Biodegradable Polymers As Drug Delivery Systems

Contents

Preface Contributors 1.

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

iii vii 1

2.

Polyanhydrides as D r u g Delivery Systems Mark Chasin, Abraham Domb, Eyal Ron, Edith Mathiowitz, Kam Leong, Cato Laurencin, Henry Brem, Stuart Grossman, and Robert Langer

43

3.

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

71

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

121

163 195

V

vi 7.

Contents Natural Polymers as D r u g Delivery Systems Simon Bogdansky

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

231

Peeters,

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, 243250, 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 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 , 8485 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, 279280, 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 Dexamethasone, 237 Dexon, 13 Dextran, 232-233 Dextran acetate, 7 Diabetes, 57, 60 Dibucaine, 24 Dicetylphosphate, 310 Dideoxykanamycin, 23 Differential scanning colorimetry ( D S C ) , 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

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 F u r , 24

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

p-Galactosidase, 60, 62 Gamma irradiation, 13 Ganglioside, 282 Gelatin, 232, 240 Gelatin microspheres, 248-250 Gelfoam, 66 Gel permeation chromatography, 44, 151

342 G e n t a m i c i n , 22, 234-235, 237, 246, 309 Giant c e l l s , 103 Glass t r a n s i t i o n t e m p e r a t u r e , 83 Glaucoma, 233, 235 Glioblastoma, 66 G l u c o s e , 58 Glucose-6-phosphate dehydrogenase. 172-173 G l u t a r i c d i a l d e h y d e , 172 G l u t a t h i o n e , 298 G n R H , 27 Good M a n u f a c t u r i n g P r a c t i c e s , 12, 31 G r o w t h hormone, 30 G r o w t h p r o m o t e r , 14

Index India i n k , 301 Indomethacin, 233 Inflammation, 65-66 I n f r a r e d s p e c t r o s c o p y , 63 Inherent v i s c o s i t y , 13 Injection m o l d i n g , 10-11, 50, 65, 151-152 Insect hormones, 24 Insecticide, 90 I n s u l i n , 29, 56-60, 242 I n t e r f e r o n , 30, 93 Intraepithelial c e r v i c a l d y s p l a s i a , 238 Intraocular l e n s e s , 184 I n u l i n , 232-233, 305

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 H e r b i c i d e s , 12, 88, 90 Herniorrhaphy, 2 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 Humidity, 3 H y a l u r o n i c 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 H y d r o c o r t i s o n e acetate, 24 H y d r o g e l s , 183, 187-188, 232233 H y d r o p e r o x i d e s , 279 u ) - H y d r o x y b u t y r 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

K i d n e y , 185 K i n e t i c s , 47 Krebs cycle, 5

L a t e x , 301 Lauryl alcohol, 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 c a r c i n o m a , 21 L H R H a n a l o g , 97, 100 (D-Trp6, des-Gly10] LHRH d i e t h y l a m i d e , 97 L H R H p o l y p e p t i d e , 14, 25-27 L i d o c a i n e , 24 Ligament r e c o n s t r u c t i o n , 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 e r i o s i s , 287 Local a n e s t h e t i c s , 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 Lysophospholipids,

313

272

M a c r o p h a g e s , 8, 103 Magnesium h y d r o x i d e , 140 Magnetic albumin m i c r o s p h e r e s , 246-247 Magnetite, 246 Mammary a d e n o c a r c i n o m a , 247 M D P - B 3 0 , 29 Mechanical s t r e n g t h , 11 Medisorb, 2 M e d r o x y p r o g e s t e r o n e , 234 Meglumine antimoniate, 284 M e l a t o n i n , 24-25 Melt r h e o m e t e r s , 11 M e l t - s p i n n i n g , 87 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 M e t h o p r e n e , 24 Methotrexate, 290, 308 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, 90, 92-93, 98-99 M i c r o f l u i d i z e d bed c o a t i n g , 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 , 2 1 , 243-245, 249 Molecular w e i g h t , 44-45, 47 M o n k e y s , 99 Monocytes, 8 Monoslaloganglioside, 288 M o r p h i n e , 19, 97 Muramyl d i p e p t i d e , 28-29 M u r a m y l t r i p e p t i d e , 313 M u t a g e n i c , 65 M y c o b a c t e r i u m , 287

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 N a n o p a r t i c l e s , 240 N a p r o x e n , 175 Narcotic a n t a g o n i s t s , 2, 15, 18, 92 N a r c o t i c s , 86 j j - N i t r o a c e t a n i l i d e , 135 E - N i t r o a n i l i n e , 49, 65, 207, 208 N i t r o f u r a n t o i n , 91 Noregestimate, 16 N o r e p i n e p h r i n e , 172 N o r e t h i n d r o n e , 87. 141-142 N o r e t h i s t e r o n e , 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, O p s o n i n s , 288 O x y t o c i n , 298

234-235

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 P a p a i n , 240 P a p a v e r i n e h y d r o c h l o r i d e , 233 P C P P r S A , 59 P e n t a e r y t h r i t o l , 123, 128-129 Periodontal d i s e a s e , 14, 23 Permeability, 86, 103 P e r o x i d a t i o n , 279 Petroleum e t h e r , 46-47 P h a g o c y t o s i s . 102 Pharmacokinetic s t u d i e s , 94 Phase s e p a r a t i o n , 8 - 9 , 22 P h a t i d y l c h o l i n e , 264 L - P h e n y l a l a n i n e mustard (melp h a l a n ) , 175 p_-Phenylenediamine, 65 P h o s g e n e , 45 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

Phosphatidylglycerol, 261, 279 Phosphatidyl inositol, 288 P h o s p h a t i d y l r i n e , 261, 310 Phospholipids, 279, 310 Phthalic acid, 154 Phthalic anhydride, 133, 144145, 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 )phosphazene], 186 Poly (bis-(£-methylphenoxy) phosphazene], 169 Poly(bisphenol A carbonate), 213 Poly( bisphenol A iminocarbonate), 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

Index

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

Index

22,

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, 175176 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 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,

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 ,

Walker 256 c a r c i n o m a , T e r b u t a l i n e , 301 T e s t o s t e r o n e , 16-17, 19-20, 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 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

Wool, 24

Wound d r e s s i n g s ,

Xylocaine,

233

24

Young's modulus,

222

282

244

48

Index

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

347