Drug delivery systems based on collagen: = Arzneistoffträger auf Basis von Kollagen
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| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Aachen
Shaker
2000
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| Ausgabe: | Als Ms. gedr. |
| Schriftenreihe: | Berichte aus der Pharmazie
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Zugl.: Erlangen-Nürnberg, Univ., Habil.-Schr., 1999 |
| Beschreibung: | 186 S. Ill., graph. Darst. |
| ISBN: | 3826569946 |
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MARC
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| 245 | 1 | 0 | |a Drug delivery systems based on collagen |b = Arzneistoffträger auf Basis von Kollagen |c Wolfgang Frieß |
| 246 | 1 | 1 | |a Arzneistoffträger auf Basis von Kollagen |
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| 264 | 1 | |a Aachen |b Shaker |c 2000 | |
| 300 | |a 186 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
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| 338 | |b nc |2 rdacarrier | ||
| 490 | 0 | |a Berichte aus der Pharmazie | |
| 500 | |a Zugl.: Erlangen-Nürnberg, Univ., Habil.-Schr., 1999 | ||
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Datensatz im Suchindex
| _version_ | 1804127720031911936 |
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| adam_text | TABLE OF CONTENTS
Zusammenfassung........ ................................................................................................. I VI
Table of Contents VII XII
List of Figures XHI XVIII
List of Tables XIX XX
List of Abbreviations XXI XXII
1. Review of Collagen, Its Properties and Current Applications for Drug Delivery 1
1.1 Biology of Collagen Type 1 2
1.1.1 Collagen Types 2
1.1.2 Biosynthesis 3
1.1.3 Sequential Structure 4
1.1.4 Higher Order Structures 5
1.1.5 Natural Crosslinks 6
1.1.6 Degradation 9
1.1.7 Antigenicity and Immunogenicity 10
1.2 Risk of BSE from Bovine Collagen Material 11
1.3 Isolation and Purification of Collagen 12
1.3.1 Neutral Salt Soluble Collagen 13
1.3.2 Acid Soluble Collagen 13
1.3.3 Alkali and Enzyme Treated Collagen 14
1.3.4 Insoluble Collagen 15
1.4 Crosslinking 15
1.4.1 Chromium Tanning 15
1.4.2 Formaldehyde 16
1.4.3 Glutaraldehyde 17
1.4.4 Hexamethylenediisocyanate 18
1.4.5 Polyepoxy Compounds 19
1.4.6 Carbodiimides 19
1.4.7 Acyl Azide Method 20
1.4.8 Physical Treatment 21
1.5 Sterilization 22
1.5.1 Ethylene Oxide Treatment 22
1.5.2 y Irradiation 23
1.6 Current Applications of Collagen for Drug Delivery Systems 23
1.6.1 Ophthalmology 24
1.6.1.1 Collagen Inserts 24
1.6.1.2 Collagen Shields 25
1.6.2 Aqueous Injectables 27
1.6.2.1 Delivery of Proteins 27
1.6.2.2 Intratumoral Delivery of Cytostatica 29
1.6.3 Collagen Sponges 29
1.6.3.1 Delivery of Antibiotics 30
1.6.3.2 Tissue Regeneration 31
1.6.4 Dense Collagen Matrices 32
1.6.5 Microparticles 32
1.7 Conclusions 33
2. Goals of the Present Thesis 35
3. Prolonged Release from Dense Insoluble Collagen Matrices..................................——.36
3.1 Dense Collagen Matrices for Drug Delivery 36
3.2 Study Objectives 37
3.3 Characterization of Insoluble Collagen Starting Material 37
3.3.1 Isoelectrical Point and Amino Acid Analysis 37
3.3.2 Microscopy and Rheometry 38
3.3.3 Differential Scanning Calorimetry and Fourier Transform Infrared
Spectroscopy 40
3.4 Non Crosslinked Insoluble Collagen Matrices 42
3.4.1 Microscopy and Thermoanalytical Characterization of Dry Matrices 42
3.4.2 Swelling 44
3.5 Crosslinked Insoluble Collagen Matrices 45
3.5.1 Crosslinking with Glutaraldehyde 45
3.5.2 Swelling 46
3.6 Collagenolytic Degradation 49
3.7 Release of Model Compounds 52
3.7.1 Release in Phosphate Buffered Saline 52
3.7.2 Release in Phosphate Buffered Saline Containing Collagenase 53
3.8 Dense Collagen Matrices Loaded with PS1 55
3.8.1 In Vitro Release 55
3.8.2 Subcutaneous Implantation in Mice 56
3.8.3 Histology 58
3.9 Summary 60
4. Prolonged Release of Gentamicin from Porous Collagen Systems 62
4.1 Carrier Systems for Local Delivery of Antibiotics 62
4.1.1 Application of Gentamicin 62
4.1.2 Polymethylmethacrylate Beads versus Collagen Sponge Loaded with Gentamicin64
4.1.3 Study Goals 66
4.2 Gentamicin Loaded PLA and PLGA Microparticles 66
4.2.1 Process Development 67
4.2.2 Gentamicin Loaded Micoparticles from Different PLA and PLGA Types 69
4.2.3 Microparticles Prepared from PLGA Polymer Blends 72
4.2.4 Mechanistic Studies of the Gentamicin Release from PLGA Microparticles 74
4.2.4.1 Water Uptake 74
4.2.4.2 Scanning Electron Microscopy 76
4.2.4.3 Molecular Weight of PLGA 79
4.2.4.4 Glass Transition Temperature 80
4.2.4.5 Summary 83
4.3 PLGA Microparticles in Collagen Dispersion 84
4.3.1 Sedimentation of PLGA Microparticles in Collagen Dispersion 84
4.3.1.1 Oscillatory Rheometry of Collagen Dispersions 84
4.3.1.2 Yield Values of Collagen Dispersion 86
4.3.1.3 Particle Sedimentation 88
4.3.2 Gentamicin Loss from PLGA Microparticles in Acidic Milieu 89
4.4 Freeze Drying of Collagen Sponge / PLGA Microparticles Composites 90
4.5 Summary 92
5. Bone Regeneration Using Recombinant Human Bone Morphogenetic Protein 2
in Combination with Porous Collagen Systems 94
5.1 Bone Regeneration with Bone Morphogenetic Proteins 94
5.1.1 Bone Induction by Morphogenetic Proteins 94
5.1.2 Biochemistry of Recombinant Human Bone Morphogenetic Protein 2 97
5.1.3 Clinical Applications of Bone Morphogenetic Proteins 98
5.1.4 Carriers for Bone Morphogenetic Proteins 99
5.2 Study Objectives 101
5.3 Collagen Starting Material 103
5.3.1 Isoelectrical Point and Amino Acid Analysis 103
5.3.2 Microscopy and Fourier Transform Infrared Spectroscopy 104
5.3.3 Oscillatory Rheometry 106
5.4 Absorbable Collagen Sponge Characterization 107
5.4.1 Free Amino Group Analysis 109
5.4.2 Melting Temperature 112
5.4.3 Collagenolytic Degradation 113
5.5 ACS in Combination with rhBMP 2 115
5.5.1 Expressate pH and Conductivity 115
5.5.2 Effect of pH and Anion Concentration on rhBMP 2 Solubility 119
5.5.3 Incorporation of rhBMP 2 in ACS 120
5.5.4 Influence of pH and Conductivity on rhBMP 2 Incorporation 122
5.5.5 Effect of Waiting Time on rhBMP 2 Incorporation 123
5.5.6 Optimization of Incorporation and Reduction of Waiting Time via
ACS Mass 124
5.5.7 Binding of rhBMP 2 Isoforms to ACS 126
5.5.8 Pharmacokinetics of rhBMP 2 after Rat Ectopic Implantation 127
5.6 ACS / Ceramic Composites with Enhanced Mechanical Strength 129
5.6.1 Compressive Strength of ACS 129
5.6.2 Composites of ACS with Biphasic Calcium Phosphate Granules 13°
5.7 Summary 134
6. Summary and Conclusions 138
7. Materials and Methods 141
7.1 Materials and Methods Applied in Chapter 3 141
7.1.1 Materials 141
7.1.2 Methods 142
7.1.2.1 Collagen Matrix Preparation 142
7.1.2.2 Determination of the Isoelectrical Point 42
7.1.2.3 Amino Acid Analysis 143
7.1.2.4 Rheometry 143
7.1.2.5 Differential Scanning Calorimetry 143
7.1.2.6 Dielectrical Thermal Analysis 143
7.1.2.7 Determination of the Water Content 144
7.1.2.8 Fourier Transform Infrared Spectroscopy 144
7.1.2.9 Scanning Electron Microscopy 144
7.1.2.10 Transmission Electron Microscopy 144
7.1.2.11 Atomic Force Microscopy 144
7.1.2.12 Swelling Studies 145
7.1.2.13 Determination of the Crosslinking Degree 145
7.1.2.14 Determination of Free Glutaraldehyde 145
7.1.2.15 Enzymatic Degradation Studies 145
7.1.2.16 Release Studies 146
7.1.2.17 Murine Sarcoma Assay 146
7.2 Materials and Methods Applied in Chapter 4 147
7.2.1 Materials 147
7.2.2 Methods 147
7.2.2.1 Preparation of Microparticles 147
7.2.2.2 Collagen Sponge Preparation 148
7.2.2.3 Drug Incorporation 148
7.2.2.4 Release Studies 148
7.2.2.5 Preparation of Gentamicin Base 148
7.2.2.6 Particle Size Analysis 149
7.2.2.7 Rheometry 149
7.2.2.8 Scanning Electron Microscopy 149
7.2.2.9 Water Uptake Studies 149
7.2.2.10 Differential Scanning Calorimetry 149
7.2.2.11 Polymer Molecular Weight Analysis (Size Exclusion
Chromatography) 149
7.2.2.12 Microscopical Investigation 150
7.2.2.13 Analysis of Particle Sedimentation 150
7.2.2.14 Mechanical Loss of Microparticles 150
7.3 Materials and Methods Applied in Chapter 5 150
7.3.1 Materials 150
7.3.2 Methods 151
7.3.2.1 ACS /Ceramic Composite Manufacturing 151
7.3.2.2 Determination of the Isoelectrical Point 151
7.3.2.3 Amino Acid Analysis 151
7.3.2.4 Scanning Electron Microscopy 151
7.3.2.5 Transmission Electron Microscopy 152
7.3.2.6 Atomic Force Microscopy 152
7.3.2.7 Fourier Transform Infrared Spectroscopy 152
7.3.2.8 Rheometry 152
7.3.2.9 X Ray Diffraction Analysis 152
7.3.2.10 Determination of Free Amino Groups 152
7.3.2.11 ACS Degradation 152
7.3.2.12 ACS Melting Temperature 152
7.3.2.13 Incorporation Analysis 153
7.3.2.14 Expressate Analysis 153
7.3.2.15 Studies of rhBMP 2 Aggregation 154
7.3.2.16 Anion and pH Dependence of rhBMP 2 Incorporation 154
7.3.2.17 Equilibrium Binding Studies 154
7.3.2.18 Pharmacokinetic Studies of rhBMP 2 /ACS Implant 154
7.3.2.19 Inductive Coupled Plasma Optical Emission Spectroscopy 155
7.3.2.20 Mechanical Testing 155
7.3.2.21 Abrasion Testing 155
8. References 156
9. Appendices 182
9.1 Appendix I Process Development for Preparation of PLGA Microparticles 182
9.2 Appendix II Publications and Presentations 185
LIST OF FIGURES
1 1: Chemical structure of collagen type 1 6
1 2: Chemical structure of natural collagen crosslinks 7
1 3: Location of natural crosslinks in collagen fibers 8
1 4: Chemical structure of crosslinks from chromium tanning of collagen 16
1 5: Chemical structure of crosslinks from formaldehyde treatment of collagen 16
1 6: Chemical structure of crosslinks from glutaraldehyde treatment of collagen 17
1 7: Chemical structure of crosslinks from hexamethylenediisocyanate treatment of
collagen 18
1 8: Chemical structure of a selection of epoxy reagents for crosslinking of collagen 19
1 9: Chemical structure of crosslinks from l ethyl 3 (3 dimethylaminopropyl)carbo
diimide (EDC) treatment of collagen 20
1 10: Crosslinking of collagen by the acyl azide method 21
3 1: SEM of lyophilized insoluble collagen starting material, TEM and AFM of a
0.1 % aqueous insoluble collagen dispersion at pH 3.5 38
3 2: Reduced viscosity of insoluble collagen dispersions pH 3.5 as a function of
collagen concentration 39
3 3: DSC scan of a 5% insoluble collagen dispersion pH 3.5 40
3 4: FT IR spectra of a 0.1 % insoluble collagen dispersion pH 3.5 41
3 5: AFM of a 0.1 % insoluble collagen dispersion pH 3.5 after heating to 60 °C and
subsequent cooling 42
3 6: SEM of an insoluble collagen matrix 43
3 7: a) DSC scan of an insoluble collagen matrix
b) DeTA scan of an insoluble collagen matrix 43
3 8: a) SEM of a swollen insoluble collagen matrix
b) Swelling ratio (height h(t) to initial height ho) of an insoluble collagen matrix
as a function of time 45
3 9: a) Crosslinking degree as a function of the amount of GTA added to an aqueous ;
1 % collagen dispersion
b) Water content, DSC maximum and onset, DeTA loss modulus maximum and
onset of insoluble collagen matrices as a function of crosslinking 46
3 10: a) Swelling ratio (final height he,) to initial height h0) of insoluble collagen matri¬
ces as a function crosslinking
b) Swelling ratio (height h(t) to initial height h0) of an insoluble collagen matrix
crosslinked at a GTA / NH2 ratio of 1 as a function of time
c) SEM of a swollen insoluble collagen matrix crosslinked at a GTA / NH2 ratio
of 0.4
d) SEM of a swollen insoluble collagen matrix crosslinked at a GTA / NH2 ratio
of 2.4
e) Water content, DSC maximum and onset, DeTA loss modulus maximum and
onset of swollen, insoluble collagen matrices as a function of crosslinking 47
3 11: Scheme for the water uptake and swelling model of insoluble collagen 48
3 12: Modeled swelling ratio (height h(t) to initial height h0) of an insoluble collagen
matrix crosslinked with GTA at a molar ratio of GTA / NH2 of 0.8 as a function
of time 49
3 13: a) Degradation of crosslinked insoluble collagen matrices in the presence of
10 U/ml bacterial collagenase at 37 °C as a function of time
b) Lineweaver Burk diagram of the collagenolytic degradation rates of crosslinked
insoluble collagen matrices 50
3 14: a) Release of indomethacin from insoluble collagen matrices crosslinked with
GTA
b) Release of cytochrome c from insoluble collagen matrices crosslinked with
GTA
c) Release of FITC dextran 20 kD from insoluble collagen matrices crosslinked
with EDC
d) Release of FITC dextran 20 kD, FITC dextran 40 kD, FITC lysozyme from
insoluble collagen matrices crosslinked at an EDC / NH2 ratio of 0.8 52
3 15: Release of FTTC BSA in absence and presence of bacterial collagenase from
insoluble collagen matrices 54
3 16: Release of PS1 from crosslinked insoluble collagen matrices in the presence of
bacterial collagenase 56
3 17: Tumor size in SI80 murine sarcoma assay for subcutaneous insertion of PS1
loaded insoluble collagen matrices 57
3 18: Histology of the implant site in S180 murine sarcoma assay 59
4 1: Structural formula of the gentamicin complex 63
4 2: Gentamicin release in vitro from a collagen sponge carrier (Sulmycin® Implant)
and PMMA beads (Septopal®) 64
4 3: Gentamicin levels after implantation of Sulmycin® Implant for treatment of bone
infection and after groin wound vascular graft surgery 65
4 4: Scheme for preparation of PLGA microparticles loaded with gentamicin via
double emulsion technique 68
4 5: Microparticle preparation from different PLA and PLGA types: gentamicin load¬
ing, particle size, and viscosity of polymer solutions in methylene chloride 71
4 6: Gentamicin release from microparticles prepared from different PLA and PLGA
types 72
4 7: Gentamicin release from microparticles prepared from RG 502H/RG 503 blends 73
4 8: Time dependent water content of microparticles prepared from RG 503, 50/50
RG 502H/RG 503, and RG 502H during incubation in phosphate buffered saline 75
4 9: Time dependent SEM of microparticles prepared from RG 503 during incubation
in phosphate buffered saline 76
4 10: Time dependent SEM of microparticles prepared from RG502H during incu¬
bation in phosphate buffered saline 77
4 11: Time dependent SEM of microparticles prepared from 50/50 RG 5O2H/RG 503
during incubation in phosphate buffered saline 78
4 12: Time dependent molecular weight of microparticles prepared from RG 503, 50/50
RG 502H/ RG 503, and RG 502H during incubation in phosphate buffered saline 79
4 13: Time dependent glass transition temperature of microparticles prepared from
RG 503, 50/50 RG 502H/RG 503, and RG 502H during incubation in phosphate
buffered saline in the wet state and after vacuum drying 81
4 14: Temperature dependent microscopy of microparticles prepared from 50/50
RG 502H/RG 503 incubated in phosphate buffered saline 82
4 15: Oscillatory rheometry of insoluble collagen dispersions 85
4 16: Rheogram of a 1 % insoluble collagen dispersion at pH 4.5 and 25 °C 87
4 17: Sedimentation of 50/50 RG502H/RG503 microparticles in insoluble collagen
dispersions pH 4.5 88
4 18: Gentamicin loss from 50/50 RG5O2H/RG5O3 microparticles in acidic
environment pH 4.5 and microscopy of 50/50 RG 502H/RG 503 microparticles
incubated for 6 h in acidic environment pH 4.5 89
4 19: Cross section of collagen sponge / PLGA microparticles composite 90
4 20: Gentamicin release from collagen sponge / PLGA microparticles composites pre¬
pared from 0.56 % collagen dispersion, a 1 % collagen dispersion and a 1 %
collagen dispersion with additional 2 mg gentamicin per 2.8 mg collagen
dissolved 91
5 1: a) Skeletal phenotype of BMP 7 deficient mouse limbs
b) Hypothetical control of bone remodeling via BMPs 95
5 2: Mandibular reconstruction using a collagen sponge 96
5 3: a) Amino acid sequence of rhBMP 2
b) Dimers of rhBMP 2
c) Schematic drawing of the rhBMP 2 monomer fold 97
5 4: Implantation procedure, height evaluation, and new formed bone in the extraction
alveolus in pivotal clinical application of rhBMP 2/ACS combination 101
5 5: Preparation of rhBMP 2/ACS combination for clinical application 102
5 6: ACS manufacturing process 102
5 7: TEM and AFM of collagen dispersion pH 6.2 for ACS preparation 105
5 8: FT IR spectra of a 1 % collagen dispersion pH 6.2 for ACS preparation at 10, 20,
30,40, and 50 °C and at 10 °C before and after heating to 50 °C 105
5 9: AFM of collagen dispersion pH 6.2 for ACS preparation after heating to 50 °C
and cooling 106
5 10: Oscillatory rheometry of a 1% collagen dispersion; frequency dependence of the
complex viscosity at pH 2.5, 6.2, 7.4, and 11 and the storage and loss modulus at
pH 2.5 and 11 107
5 11: SEM of wet ACS after fixation and drying 108
5 12: X ray diffraction pattern of ACS, dry collagen starting material, and a dispersion
pH 6.2 dried at 80 °C 108
5 13: a) Absorbance at 346 nm from 2,4,6 trinitrobenzensulfonic acid (TNBS)
derivatization for ACS and collagen reference material
b) Absorbance at 346 nm from TNBS derivatization for non sterilized ACS;
weight limited between 1 and 5 mg 110
i 5 14: Free amino group analysis of ACS as a function of sterilization, sponge mass, and
crosslinking time Ill
5 15: CH2O distribution in ACS during diffusion controlled crosslinking 111
5 16: Melting temperature of ACS as a function of sterilization, sponge mass, and
crosslinking time 113
5 17: Collagenase degradation of ACS as a function of sterilization, sponge mass, and
crosslinking time 114
5 18: Expressate analysis setup 116
5 19: Expressate pH as a function of sterilization, sponge mass, and crosslinking time 117
5 20: Expressate conductivity as a function of sterilization, sponge mass, and
crosslinking time 118
5 21: Precipitation of rhBMP 2 as a function of pH and NaCl concentration, pH and
Na2SO4 concentration, pH and NaCl + Na2SC 4 concentration 119
5 22: Incorporation of rhBMP 2 at 1.5 mg/ml in ACS as a function of sterilization,
sponge mass, and crosslinking time 121
5 23: Binding of rhBMP 2 to ACS 122
5 24: Incorporation of rhBMP 2 as a function of pH and NaCl concentration, pH and
Na2SO4 concentration, pH and NaCl + Na2SO4 concentration 123
5 25: Time dependent incorporation of rhBMP 2 into ACS 124
5 26: Incorporation of rhBMP 2 as a function of ACS mass and waiting time at
0.75 mg/ml rhBMP 2 and 1.5 mg/ml rhBMP 2 125
5 27: Expressate pH and conductivity at 0.75 mg/ml and 1.5 mg/ml rhBMP 2 126
5 28: Incorporation of rhBMP 2 isoforms in ACS 127
5 29: Retention of rhBMP 2 at the implant site in rat ectopic test 128
5 30: Mechanical testing curve of ACS 129
5 31:SEM of BCP granules 131
5 32: X ray diffraction pattern of BCP granules, HOAp, and TCP 131
5 33: SEM of collagen/BCP composite 132
5 34: Friability testing of BCP granules and collagen / BCP composites 133
5 35: Optimization strategy based on ACS mass 136
LIST OF TABLES
1 1: Chain composition and body distribution of collagen types 2
1 2: Amino acid composition of type I collagen from calf skin 4
1 3: Main applications of collagen for drug delivery systems 24
3 1: Enzymatic degradation rates of crosslinked insoluble collagen matrices 51
3 2: Tumor incidence in S180 murine sarcoma assay for subcutaneous insertion of PS 1
loaded collagen matrices 57
4 1: Process parameters tested and selected for preparation of PLA and PLGA
microparticles loaded with gentamicin via double emulsion technique 69
4 2: Poly(a hydroxy acid)s tested for preparation of microparticles loaded with
gentamicin 70
4 3: Gentamicin loading, particle size, and viscosity of polymer solution in 0.66 ml
methylene chloride for microparticle preparation from RG 503, 50/50
RG 502H/RG 503, and RG 502H 74
4 4: Yield values of insoluble collagen dispersions at different concentration, pH, and
temperature 87
5 1: Bone inducing capability and expression of BMP 2 to 7 94
5 2: Time dependent extraskeletal bone morphogenesis induced by BMP in rat 96
5 3: Theoretical number and pK values of basic and acidic amino acids per collagen
triple helix 104
5 4: Average chloride and sulfate concentrations [mM] in expressates from sterilized
ACS material : 117
5 5: Pharmacokinetic data from rhBMP 2 retention at implant site in rat ectopic test 128
5 6: Compression stress value F6o% upon 4th compression of ACS 130
5 7: Compression stress value Fw% upon 1st compression of collagen / BCP com¬
posites 132
9 1: Influence of inner water phase volume and gentamicin quantity on PLGA
microparticles appearance and loading 182
9 2: Influence of using gentamicin suspended in methylene chloride phase on PLGA
microparticles appearance and loading 182
9 3: Influence of stirring time, amount of polymer, methylene chloride volume, outer
water phase volume, and PVA concentration on PLGA microparticles appearance
and loading 183
9 4: Influence of sonication time on PLGA microparticles appearance and loading 184
9 5: Influence of methylene chloride volume on PLGA microparticles appearance and
loading 184
|
| any_adam_object | 1 |
| author | Frieß, Wolfgang |
| author_facet | Frieß, Wolfgang |
| author_role | aut |
| author_sort | Frieß, Wolfgang |
| author_variant | w f wf |
| building | Verbundindex |
| bvnumber | BV013022327 |
| classification_rvk | VX 8560 |
| ctrlnum | (OCoLC)48478197 (DE-599)BVBBV013022327 |
| discipline | Chemie / Pharmazie |
| edition | Als Ms. gedr. |
| format | Book |
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| genre | (DE-588)4113937-9 Hochschulschrift gnd-content |
| genre_facet | Hochschulschrift |
| id | DE-604.BV013022327 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T18:37:50Z |
| institution | BVB |
| isbn | 3826569946 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-008872532 |
| oclc_num | 48478197 |
| open_access_boolean | |
| owner | DE-29 DE-29T |
| owner_facet | DE-29 DE-29T |
| physical | 186 S. Ill., graph. Darst. |
| publishDate | 2000 |
| publishDateSearch | 2000 |
| publishDateSort | 2000 |
| publisher | Shaker |
| record_format | marc |
| series2 | Berichte aus der Pharmazie |
| spelling | Frieß, Wolfgang Verfasser aut Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen Wolfgang Frieß Arzneistoffträger auf Basis von Kollagen Als Ms. gedr. Aachen Shaker 2000 186 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Berichte aus der Pharmazie Zugl.: Erlangen-Nürnberg, Univ., Habil.-Schr., 1999 Biologischer Abbau (DE-588)4145625-7 gnd rswk-swf Arzneistoffträger (DE-588)4278196-6 gnd rswk-swf Kollagen (DE-588)4164652-6 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Arzneistoffträger (DE-588)4278196-6 s Kollagen (DE-588)4164652-6 s Biologischer Abbau (DE-588)4145625-7 s DE-604 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=008872532&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Frieß, Wolfgang Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen Biologischer Abbau (DE-588)4145625-7 gnd Arzneistoffträger (DE-588)4278196-6 gnd Kollagen (DE-588)4164652-6 gnd |
| subject_GND | (DE-588)4145625-7 (DE-588)4278196-6 (DE-588)4164652-6 (DE-588)4113937-9 |
| title | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen |
| title_alt | Arzneistoffträger auf Basis von Kollagen |
| title_auth | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen |
| title_exact_search | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen |
| title_full | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen Wolfgang Frieß |
| title_fullStr | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen Wolfgang Frieß |
| title_full_unstemmed | Drug delivery systems based on collagen = Arzneistoffträger auf Basis von Kollagen Wolfgang Frieß |
| title_short | Drug delivery systems based on collagen |
| title_sort | drug delivery systems based on collagen arzneistofftrager auf basis von kollagen |
| title_sub | = Arzneistoffträger auf Basis von Kollagen |
| topic | Biologischer Abbau (DE-588)4145625-7 gnd Arzneistoffträger (DE-588)4278196-6 gnd Kollagen (DE-588)4164652-6 gnd |
| topic_facet | Biologischer Abbau Arzneistoffträger Kollagen Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=008872532&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT frießwolfgang drugdeliverysystemsbasedoncollagenarzneistofftrageraufbasisvonkollagen AT frießwolfgang arzneistofftrageraufbasisvonkollagen |