acid, 30 Polylactic/glycolic acid, 85 Polylactide I polyglycolide:

biodegradation, 3, 5-7, 13 enhancement, 5 enzymes, 5

crystallinity, 3, 6 degradation, 7 density, 4 fibers, 11 glass transition temperature, 3

Index 3U5

(Poly lac tide/ poly glycolide) hydrolysis, 5 hydrophobicity . 3 implants, 10 in vivo, 6 melting point, 3-4 microcapsules, 8-9 microspheres, 6, 8-10 molecular weight, 2-3, 13 monomer acidity, 3 monomer purity, 3 monomer stereochemistry, 3 polymer characteristics, 3 solubility, 4

dioxane, 4 ethyl acetate, 4 halogenated hydrocarbons,

4 hexafluoroisopropanol, 4 tetrahydrofuran ( T H F ) , 4

synthesis, 2 toxicity, 2 water uptake, 3, 5

Polymer hydrolysis, 128 Polymer processing, 150 Polymer synthesis, 121 Poly(\-methyl-D-glutamate), 222 Polymyxin B , 22 Polyols, 123 Poly( n-palmitoylhydroxyproline),

210 Poly (n-palmitoylhydroxyproline

ester), 204-206 Poly( phenylenedipropionic

acid), 62 Polyp hosphazenes:

biocompatibility, 166-177 hydrophilic, 168 hydrophobic, 167 insoluble, 168 irritation, 175 synthesis, 164 toxicity, 175

Poly (Setoff's base), 201 Poly(sebacic acid), 62, 64 Poly(L-serine), 200 Polyserine, 197

Poly(serine ester), 197 Poly (serine imine), 201 Polystyrene, 4 Poly(terephthalic acid), 54 Poly(terephthalic acid: sebacic

acid), 54 Poly (n-tetradecanoly hydroxy-

proline ester), 204 Poly (L-tyrosine). 212, 223-224 Polyvinylalcohol, 7 Poly-(4-vinylpyridine), 45 Pore size, 88 Prednisolone, 242 Procaine, 179 Procaine penicillin, 235 Progesterone, 15-16, 86-89, 91,

177-178, 238 Progestins, 27 Prostate cancer, 14 Protein A , 247 Proteins, 10, 15 2,3-Pyridine dicarboxylic an­

hydride), 133 Pyrimethamine, 21

Quinazoline, 20

Y Radiation, 183-184 Regulatory approval, 2 Release characteristics, 49 Release kinetics, 11 Reservoir devices, 93, 95-96,

98-99 Rheumatoid arthritis, 242 RIA, 30 Right Valley fever, 30 RNA, 25, 30

Safety, 66 Salmonellosis, 287 Screw extrusion, 10

346

Sebacic a c i d , 44 Sebacoyl c h l o r i d e , 45 L - s e r i n e , 198, 200 Ser ine-0- lactones , 200 S h i p p i n g f e v e r , 30 Si last ic , 79 Silicone o i l , 9, 46, 47 Smooth muscle ce l l s , 65 Sodium cromoglycate , 245 Soft- t issue prostheses , 184 Solvent evaporat ion , 8, 16, 22,

24, 29 Solvent film cas t ing , 29, 87 Somatostatin, 25 Sphingomyel in , 282, 288 Sp leen , 185 Sponges , 232 S tab i l i t y , 62 Stannous ch lor ide , 2 Stannous octoate, 2 S t a r c h , 30, 232-233 Stealth liposomes, 289 Stearylamine, 261, 310 Stereoisomers, 2 Ster i l i zat ion , 12 S t e r o i d s , 6, 9, 11, 15, 86, 175-

176 Streptozotoc in , 57 Sul fadiaz ine , 20, 177, 242 Surg i ca l d r e s s i n g s , 2 S u r g i c e l , 66 S u t u r e , 2, 6, 11, 233 Synthes i s , 44

T e r b u t a l i n e , 301 Tes tos terone , 16-17, 19-20,

87, 94-95 Testosterone propionate , 16 T e t r a c y c l i n e , 14, 22-23, 88,

238-239 T h e r m o gravimetric ana lys i s , 221 Thermoplas t i c , 154 T h i o r i d a z i n e , 5 Timolo l , 233

Index

T o b r a m y c i n , 236-237 a - T o c o p h e r o l , 280 p -To luene sulfonic a c i d , 2, 44 T o x i c , 65 T r a c h e a , 2 Trans -cyc lohexaned imethano l ,

126, 144-145, 152-153, 156

T r a n s - r e t i n o i c a c i d , 238 Triamcinolone , 242 T r i c a p r o i n , 94 T r i g l y c e r i d e s , 267 T r i t u r a t i o n , 50-53 T r y p s i n , 172, 240 T y r a m i n e , 220 L - t y r o s i n e , 211 T y r o s i n e , 197, 201, 210, 212,

214-215, 220, 222-223, 225

Unsaturated p o l y a n h y d r i d e s , 48

Vacc ine , 14, 27-28 Va l inomyc in , 272 Vancomyc in , 237 V inb las t ine , 272 V i s c o s i t y , 44 V o n Willebrand factor , 282

Walker 256 carc inoma, 244 Wool, 24 Wound d r e s s i n g s , 233

Xylocaine, 24

Young's modulus , 222

Index

Zero-order degradation, 48 Zero-order release, 176 Zinc, 63 Z n E t 2 - H 2 0 , 44

347