Contents

Preface iii
Contributors vii

1. Controlled Release of Bioactive Agents from Lactide/

Glycolide Polymers 1
Danny H. Lewis

2. Polyanhydrides as D r u g Delivery Systems 43

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 71
Colin G. Pitt

4. Poly(ortho esters) 121

Jorge Heller, Randall V. Sparer, and Gaylen M. Zentner

5. Polyphosphazenes as New Biomedical and Bioactive

Materials 163
Harry R. Allcock

6. Pseudopoly(amino acids) 195

Joachim Kohn

V
vi Contents
7. Natural Polymers as D r u g Delivery Systems 231
Simon Bogdansky

8. Liposomes
Vila K. Nassander, Gert Storm, Pierre A. M. Peeters, 261
and Daan J. A. Crommelin
Index
339

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
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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 c o p o l y m e r s , 84
Blood, 8
B o n e , 239
Bovine growth hormone, 30, 60,
63
B r a i n , 53-55, 66
B r e a s t c a n c e r , 245
p_-Bromoaniline, 65
B r u c e l l o s i s , 287
B u l k e r o s i o n , 5, 97
B u t y l £ - a m i n o b e n z o a t e , 179
B u t y l a t e d 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
C a l c i t o n i n , 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
C a r c i n o m a , 57
C a r m u s t i n e (see B C N U )
C a r t i l a g e , 61, 239
C a s e i n m i c r o s p h e r e s , 248
Catecholamine, 172-173
Cattle s y n c h r o n i z a t i o n , 14
C C N U , 21
C e l l u l o s e , 232-233
Cellulose acetate b u t y r a t e , 84-
85
Cellulose p r o p i o n a t e , 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
C h l o r a m p h e n i c o l , 22
C h l o r i n e d i o x i d e , 24
C h l o r o f o r m , 64
C h l o r o p r o c a i n e , 179
C h l o r o p r o m a z i n e , 90-91
Index
C h l o r o q u i n e , 297
C h o l a t e , 269
C h o l e s t e r o l , 264-265, 277, 279-
280, 285, 288, 301, 310
Cholesterolhemisuccinate, 261
Chondrogenic stimulating p r o -
t e i n s , 56, 61
C i s p l a t i n , 185, 290, 300
C l i n i c a l t r i a l s , 17-18
C o d e i n e , 87
C o l l a g e n , 232-234
dimensional s t a b i l i t y , 234
mechanical s t r e n g t h , 234
t i s s u e i r r i t a t i o n , 234
Complement, 282
C o m p r e s s i o n m o l d i n g , 10, 50,
52, 63, 87, 208
C o n j u n c t i v i t i s , 233
Contact a n g l e s , 167-168, 183
C o n t a c t l e n s e s , 184
C o n t i n u o u s - f l o w r e a c t o r s , 172
C o n t r a c e p t i v e 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 s h i e l d s , 236
C o r t i c o s t e r o i d s , 242, 299, 308
C o r t i s o n e , 56
C o r t i s o n e a c e t a t e , 54
C r o m o g l y c a t e , 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 b r o m i d e , 219
C y a n o g e n h a l i d e , 218
C y c l a z o c i n e , 18
Cyclobenzaprine hydrochloride,
145, 149, 153, 155
C y c l o p h o s p h a m i d e , 285
C y t o s i n e a r a b i n o s i d e , 90, 298,
300
Dental, 2
Deoxycholate, 269, 285
Desami no t y r o s i n e , 220
D e v o n o r g e s t r e l , 143
Index 341

Dexamethasone, 237 Estradiol, 238

Dexon, 13 Estradiol benzoate, 16
Dextran, 232-233 Estrogen, 14, 27
Dextran acetate, 7 Estrus, 26
Diabetes, 57, 60 Ethinyl estradiol, 16, 87
Dibucaine, 24 Ethylene oxide, 13
Dicetylphosphate, 310 Ethylene vinyl acetate, 65, 88
Dideoxykanamycin, 23 Ethyl oleate, 94
Differential scanning colorim- Extrusion, 87
etry ( D S C ) , 3
Diffusion, 17, 26, 88
Diffusion coefficients, 86
Diketene acetal, 122-123, 127 Fabrication, 87
4-Dimethylaminopyridine, 45 Fibers, 11, 87, 232
Dimiristoy lphosphatidy (choline t Fibrinogen, 282
286 Fibrinogen microspheres, 250
Dimiristoy lphosphatidylglycerol, Fibroblasts, 103
286 Fibronectin, 282
Dioleoylphosphatidic acid, 266 Films, 232, 234
Diphenol, 218 Fluidized bed coating, 8-9
l,6-Diphenyl-l,3,5-hexatriene, 5-Fluorouracil, 90, 238-239, 243,
276 249-250
Diphosgene, 45 Flurbiprofen, 237
Diquat, 12 Fluridone, 12, 90
Distearoylphosphatidylcholine, Formulations, 45
288 compression molding, 10, 45,
Dopamine, 172-173, 177 50, 52, 63, 87, 208
Doxorubicin, 233, 243, 247, "hot melt" microencapsulation,
250, 272, 290-294 46
DuPont, 2 injection molding, 10, 11, 45
microsphere preparation by
solvent removal, 46
Fracture, 2
Earth metal oxides, 44 FSH, 14
Ehrlich ascites carcinoma, 244, Fumaric acid, 49
250 F u r , 24
ELISA, 30
Endothal, 12
Endothelial cells, 65
Enzymatic degradation, 105 p-Galactosidase, 60, 62
Enzymes, 56 Gamma irradiation, 13
Epinephrine, 172 Ganglioside, 282
Epirubicin, 244 Gelatin, 232, 240
Epoxyhydrodienes, 279 Gelatin microspheres, 248-250
Erythrocytes, 301 Gelfoam, 66
Erythromycin, 235 Gel permeation chromatography,
Erythromycin estolate, 235 44, 151
342 Index

G e n t a m i c i n , 22, 234-235, 237, India i n k , 301

246, 309 Indomethacin, 233
Giant c e l l s , 103 Inflammation, 65-66
Glass t r a n s i t i o n t e m p e r a t u r e , 83 I n f r a r e d s p e c t r o s c o p y , 63
Glaucoma, 233, 235 Inherent v i s c o s i t y , 13
Glioblastoma, 66 Injection m o l d i n g , 10-11, 50, 65,
G l u c o s e , 58 151-152
Glucose-6-phosphate dehydro- Insect hormones, 24
genase. 172-173 Insecticide, 90
G l u t a r i c d i a l d e h y d e , 172 I n s u l i n , 29, 56-60, 242
G l u t a t h i o n e , 298 I n t e r f e r o n , 30, 93
G n R H , 27 Intraepithelial c e r v i c a l d y s p l a s i a ,
Good M a n u f a c t u r i n g P r a c t i c e s , 238
12, 31 Intraocular l e n s e s , 184
G r o w t h hormone, 30 I n u l i n , 232-233, 305
G r o w t h p r o m o t e r , 14

J u v e n i l e hormone, 24
S - H C G , 28
H e p a r i n , 168-170
Hepatic c a n c e r , 245
H e p a t o c y t e s , 282 K i d n e y , 185
H e r b i c i d e s , 12, 88, 90 K i n e t i c s , 47
Herniorrhaphy, 2 Krebs cycle, 5
1 , 6 - H e x a n e d i o l , 126, 129, 144,
152-153, 155-156
Histamine, 300
H o r s e , 17 L a t e x , 301
Humidity, 3 Lauryl alcohol, 2
H y a l u r o n i c a c i d , 232-233 Leishmaniasis, 282
H y d r i l l a , 90 L e v o n o r g e s t r e l , 11, 16. 88. 94. 96
H y d r o c o r t i s o n e , 24 110-112, 142, 144, 146
H y d r o c o r t i s o n e acetate, 24 Lewis l u n g c a r c i n o m a , 21
H y d r o g e l s , 183, 187-188, 232- L H R H a n a l o g , 97, 100
233 (D-Trp6, des-Gly10] LHRH d i -
H y d r o p e r o x i d e s , 279 e t h y l a m i d e , 97
u ) - H y d r o x y b u t y r i c a c i d , 122 L H R H p o l y p e p t i d e , 14, 25-27
2 0 - H y d r o x y e c d y s o n e . 97 L i d o c a i n e , 24
H y d r o x y p h o s p h a z e n e s , 175 Ligament r e c o n s t r u c t i o n , 2
H y d r o x y p r o l i n e , 202, 205, 208 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 e r i o s i s , 287
Local a n e s t h e t i c s , 179
Immunization, 27 L y p r e s s i n , 25
Immunoglobulins, 282 L - l y s i n e , 196
Implants, 10 L y s i n e , 211
Index 313

Lysophospholipids, 272 N a f a r e l i n acetate, 26

Naloxone, 18
N a l t r e x o n e , 18-19, 87, 93-94,
97-99, 122
M a c r o p h a g e s , 8, 103 N a n o p a r t i c l e s , 240
Magnesium h y d r o x i d e , 140 N a p r o x e n , 175
Magnetic albumin m i c r o s p h e r e s , Narcotic a n t a g o n i s t s , 2, 15, 18,
246-247 92
Magnetite, 246 N a r c o t i c s , 86
Mammary a d e n o c a r c i n o m a , 247 j j - N i t r o a c e t a n i l i d e , 135
M D P - B 3 0 , 29 E - N i t r o a n i l i n e , 49, 65, 207, 208
Mechanical s t r e n g t h , 11 N i t r o f u r a n t o i n , 91
Medisorb, 2 Noregestimate, 16
M e d r o x y p r o g e s t e r o n e , 234 N o r e p i n e p h r i n e , 172
Meglumine antimoniate, 284 N o r e t h i n d r o n e , 87. 141-142
M e l a t o n i n , 24-25 N o r e t h i s t e r o n e , 6, 9-10, 14-18,
Melt r h e o m e t e r s , 11 122
M e l t - s p i n n i n g , 87 N o r g e s t r e l , 15, 87, 242
M e p e r i d i n e , 87
M e s h e s , 232
M e t a p r o t e r e n o l , 299
L - M e t h a d o n e , 18-20, 87, 92-93 O c u l a r i n s e r t s , 232, 234-235
M e t h o p r e n e , 24 O p s o n i n s , 288
Methotrexate, 290, 308 O x y t o c i n , 298
Methylene c h l o r i d e , 46-47, 50,
213
M e t h y l p r e d n i s o l o n e , 24
M i c r o c a p s u l e s , 6, 8 - 9 , 85, 87, 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
90, 92-93, 98-99 P a p a i n , 240
M i c r o f l u i d i z e d bed c o a t i n g , 19 P a p a v e r i n e h y d r o c h l o r i d e , 233
M i c r o s p h e r e s , 6, 8-10, 16-17, P C P P r S A , 59
19-25, 28-29, 87, 91, 93, P e n t a e r y t h r i t o l , 123, 128-129
232, 240-249 Periodontal d i s e a s e , 14, 23
Milk, 28 Permeability, 86, 103
Misonidazole, 22 P e r o x i d a t i o n , 279
Mitomycin C , 2 1 , 243-245, 249 Petroleum e t h e r , 46-47
Molecular w e i g h t , 44-45, 47 P h a g o c y t o s i s . 102
M o n k e y s , 99 Pharmacokinetic s t u d i e s , 94
Monocytes, 8 Phase s e p a r a t i o n , 8 - 9 , 22
Monoslaloganglioside, 288 P h a t i d y l c h o l i n e , 264
M o r p h i n e , 19, 97 L - P h e n y l a l a n i n e mustard (mel-
Muramyl d i p e p t i d e , 28-29 p h a l a n ) , 175
M u r a m y l t r i p e p t i d e , 313 p_-Phenylenediamine, 65
M u t a g e n i c , 65 P h o s g e n e , 45
M y c o b a c t e r i u m , 287 P h o s p h a t i d y l c h o l i n e , 261, 266,
270, 275, 277, 279
34U Index

Phosphatidylglycerol, 261, 279 [ Poly - c- Caprolactone ]

Phosphatidyl inositol, 288 solubility, 82
P h o s p h a t i d y l r i n e , 261, 310 synthesis, 72
Phospholipids, 279, 310 tensile strength, 84
Phthalic acid, 154 toxicology, 110
Phthalic anhydride, 133, 144- Poly<carboxyphenoxy acetic
145, 148, 153-155 acid), 51
Pilocarpine, 234-235, 237 PolyI(£-carboxyphenoxy) alkanel,
n-Pivalohydroxyproline, 203 47
Plasma extenders, 187 Poly(carboxyphenoxy) hexane,
Platinum antitumor agents, 185 62, 64
Pluronic F68, 88 Poly(carboxyphenoxy) methane,
Poly(acryl) starch, 232 62, 64
Poly (n-acylhydroxyproline Poly ( carboxyphenoxyoctanoic
ester), 202, 204, 207, acid), 51
209 Poly(carboxyphenoxy) propane,
Polylbis(methoxyethoxyeihoxy)- 62
phosphazene) "MEEP", Poly (carboxyphenoxypropane-
184 sebacic acid), 47, 54, 64-
Poly [ bis( methy lamino )phospha- 66
zene], 186 Poly(carboxyphenoxyvaleric acid),
Poly (bis-(£-methylphenoxy) - 51
phosphazene], 169 Polycytidylic acid, 30
Poly(bisphenol A carbonate), Poly(diphenoxyphosphazene),
213 169
Poly( bisphenol A iminocar- Polyesters, 71
bonate), 213, 224 Polyester-urethanes, 84
Poly [ bis (phenoxy) phosphazene 1, Polyether ether ketone, 210-211
170 Polyglactin, 8
Polycaprolactone, 12 Poly (glutamic acid), 196
Poly-c-Caprolactone: Poly(hydroxyethyl methacrylate),
anionic polymerization, 73 65
biodegradable packaging, 71 Poly(hydroxyproline esters), 208
biodegradation, 81, 97 Poly(iminocarbonates), 212-215,
blends, 84 218-219, 221-223, 225
cationic polymerization, 75 Polyisoprene, 4
coordination polymerization, Polyisosinic acid, 30
77 Polylactic/glycolic acid, 85
crystallinity, 81, 102-103, 105 Polylactide I polyglycolide:
glass transition temperature, biodegradation, 3, 5-7, 13
81 enhancement, 5
heat of fusion, 81 enzymes, 5
melting point, 81 crystallinity, 3, 6
monomer synthesis, 72 degradation, 7
permeability, 86 density, 4
physical properties, 84 fibers, 11
radical polymerization, 80 glass transition temperature, 3
Index
(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 Progestins, 27
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
3U5
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
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 Index

Sebacic a c i d , 44
S e b a c o y l c h l o r i d e , 45
L - s e r i n e , 198, 200
S e r i n e - 0 - l a c t o n e s , 200
S h i p p i n g f e v e r , 30
S i l a s t i c , 79
Silicone o i l , 9, 46, 47
Smooth muscle c e l l s , 65
Sodium cromoglycate, 245
S o f t - t i s s u e p r o s t h e s e s , 184
Solvent e v a p o r a t i o n , 8, 16,
24, 29
Solvent film c a s t i n g , 29, 87
Somatostatin, 25
S p h i n g o m y e l i n , 282, 288
S p l e e n , 185
S p o n g e s , 232
S t a b i l i t y , 62
Stannous chloride, 2
S t a n n o u s octoate, 2
S t a r c h , 30, 232-233
Stealth liposomes, 289
S t e a r y l a m i n e , 261, 310
Stereoisomers, 2
S t e r i l i z a t i o n , 12
S t e r o i d s , 6, 9, 11, 15, 86, 175-
176
S t r e p t o z o t o c i n , 57
S u l f a d i a z i n e , 20, 177, 242
Surgical dressings, 2
S u r g i c e l , 66
S u t u r e , 2, 6, 11, 233
S y n t h e s i s , 44
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 - T o l u e n e sulfonic a c i d , 2, 44
T o x i c , 65
Trachea, 2
Trans-cyclohexanedimethanol,
126, 144-145, 152-153,
156
T r a n s - r e t i n o i c a c i d , 238
T r i a m c i n o l o n e , 242
22, 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 polyanhydrides, 48
V a c c i n e , 14, 27-28
V a l i n o m y c i n , 272
V a n c o m y c i n , 237
V i n b l a s t i n e , 272
V i s c o s i t y , 44
V o n Willebrand f a c t o r , 282

Walker 256 c a r c i n o m a , 244

T e r b u t a l i n e , 301 Wool, 24
T e s t o s t e r o n e , 16-17, 19-20, Wound d r e s s i n g s , 233
87, 94-95
T e s t o s t e r o n e p r o p i o n a t e , 16
T e t r a c y c l i n e , 14, 22-23, 88,
238-239 Xylocaine, 24
T h e r m o gravimetric a n a l y s i s , 221
T h e r m o p l a s t i c , 154
Thioridazine, 5
T i m o l o l , 233 Young's modulus, 222
Index 347

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