In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems:
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| Format: | Thesis Book |
| Language: | English |
| Published: |
2002
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Physical Description: | X, 293 S. Ill., graph. Darst. |
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Record in the Search Index
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| adam_text | IN VITRO AND IN VIVO PROPERTIES OF INJECTABLE BIODEGRADABLE IN SITU
FORMING MICROPARTICLE SYSTEMS INAUGURAL-DISSERTATION ZUR ERIANGUNG DCR
DOKTORWIIRDE IM FACHBEREICH BIOLOGIE, CHEMIE, PHARMAZIC DER FREIEN
UNIVERSITAT BERLIN VORGELEGT VON WANDEE IM-EMSAP BERLIN 2002 TABLE OF
CONTENTS TABLE OF CONTENTS PAGE ACKNOWLEDGMENT I TABLE OF CONTENTS III
CHAPTER 1: INTRODUCTION 1.1 RATIONAL FOR CONTROLLED DRUG DELIVERY
SYSTEMS 1 1.2 PARENTERAL CONTROLLED RELEASE DRUG DELIVERY SYSTEMS 2
1.2.1 POLYMERIC CONTROLLED DRUG DELIVERY SYSTEMS 3 1.2.1.1
NONBIODEGRADABLE POLYMERS 3 1.2.1.2 BIODEGRADABLE POLYMERS 3 1.2.1.2.1
TYPE OF BIODEGRADABLE POLYMERS 4 1.2.1.2.1.1 POLY (ORTHO ESTERS) 4
1.2.1.2.1.2 POLYANHYDRIDE 4 1.2.1.2.1.3 POLY(S-CAPROLACTONE) 5
1.2.1.2.1.4 POLYESTERS 5 A) SYNTHESIS OF POLYESTERS 6 B) POLYGLYCOLIDE 6
C) POLYLACTIDE 8 D) COPOLYMER OF LACTIDE AND GLYCOLIDE 8 1.2.1.2.2
POLYMER CHEMISTRY 8 1.2.1.2.2.1 POLYMER CRYSTALLINITY 8 1.2.1.2.2.2
POLYMER MOLECULAR WEIGHT 9 1.2.1.2.2.3 GLASS TRANSITION TEMPERATURE 10
1.2.1.2.3 BIODEGRADATION 10 1.2.2 POLYMERIC DRUG DELIVERY DEVICES FOR
PARENTERAL APPLICATIONS 11 1.2.2.1 IMPLANTS 12 1.2.2.1.1
NONBIODEGRADABLE IMPLANTS 12 1.2.2.1.2 BIODEGRADABLE IMPLANTS 12 1.2.2.2
MICROPARTICLES 13 1.2.2.2.1 SOLVENT EVAPORATION METHOD 13 1.2.2.2.1.1
SINGLE EMULSION SOLVENT EVAPORATION METHOD 14 TABLE OF CONTENTS A) O/W
EMULSIFICATION PROCESS 14 DRUGS 15 SOLVENTS 16 EMULSIFIERS 19 POLYMERS
19 STIRRING CONDITIONS 20 B) O/O EMULSIFICATION PROCESS 20 1.2.2.2.1.2
MULTIPLE EMULSION SOLVENT EVAPORATION METHOD 21 1.2.2.2.2 COACERVATION
METHOD (PHASE SEPARATION) 23 1.2.2.2.3 SPRAY-DRYING 24 1.2.2.3 IN SITU
FORMING DRUG DELIVERY SYSTEMS 25 1.2.2.3.1 IN SITU FORMING IMPLANTS 26
1.2.2.3.1.1 SOLVENT EXCHANGE SYSTEMS 27 A) TECHNOLOGY FROM ATRIX
LABORATORIES 27 B) TECHNOLOGY FROM ALZA DRUG COOPERATION 32 C)
TECHNOLOGY FROM SOUTHERN BIOSYSTEM 33 1.2.2.3.1.2 THERMO/PH SENSITIVE
SYSTEMS 34 1.2.2.3.2 IN SITU FORMING MICROPARTICLE SYSTEMS 38
1.2.2.3.2.1 BASED ON COACERVATION MECHANISM 39 1.2.2.3.2.2 BASED ON
SOLVENT EXCHANGE MECHANISM 39 1.2.3 MECHANISMS OF DRUG RELEASE FROM
POLYMERIC MICROPARTICLES 40 1.2.3.1 RESERVOIR SYSTEMS 42 1.2.3.2
MONOLITHNIC SYSTEMS 42 1.2.3.3 BIODEGRADABLE SYSTEMS 42 1.2.3.4 SWELLING
CONTROLLED SYSTEMS 43 1.2.4 BIOCOMPATIBILITY OF POLYMERIC DRUG DELIVERY
SYSTEMS 43 1.2.4.1 MYOTOXICITY STUDY 43 1.2.4.1.1 IN VITRO MYOTOXICITY
PROTOCOL 44 1.2.4.1.2 IN VIVO MYOTOXICITY PROTOCOL 45 1.2.4.2
HISTOLOGICAL EXAMINATION 46 1.2.5 STERILIZATION FOR POLYMERIC DRUG
DELIVERY SYSTEMS 47 1.2.5.1 ETHYLENE OXIDE 47 1.2.5.2 ULTRAVIOLET LIGHT
47 1.2.5.3 GAMMA IRRADIATION 48 TABLE OF CONTENTS 1.2.5.4 HIGH PRESSURE
STERILIZATION 48 1.2.5.5 STERILE FILTRATION WITH ASEPTIC PROCESSING 49
1.3 HORMONE THERAPY 50 1.3.1 ESTRADIOL 50 1.3.2 LEUPROLIDE ACETATE 50
1.4 RESEARCH OBJECTIVES 54 CHAPTER 2: MATERIALS AND EXPERIMENTAL METHODS
2.1 MATERIALS AND SUPPLIERS 56 2.1.1 DRUGS 56 2.1.2 BIODEGRADABLE
POLYMERS 56 2.1.3 SOLVENTS 56 2.1.4 OILS 57 2.1.5 SURFACTANTS 57 2.1.6
BUFFERING AGENTS 57 2.1.7 ADDITIVES 58 2.1.8 ANESTHETIC AGENTS 58 2.1.9
ANIMALS 58 2.1.10 MISCELLANEOUS 58 2.2 EXPERIMENTAL METHODS 59 2.2.1 IN
VITRO STUDIES 59 2.2.1.1 PREPARATIONS OF FORMULATIONS 59 2.2.1.1.1 OILY
DRUG SUSPENSIONS 59 2.2.1.1.2 IN SITU FORMING IMPLANTS 59 2.2.1.1.3 IN
SITU FORMING MICROPARTICLE (ISM) SYSTEMS 60 2.2.1.1.3.1 O/W-ISM SYSTEMS
60 2.2.1.1.3.2 O/O-ISM SYSTEMS 60 2.2.1.1.3.3 W/0/W-ISM SYSTEMS 60
2.2.1.1.3.4 IN SITU FORMING COMPLEX (ISC) IN ISM SYSTEMS 61 A)
LEUPROLIDE/OLEATE ISC IN O/W-ISM SYSTEMS 61 B) LEUPROLIDE/OLEATE ISC IN
O/O-ISM SYSTEMS 61 2.2.1.1.4 CONVENTIONAL MICROPARTICLES 62 2.2.1.1.5
FILM PREPARATION 62 2.2.1.2 MISCIBILITY STUDIES 62 TABLE OF CONTENTS A)
MISCIBILITY OF SOLVENT IN AQUEOUS SOLUTIONS 62 B) MISCIBILITY OF OILS
AND SOLVENTS 63 2.2.1.3 SOLUBILITY STUDIES 63 2.2.1.4 DETERMINATION OF
PARTITION COEFFICIENT 63 A) LEUPROLIDE ACETATE 63 B) 1713-ESTRADIOL
HEMIHYDRATE 64 2.2.1.5 RELEASE STUDIES AND DRUG CONTENT DETERMINATION 64
2.2.1.5.1 ETHYL ACETATE RELEA SE STUDY 64 2.2.1.5.2 DRUG RELEASE STUDIES
65 2.2.1.6 DETERMINATION OF ENCAPSULATION EFFICIENCY 66 2.2.1.7
CONSTRUCTION OF TERNARY PHASE DIAGRAM 67 2.2.1.8 TEST OF MICROPARTICLE
SOLIDIFICATION 67 2.2.1.9 DROPLET AND PARTICLE SIZE MEASUREMENT 68
2.2.1.9.1 OPTICAL LIGHT MICROSCOPE 68 2.2.1.9.2 LASER DIFFRACTION
MEASUREMENT 68 2.2.1.9.3 PHOTON CORRELATED SPECTROSCOPY 68 2.2.1.10STUDY
OF FLOW BEHAVIOR AND VISCOSITY MEASUREMENT 69 2.2.1.11 DETERMINATION OF
REQUIRED INJECTION FORCE 69 2.2.1.12TURBIDITY MEASUREMENT 70 2.2.1.13
CHARACTERIZATIONS OF PHYSICAL DRUG STATE 71 2.2.1.13.1 DIFFERENTIAL
SCANNING CALORIMETRY (DSC) 71 2.2.1.13.2 X-RAY POWDER DIFFRACTION 71
2.2.1.13.3 SCANNING ELECTRON MICROSCOPE (SEM) 71 2.2.1.14 STERILIZATION
71 2.2.1.14.1 GAMMA IRRADIATION 71 2.2.1.14.2 HIGH PRESSURE
STERILIZATION 72 / 2.2.1.14.3 BACTERIOLOGICAL PROCEDURES 72 2.2.1.14.4
DETERMINATION OF POLYMER MOLECULAR WEIGHT 73 2.2.2 IN VIVO STUDIES 73
2.2.2.1 ANIMAL PROCEDURES 73 2.2.2.1.1 SURGICAL PROCEDURES 74 2.2.2.1.2
ESTRADIOL RELEASE STUDIES 74 2.2.2.1.2.1 INITIAL DRUG BURST RELEASE 74
A) ESTRADIOL LOADED SILASTIC TUBES 74 VI TABLE OF CONTENTS B) ESTRADIOL
LOADED ISM SYSTEMS 75 2.2.2.1.2.2 ONE MONTH IN VIVO DRUG RELEASE STUDY
75 2.2.2.1.3 DETERMINATION OF PLASMA DRUG CONTENT 75 2.2.2.1.4
INVESTIGATION OF GENITAL ORGAN WEIGHT 76 2.2.2.2 BIOCOMPATIBILITY
STUDIES 76 2.2.2.2.1 MYOTOXICITY PROTOCOLS 76 2.2.2.2.1.1 IN VITRO
MYOTOXICITY STUDIES 76 2.2.2.2.1.2 IN VIVO MYOTOXICITY STUDIES 77
2.2.2.2.2 HISTOLOGICAL EXAMINATION 77 2.2.2.3 DATA ANALYSIS 78 CHAPTER
3: RESULTS AND DISCUSSION 3.1 DEVELOPMENT OF BIODEGRADABLE INJECTABLE
O/W-ISM SYSTEMS 79 3.1.1 SELECTION OF SOLVENTS FOR O/W-ISM SYSTEMS 80
3.1.2 MECHANISM OF O/W-ISM FORMATION 86 3.1.3 PARAMETERS AFFECTING
PARTICLE SIZE OF O/W-ISM SYSTEMS 90 3.1.4 REPRODUCIBILITY 93 3.1.5 ETHYL
ACETATE RELEASE FROM ISM SYSTEMS 94 3.1.6 EFFECT OF POLYMER TYPE AND
PHASE RATIO ON THE FORMATION OF O/W-ISM SYSTEMS 96 3.1.7 INVESTIGATION
OF SOLVENT MIXTURES FOR O/W-ISM SYSTEMS 98 3.1.8 IN VITRO DRUG RELEASE
STUDIES 103 3.1.8.1 EFFECT OF DRUG LOADING 103 3.1.8.2 EFFECT OF
INTERNAL TO EXTERNAL PHASE RATIO 103 3.1.8.3 EFFECT OF POLYMER
CONCENTRATION 104 3.1.8.4 EFFECT OF POLYMER TYPE 105 3.1.9 COMPARISON OF
PREPARATION METHODS 106 3.1.10DEVELOPMENT OF W/0/W-ISM SYSTEMS 108
3.1.10.1 INFLUENCE OF SOLVENT SYSTEMS ON EMULSION FORMATION 109 3.1.10.2
IN VITRO DRUG RELEASE STUDIES 110 3.1.10.2.1 EFFECT OF SOLVENT SYSTEMS
ON DRUG RELEASE 110 3.1.10.2.2 EFFECT OF POLYMER CONCENTRATION ILL
3.1.10.2.3 EFFECT OF EMULSION PHASE RATIO 112 3.1.10.2.4 EFFECT OF
STABILIZER 113 TABLE OF CONTENTS 3.1.11 CHARACTERIZATION OF PHYSICAL
DRUG-STATE IN POLYMER MATRIX 115 3.1.11.1 CHARACTERIZATION OFDRUG STATE
BY DSC 116 3.1.11.2 CHARACTERIZATION OFDRUG STATE BY POWDER X-RAY
DIFFRACTION 120 3.1.11.3 CHARACTERIZATION OFDRUG STATE BY SEM 121
3.1.11.4 EFFECT OFDRUG LOADING ON IN VITRO DRUG RELEASE 123 3.1.11.5
COMPARISON OF PHYSICAL DRUG STATE FROM ISM SYSTEMS AND MICROPARTICLES
126 3.2 PREPARATION OF NONAQUEOUS EMULSIONS OF ISM SYSTEM 132 3.2.1
SELECTION OF OIL PHASE AND SOLVENT SYSTEMS 132 3.2.2 PARAMETERS
INFLUENCING ON IN VITRO DRUG RELEASE STUDIES 136 3.2.2.1 MIXING METHODS
136 3.2.2.2 EFFECT OFDRUG LOADING AND POLYMER CONCENTRATION 138 3.2.2.3
EFFECT OF POLYMER TO OIL PHASE RATIO 140 3.2.2.4 COMPARISON OF DOSAGE
FORMS 141 3.2.2.5 CHARACTERIZATION OF PHYSICAL DRUG STATE 142 3.3
INJECTABILITY OF ISM SYSTEMS 145 3.3.1 INVESTIGATION OF FLOW BEHAVIOUR
145 3.3.2 DETERMINATION OF VISCOSITY 147 3.3.3 DETERMINATION OF REQUIRED
INJECTION FORCES 155 3.3.3.1 INJECTION TEST 155 3.3.3.2 RELATIONSHIP
BETWEEN INJECTION FORCE AND INJECTION SPEED 157 3.3.3.3 RELATIONSHIP
BETWEEN INJECTION FORCE AND VISCOSITY 158 3.3.3.4 RELATIONSHIP BETWEEN
INJECTION FORCE AND SYRINGE SIZE 159 3.3.3.5 RELATIONSHIP BETWEEN
INJECTION FORCE AND NEEDLE SIZE 160 3.3.3.6 RELATIONSHIP BETWEEN
INJECTION FORCE AND INJECTION SITE 162 3.3.3.7 CORRELATION OF INJECTION
FORCE IN VITRO AND IN VIVO 164 3.4, APPLICATIONS OF ISM SYSTEMS 166
3.4.1 DELIVERY OF 17(3-ESTRADIOL HEMIHYDRATE 166 3.4.1.1 IN VIVO DRUG
RELEASE STUDIES 167 3.4.1.2 INVESTIGATION OF UTERINE WEIGHTS 170 3.4.1.3
MYOTOXICITY OF E2 LOADED FORMULATIONS 171 3.4.1.4 OBSERVATION OF
FORMULATIONS AT INJECTION SITES 173 3.4.2 DELIVERY OF LEUPROLIDE ACETATE
174 3.4.2.1 FUNDAMENTAL INVESTIGATIONS 175 VIII TABLE OF CONTENTS.
3.4.2.1.1 FORMULATION OF ISM SYSTEMS 175 A) O/O-ISM SYSTEMS 175 B)
O/W-ISM SYSTEMS 179 3.4.2.1.2 IN-VITRO DRUG RELEASE CONDITIONS 181
3.4.2.1.3 IN VIVO STUDIES 185 3.4.2.2 LEUPROLIDE LOADED ISM SYSTEMS
USING NMP 185 3.4.2.2.1 INFLUENCE OF OIL PHASE 186 3.4.2.2.2 INFLUENCE
OF OIL TYPE 191 3.4.2.2.3 INFLUENCE OF EMULSION PHASE RATIO 193
3.4.2.2.4 INFLUENCE OFDRUG LOADING 195 3.4.2.2.5 EFFECT OF POLYMER
CONCENTRATION 197 3.4.2.2.6 EFFECT OF POLYMER TYPE 197 3.4.2.2.7
COMPARISON OF DOSAGE FORMS 200 3.4.2.2.8 COMPARISON OF ROUTE OF
ADMINISTRATION 202 3.4.2.3 LEUPROLIDE/OLEATE ISC FORMATION LOADED ISM
SYSTEMS 204 3.4.2.3.1 FORMATION OF LEUPROLIDE/OLEATE COMPLEX 204
3.4.2.3.2 TRANSMITTANCE AND PARTICLE SIZE MEASUREMENT 206 3.4.2.3.3
SOLUBILITY OF LEUPROLIDE/OLEATE COMPLEX 207 3.4.2.3.4 ENCAPSULATION OF
LEUPROLIDE/OLEATE ISC INTO ISM SYSTEMS 209 A) LEUPROLIDE/OLEATE ISC IN
O/W-ISM SYSTEMS 209 B) LEUPROLIDE/OLEATE ISC IN O/O-ISM SYSTEMS 209
3.4.2.3.5 CHARACTERIZATION OF MICROPARTICLES OF THE ISM SYSTEMS 210
3.4.2.3.6 DETERMINATION OF IN VITRO DRUG RELEASE AND PLASMA TESTOSTERONE
LEVELS 213 3.4.2.4 LEUPROLIDE LOADED ISM SYSTEMS USING 2-PYRROLIDONE 217
3.4.2.4.1 COMPARISON OF NMP AND 2-PYRROLIDONE 218 3.4.2.4.2
DETERMINATION OF LEUPROLIDE PARTITION COEFFICIENT 221 3.4.2.4.3 EFFECT
OFDRUG LOADING 222 3.4.2.4.4 POLYMER CONCENTRATION AND MOLECULAR WEIGHT
223 3.4.2.4.5 COMPARISON OF DOSAGE FORMS 224 3.4.2.4.6 MONITORING OF
BODY WEIGHT CHANGE 225 3.4.2.4.7 INVESTIGATION OF GENITAL ORGAN WEIGHT
226 TABLE OF CONTENTS 3.5 BIOCOMPATIBILITY OF ISM SYSTEMS 229 3.5.1
MYOTOXICITY STUDIES 229 3.5.1.1 INTERFERENCE OF ASSAY 231 3.5.1.2 IN
VITRO MYOTOXICITY OF PURE SOLVENT 232 3.5.1.3 VISCOSITY OF SOLVENT AND
POLYMER SOLUTION 233 3.5.1.4 IN VITRO MYOTOXICITY OF FORMULATIONS 233
3.5.1.5 IN VIVO MYOTOXICITY OF IN SITU FORMING FORMULATIONS 235 3.5.1.6
FORMATION OF ISM WITH ETHYL ACETATE AND COSOLVENT 237 3.5.2 HISTOLOGICAL
EVALUATION 237 3.5.2.1 EVALUATION OF SOLVENT TOXICITY 238 3.5.2.2
EVALUATION OF CONVENTIONAL MICROPARTICLES AND POLYMER SOLUTIONS .. 241
3.5.2.3 EVALUATION OF ISM SYSTEMS 244 3.6 STERILIZATION OF BIODEGRADABLE
POLYMER SOLUTIONS 246 3.6.1 EFFECT OF GAMMA IRRADIATION DOSE AND STORAGE
TIME 246 3.6.2 EFFECT OF SOLVENT TYPES ON POLYMER MW AFTER GAMMA
IRRADIATION 248 3.6.3 EFFECT OF LACTIDE COMPOSITION ON POLYMER
DEGRADATION 249 3.6.4 EFFECT OF POLYMER CONCENTRATION ON RADIOLYSIS 251
3.6.5 MICROBIOLOGICAL STUDIES 251 3.6.5.1 EFFECT OF GAMMA IRRADIATION
DOSE ON BIOBURDEN 252 3.6.5.2 HIGH PRESSURE STERILIZATION 254 3.6.5.3
STERILE FILTRATION 255 CHAPTER 4: SUMMARY 256 CHAPTER 5: REFERENCES 262
CHAPTER 6: LIST OF PUBLICATIONS 291 CHAPTER 7: CURRICULUM VITAE 293
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| genre | (DE-588)4113937-9 Hochschulschrift gnd-content |
| genre_facet | Hochschulschrift |
| id | DE-604.BV017033777 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T19:13:02Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-010281600 |
| oclc_num | 76430430 |
| open_access_boolean | |
| owner | DE-12 DE-29T DE-355 DE-BY-UBR DE-83 |
| owner_facet | DE-12 DE-29T DE-355 DE-BY-UBR DE-83 |
| physical | X, 293 S. Ill., graph. Darst. |
| publishDate | 2002 |
| publishDateSearch | 2002 |
| publishDateSort | 2002 |
| record_format | marc |
| spelling | Im-Emsap, Wandee 1967- Verfasser (DE-588)124503802 aut In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems vorgelegt von Wandee Im-Emsap 2002 X, 293 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Berlin, Freie Univ., Diss., 2002 Kontrollierte Wirkstofffreisetzung (DE-588)4165181-9 gnd rswk-swf Mikropartikel (DE-588)4336527-9 gnd rswk-swf Biologisch abbaubarer Kunststoff (DE-588)4634464-0 gnd rswk-swf In situ (DE-588)4293230-0 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Kontrollierte Wirkstofffreisetzung (DE-588)4165181-9 s Mikropartikel (DE-588)4336527-9 s Biologisch abbaubarer Kunststoff (DE-588)4634464-0 s In situ (DE-588)4293230-0 s DE-604 GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=010281600&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Im-Emsap, Wandee 1967- In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems Kontrollierte Wirkstofffreisetzung (DE-588)4165181-9 gnd Mikropartikel (DE-588)4336527-9 gnd Biologisch abbaubarer Kunststoff (DE-588)4634464-0 gnd In situ (DE-588)4293230-0 gnd |
| subject_GND | (DE-588)4165181-9 (DE-588)4336527-9 (DE-588)4634464-0 (DE-588)4293230-0 (DE-588)4113937-9 |
| title | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems |
| title_auth | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems |
| title_exact_search | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems |
| title_full | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems vorgelegt von Wandee Im-Emsap |
| title_fullStr | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems vorgelegt von Wandee Im-Emsap |
| title_full_unstemmed | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems vorgelegt von Wandee Im-Emsap |
| title_short | In vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems |
| title_sort | in vitro and in vivo properties of injectable biodegradable in situ forming microparticle systems |
| topic | Kontrollierte Wirkstofffreisetzung (DE-588)4165181-9 gnd Mikropartikel (DE-588)4336527-9 gnd Biologisch abbaubarer Kunststoff (DE-588)4634464-0 gnd In situ (DE-588)4293230-0 gnd |
| topic_facet | Kontrollierte Wirkstofffreisetzung Mikropartikel Biologisch abbaubarer Kunststoff In situ Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=010281600&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT imemsapwandee invitroandinvivopropertiesofinjectablebiodegradableinsituformingmicroparticlesystems |