Biopharmaceutics applications in drug development
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2008
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| 008 | 080528s2008 xx ad|| |||| 00||| eng d | ||
| 015 | |a GBA770535 |2 dnb | ||
| 020 | |a 9780387723785 |9 978-0-387-72378-5 | ||
| 020 | |a 0387723781 |c (hbk.) : £96.00 |9 0-387-72378-1 | ||
| 035 | |a (OCoLC)166358030 | ||
| 035 | |a (DE-599)HBZHT015517862 | ||
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| 245 | 1 | 0 | |a Biopharmaceutics applications in drug development |c ed. by Rajesh Krishna ... |
| 264 | 1 | |a New York, NY |b Springer |c 2008 | |
| 300 | |a XXII, 396 S. |b Ill., graph. Darst. |c 24cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 500 | |a Includes index | ||
| 650 | 4 | |a Biopharmaceutics | |
| 650 | 4 | |a Biopharmaceutics |x methods | |
| 650 | 4 | |a Drug Design | |
| 650 | 4 | |a Drug development | |
| 650 | 4 | |a Pharmaceutical Preparations | |
| 700 | 1 | |a Krishna, Rajesh |e Sonstige |4 oth | |
| 856 | 4 | 2 | |m HBZ Datenaustausch |q application/pdf |u http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016501093&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |3 Inhaltsverzeichnis |
| 943 | 1 | |a oai:aleph.bib-bvb.de:BVB01-016501093 | |
Datensatz im Suchindex
| _version_ | 1819775364472242176 |
|---|---|
| adam_text | Contents
Contributors xxi
1 Introduction to Biopharmaceutics and its Role in Drug Development . . 1
1.1 Introduction to Biopharmaceutics 1
1.1.1 What is Biopharmaceutics? 1
1.1.2 Physical Pharmacy: Physical-Chemical Principles .... 2
1.1.2.1 Solubility 2
1.1.2.2 Hydrophilicity/Lipophilicity 2
1.1.2.3 Salt Forms and Polymorphs 2
1.1.2.4 Stability 3
1.1.2.5 Particle and Powder Properties 3
1.1.2.6 Ionization and p^Ta 3
1.1.3 Formulation Principles 4
1.1.4 Physiological/Biological Principles 4
1.1.4.1 Pharmacokinetics 4
1.1.5 Biopharmaceutics: Integration of Physical/Chemical
and Biological/Pharmacokinetic Principles
and Impact on Clinical Efficacy 6
1.1.5.1 Introduction to the Biopharmaceutics
Classification System 6
1.1.5.2 Impact of Physical/Chemical Properties
on Absorption and Transport 7
1.1.5.3 Strategies to Achieve Target Pharmacokinetic
Profile 10
1.2 Role of Biopharmaceutics in Drug Development 14
1.2.1 Importance of Biopharmaceutics in the Overall
Development Process 14
1.2.2 Discovery and Preclinical Development:
Candidate Selection 15
1.2.3 Preclinical Development: Preparation
for Phase I Clinical Studies 16
1.2.4 Early Clinical Development 17
1.2.5 Advanced Clinical Development 19
1.2.6 Postapproval Considerations 20
xi
xii Contents
1.2.7 Regulatory Considerations 21
1.3 Summary 21
2 Molecular and Physicochemical Properties Impacting
Oral Absorption of Drugs 26
2.1 Introduction 26
2.2 Molecular and Physicochemical Properties
Impacting Oral Absorption 27
2.2.1 Molecular Weight, Log P, the Number of H-Bond Donors
and Acceptors, Polar Surface Area, and the
Number of Rotatable Bonds 27
2.2.2 Chirality 29
2.2.3 Dissolution 29
2.2.4 Solubility 30
2.2.4.1 Definition of Solubility 30
2.2.4.2 Factors Contributing
to Poor Aqueous Solubility 30
2.2.4.3 pH-Solubility Profile 31
2.2.4.4 Effectof Temperatureon Solubility 34
2.2.4.5 Solubility in Gastric and Intestinal Fluids .... 35
2.2.4.6 Solubility as a Limiting Factor to Absorption . . 36
2.2.4.7 Solubility Determination 36
2.2.4.8 Solubility Prediction 38
2.2.5 Chemical Stability 38
2.2.6 Solid State Properties 39
2.2.6.1 Polymorphism 39
2.2.6.2 Amorphous Material 40
2.2.6.3 ParticleSize 41
2.3 Physicochemical Properties and Drug Delivery Systems 41
2.4 Summary 43
3 Dissolution Testing 47
3.1 Introduction 47
3.2 Significance of Dissolution in Drug Absorption 47
3.3 Theories of Dissolution 49
3.4 Factors Affecting Dissolution 51
3.4.1 Factors Related to the Physicochemical Properties
of the Drug Substance 52
3.4.1.1 Solubility 52
3.4.1.2 ParticleSize 52
3.4.1.3 Solid Phase Characteristics 53
3.4.1.4 SaltEffects 53
3.4.2 Factors Related to Drug Product Formulation 53
3.4.3 Factors Related to Manufacturing Processes 54
3.4.4 Factors Related to Dissolution Testing Conditions 55
3.5 Roles of Dissolution Testing 55
Contents xiii
3.6 In Vitro Dissolution Testing as a Quality Control Tool 56
3.6.1 Dissolution Method for Quality Control of
Immediate-Release Dosage Forms 57
3.6.1.1 Dissolution Media 57
3.6.1.2 Apparatus and Test Conditions 58
3.6.2 Dissolution Method for Quality Control of
Modified-Release Dosage Forms . 58
3.6.2.1 Dissolution Media 58
3.6.2.2 Apparatus and Test Conditions 59
3.6.3 Limitations of Quality Control Dissolution Tests 59
3.7 Biorelevant Dissolution Testing 60
3.7.1 In Vivo-In Vitro Correlations 61
3.7.2 The Importance of BCS on Biorelevant
Dissolution Testing 61
3.7.3 Biorelevant Dissolution Methods 64
3.7.3.1 Biorelevant Dissolution Media for
Gastric Conditions 65
3.7.3.2 Apparatus and Test Conditions for
Simulating the Stomach 66
3.7.3.3 Biorelevant Dissolution Media for
Intestinal Conditions . • 67
3.7.3.4 Apparatus and Test Conditions for
Simulating Small Intestine 69
3.7.3.5 Biorelevant Methods for Extended-Release
Dosage Forms 69
3.7.3.6 Remaining Challenges . 69
3.8 Conclusions 70
4 Drug Absorption Principles . 75
4.1 Drug Absorption and Bioavailability 75
4.2 Types of Intestinal Membrane Transport ¦ 76
4.2.1 Passive Diffusion 76
4.2.2 Carrier-Mediated Transport 78
4.2.2.1 Facilitated Diffusion 78
4.2.2.2 Active Transport 79
4.2.3 Paracellular Transport 79
4.2.4 Endocytosis • 79
4.2.5 Which Absorption Path Dominates Drug Absorption? . . 80
4.3 Three Primary Factors Influence Drug Absorption 80
4.3.1 Membrane Perrneability 81
4.3.1.1 Effective Perrneability • 81
4.3.1.2 Fraction of Drug Absorbed 81
4.3.1.3 Perrneability and Absorption Rate Constant . . 82
4.3.2 Solubility - 82
4.3.3 Dissolution of Solid Dosage Forms 83
xiv Contents
4.4 Secondary Factors Influencing Drug Absorption 84
4.4.1 Biological Factors of Gastrio Intestinal Tract 84
4.4.1.1 Gastric Emptying Time 84
4.4.1.2 SurfaceArea 84
4.4.1.3 GI Transit Time 84
4.4.1.4 Intestinal Motility 85
4.4.1.5 Components, Volume, and Properties of
Gastrointestinal Fluids 85
4.4.1.6 Food 85
4.4.1.7 BloodFlow 85
4.4.1.8 Age 86
4.4.2 Dosage Factors Influencing Absorption 86
4.5 Evaluation of Oral Drug Absorption in Humans 86
4.5.1 Drug Absorption Assessment Using In Vivo Data 86
4.5.1.1 Estimation of Fraction of Drug Absorbed
Using Experimental Intestinal Permeability
In Vivo 86
4.5.1.2 Estimation of Maximum Absorbable Dose
Using In Vivo Absorption Rate Constant
and Drug Solubility 88
4.5.1.3 Estimation of MAD from Drug In Vivo
Permeability in Human and Drug Solubility . . 89
4.5.2 Drug Absorption Assessment Using In Vitro Data 90
4.5.2.1 In Vitro Testing Conditions for Determining
Drug Permeability in Caco-2 Cells
and In Vitrolln Vivo Permeability
Correlation 90
4.5.2.2 Estimation of Fraction of Drug Absorbed
In Humans Using In Vitro Drug Permeability
in Caco-2 Cells 92
4.5.2.3 Estimation of MAD in Human Based
on In Vitro Data 93
4.5.3 Correlation of Oral Drug Bioavailability and
Intestinal Permeability Between Rat and Human 95
4.6 Summary 97
5 Evaluation of Permeability and P-glycoprotein Interactions:
Industry Outlook 101
5.1 Introduction 101
5.2 AnatomyandPhysiologyoftheSmalllntestine 104
5.3 Permeability Absorption Models 105
5.3.1 Physicochemical Methods 105
5.3.1.1 Lipophilicity (Log P/Log D) 105
5.3.1.2 Absorption Potential 105
5.3.1.3 Immobilized Artificial Membrane (IAM) .... 106
Contents xv
5.3.2 In Vitro Methods 106
5.3.2.1 Animal Tissue-Based Methods 107
5.3.2.2 Cell-Based Methods 109
5.3.3 In Situ Methods 111
5.3.4 In Vivo Methods 112
5.3.5 In Silico Methods 113
5.4 Comparisonof PAMPA and Caco-2Cells 114
5.4.1 Parallel Artificial Membrane Permeability Assay 114
5.4.1.1 PAMPA Study Protocol 115
5.4.2 Caco-2Cells 115
5.4.2.1 Caco-2 Cell Culture 116
5.4.2.2 Caco-2 cells Study Protocol 116
5.4.3 PAMPA and Caco-2 Cell: Synergies 116
5.4.4 PAMPA and Caco-2 Cell: Caveats 123
5.4.4.1 Transporter- and Paracellular-Mediated
Absorption 123
5.4.4.2 Incomplete Mass-Balance Due to
Nonspecific Binding 125
5.4.4.3 Inadequate Aqueous Solubility 125
5.4.4.4 Other Experimental Variability 126
5.5 P-gp Studies Using Caco-2 Cells 127
5.5.1 Experimental Factors Effecting Efflux Ratio 129
5.6 Conclusions 132
6 Excipients as Absorption Enhancers 139
6.1 Introduction 139
6.2 Basic Mechanisms in Transcellular and Paracellular Transport . . 140
6.2.1 Transcellular Transport 141
6.2.2 Paracellular Transport 142
6.2.3 Mechanisms of Action of Absorption Enhancers 142
6.2.3.1 Action on the Mucus Layer 143
6.2.3.2 Action on Membrane Components 143
6.3 Mucoadhesive Polymers as Absorption Enhancers 148
6.3.1 Theories of Mucoadhesion 148
6.3.2 Material Properties of Mucoadhesives 150
6.3.3 Classes of Mucoadhesive Polymers 152
6.3.3.1 Polyacrylates 152
6.3.3.2 Chitosan 156
6.3.3.3 N,N,N,-Trimethyl Chitosan Hydrochloride
(TMC) 158
6.3.3.4 Monocarboxymethyl Chitosan 161
6.3.3.5 Thiolated Polymers 162
6.3.3.6 Solid Dosage Form Design Based on TMC
and Thiolated Polymers and Their
In Vivo Evaluation 164
6.4 Conclusions 166
xvi Contents
7 Intestinal Transporters in Drug Absorption 175
7.1 Introduction 175
7.2 ATP Binding Cassette Transporters 179
7.2.1 P-Glycoprotein(P-gp;ABCBl) 183
7.2.1.1 The Expression ofP-gp 183
7.2.1.2 The Regulation ofP-gp Expression 184
7.2.1.3 P-gp Mediated Drug Transport 185
7.2.1.4 The Substrate Specificity of P-gp 185
7.2.2 Multidrug Resistance-Associated Protein Family
(MRP;ABCC) 188
7.2.2.1 The Expression ofMRPs 188
7.2.2.2 The Regulation ofMRP Isoform Expression . . 190
7.2.2.3 The Substrate Specificity of MRP s 190
7.2.3 Breast Cancer Resistance Protein (BCRP; ABCG2) .... 193
7.3 Solute Carrier Transporters 195
7.3.1 Proton/Oligopeptide Transporters (POT; SLC15A) .... 195
7.3.1.1 Peptide Transporter Mediated Transport .... 197
7.3.1.2 The Substrate Specificity of Peptide
Transporters 198
7.3.1.3 The Regulation of Peptide Transporters 200
7.3.2 Organic Anion Transporters
(OAT, SLC22A; OATP, SLCO) 202
7.3.2.1 OAT(SLC22A) 202
7.3.2.2 OATP (SLCO) 204
7.3.3 Organic Cation Transporters (OCT, OCTN; SLC22A) . . 209
7.3.3.1 The Substrate Specificity of Organic Cation
Transporters 210
7.3.3.2 Organic Cation Transporter Mediated
Transport 211
7.3.3.3 The Expression of Organic Cation
Transporters 211
7.3.3.4 The Regulation of Organic Cation
Transporters 212
7.3.4 Nucleoside Transporters
(CNT, SLC28A; ENT, SLC29A) 214
7.3.4.1 The Molecular and Structural Characteristics
of Nucleoside Transporters 215
7.3.4.2 The Substrate Specificities of Nucleoside
Transporters 217
7.3.4.3 The Expression of Nucleoside Transporters . . . 219
7.3.4.4 The Regulation of Nucleoside Transporters . . . 220
7.3.5 Monocarboxylate Transporters (MCT; SLC16A) 221
7.3.5.1 Molecular and Structural Characteristics
of Monocarboxylate Transporters 222
Contents xvii
7.3.5.2 The Substrate Specificity of Monocarboxylate
Transporters 222
7.3.5.3 The Expression of Monocarboxylate
Transporters 223
7.3.5.4 The Regulation of Monocarboxylate
Transporters 224
7.4 Impact of Intestinal Transporters on Bioavailability 225
8 Bioavailability and Bioequivalence 262
8.1 Introduction 262
8.2 Bioavailability and Bioequivalence 262
8.2.1 Bioavailability and its Utility in Drug Development
and Regulation 262
8.2.2 Bioequivalence and its Utility in Drug Development
and Regulation 263
8.2.3 Bioavailability and Bioequivalence Studies: General
Approaches 264
8.3 Pharmacokinetic Bioavailability and Bioequivalence Studies . . . 265
8.3.1 Bioavailability Studies: General Guidelines
and Recommendations 265
8.3.2 Bioequivalence Studies: General Guidelines
and Recommendations 267
8.3.2.1 Study Design 267
8.3.2.2 Dose 267
8.3.2.3 Subjects 268
8.3.2.4 Statistical Analysis of Bioequivalence 268
8.4 Bioequivalence: Challenging Topics 271
8.4.1 Drugs with Active Metabolites 271
8.4.2 Enantiomers vs. Racemates 273
8.4.3 Endogenous Substances 273
8.4.4 Highly Variable Drugs 274
8.4.4.1 Static Expansion oftheBE Limits 274
8.4.4.2 Expansion of Bioequivalence Limits Based
on Fixed Sample Size 275
8.4.4.3 Scaled Average Bioequivalence 275
8.5 Biowaivers 276
8.5.1 Solutions 276
8.5.2 Lower Strength 278
8.5.3 Biopharmaceutical Classification System 279
8.5.3.1 Biowaivers for BCS Class 2 Drugs with pH
Dependent Solubility 280
8.5.3.2 Biowaivers for BCS Class 3 Drugs 280
8.6 Locally Acting Drugs 281
8.6.1 Topical Dermatological Products 281
xviii Contents
8.6.2 Locally Acting Nasal and Oral Inhalation Drug
Products 283
8.6.2.1 Nasal Spray Products 284
8.6.2.2 Oral Inhalation Products 285
8.7 Conclusions 287
9 A Biopharmaceutical Classification System Approach to Dissolution:
Mechanisms and Strategies 290
9.1 Introduction 290
9.2 Biopharmaceutical Classification System Approach to Dissolution 290
9.3 In Vitro-In Vivo Dissolution Correlation 292
9.4 Recent Climate: Pharmaceutical Quality Assessment 294
9.5 Discussion 296
9.5.1 BCS Class I and III Case Studies 296
9.5.1.1 Case Study 1: Fast Release ( 85% Release in
15 min) with Disintegration Controlled
Dissolution 298
9.5.1.2 Case Study 2: 85% Release in 15 min
with Disintegration/Erosion Controlled
Dissolution 299
9.5.1.3 Case Study 3: Dissolution Mechanism
not Dependent on Disintegration/Erosion .... 301
9.5.2 BCS Class II and IV Case Studies 302
9.5.2.1 Case Study 4: Liquid Filled (True Solution)
Capsules 303
9.5.2.2 Case Studies 5,6, and 7: Intrinsic Rate of Drug
Solubilization Controlled Dissolution 303
9.5.2.3 Case Studies 8 and 9: Mixed Contribution
of Formulation Colligative Properties and
Intrinsic Rate of Drug Solubilization 306
9.5.2.4 Case Study 10: API with High Solubility
atGastricpHs 309
9.5.3 Controlled Release Dosage Form Case Study 310
9.5.4 Pharmaceutical Quality Assessment Implications
of Dissolution 313
9.6 Conclusion 314
10 Food Effects on Drug Bioavailability: Implications for New and Generic
Drug Development 317
10.1 Introduction 317
10.1.1 Objectives 317
10.1.2 Oral Bioavailability Defined 317
10.1.3 How Food Can Affect Drug Bioavailability 317
10.2 Food Interactions with Drug Substance 318
Contents xix
10.2.1 Pharmacokinetic Parameters Used to Characterize Food
Effects on Drag Bioavailability 318
10.2.2 Prolonged Rate of Drug Absorption in the Presence
ofFood 318
10.2.3 Decreased Drug Absorption in the Presence of Food ... 319
10.2.3.1 Overview 319
10.2.3.2 Instability in Gastric Acids 319
10.2.3.3 Physical or Chemical Binding with
Food Components 319
10.2.3.4 Increased First-Pass Metabolism and
Clearance 320
10.2.4 Increased Drug Absorption in the Presence of Food . . . . 320
10.2.4.1 Inhibition of First-Pass Effect 320
10.2.4.2 Physicochemical and Physiological Effects ... 321
10.2.4.3 Effects ofBile Release 322
10.2.4.4 Effects of Longer Gastric Residence Time ... 322
10.2.5 Drug Absorption Unaffected by Food 322
10.2.6 FDA Guidance for Industry on Characterizing Food
Effects in Drag Development 323
10.2.6.1 Objectives 323
10.2.6.2 Recommended Designs for Food-Effect
Bioavailability Studies 323
10.2.6.3 Recommendations for Drag Product
Labeling 323
10.3 Food Interactions with Drag Product 324
10.3.1 Introduction 324
10.3.2 Issues with Modified-Release Drag Products:
Potential for Dose-Dumping 325
10.3.3 Issues with Modified-Release Drag Products:
Formulation-Dependant Food Effects 326
10.3.3.1 In Vitro Drag Release Predictive of
Food Effects 326
10.3.3.2 In Vitw Drag Release Profiles Not Predictive of
Food Effects 326
10.3.4 Implications for Development of Generic
Modified-Release Drag Products 327
10.3.4.1 Introduction 327
10.3.4.2 Roleof/n V/vo Fed Bioequivalence Studies . . 327
10.3.5 Implications for Development of Generic
Immediate-Release Drag Products 328
10.3.5.1 BCS Class I Drugs 328
10.3.5.2 Label-Driven Criteria for Requesting Fed
Bioequivalence Studies 329
10.3.6 Recommendations for Designing Fed Bioequivalence
Studies 330
xx Contents
10.3.7 Food Effects and Generic Drug Product Labeling 331
10.3.8 Sprinkle Studies in New and Generic Drug Product
Development 331
10.3.8.1 Sprinkle Studies in Development of
New Modified-Release Capsules 331
10.3.8.2 Sprinkle Studies in Development of Generic
Modified-Release Capsules 331
10.3.8.3 Example 332
10.4 Summary and Conclusions 332
11 In Vitro-In Vivo Correlation on Parenteral Dosage Forms 336
11.1 IVIVC Definition 336
11.2 Modified Release Parenteral Products 336
11.3 Factors to Consider for Meaningful IVIVC 337
11.3.1 Product Related Factors 337
11.3.2 Factors Affecting In Vitro Release 338
11.3.2.1 Accelerated In Vitro Release Testing 341
11.3.3 Mathematical Models of In Vitro Drug Release 341
11.3.4 Factors Affecting In Vivo Release 343
11.4 In Vitro-In Vivo Correlation 344
11.5 Microspheres 345
11.6 Liposomes 347
11.7 Emulsions 349
11.8 Hydrogels, Implants 350
11.9 Dendrimers 351
12 In Vitro-In Vivo Correlation in Dosage Form Development:
Case Studies 359
12.1 Introduction 359
12.2 IVIVC in Drug Product Development: A Four-Tier Approach . . . 360
12.3 Case Studies 363
12.3.1 Tier 1 - Discovery and Early Preclinical
Development: Assessing Developability
and Formulation Principles 363
12.3.2 Tier 2 - Preclinical Product Development: Selection
of a Meaningful Dissolution Method 367
12.3.3 Tier 3 - Füll Development: Deconvolution of Human
Pharmacokinetic Data and Comparison with
In Vitro Dissolution Data 372
12.4 Deconvolution and Convolution 372
12.4.1 Tier 4: Application of IVIVC in LCM 376
12.5 Conclusions 380
Index 383
|
| any_adam_object | 1 |
| building | Verbundindex |
| bvnumber | BV023316927 |
| callnumber-first | R - Medicine |
| callnumber-label | RM301 |
| callnumber-raw | RM301.4 |
| callnumber-search | RM301.4 |
| callnumber-sort | RM 3301.4 |
| callnumber-subject | RM - Therapeutics and Pharmacology |
| classification_rvk | VX 8500 |
| ctrlnum | (OCoLC)166358030 (DE-599)HBZHT015517862 |
| dewey-full | 615.19 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| id | DE-604.BV023316927 |
| illustrated | Illustrated |
| indexdate | 2024-12-23T21:01:02Z |
| institution | BVB |
| isbn | 9780387723785 0387723781 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-016501093 |
| oclc_num | 166358030 |
| open_access_boolean | |
| owner | DE-19 DE-BY-UBM |
| owner_facet | DE-19 DE-BY-UBM |
| physical | XXII, 396 S. Ill., graph. Darst. 24cm |
| publishDate | 2008 |
| publishDateSearch | 2008 |
| publishDateSort | 2008 |
| publisher | Springer |
| record_format | marc |
| spellingShingle | Biopharmaceutics applications in drug development Biopharmaceutics Biopharmaceutics methods Drug Design Drug development Pharmaceutical Preparations |
| title | Biopharmaceutics applications in drug development |
| title_auth | Biopharmaceutics applications in drug development |
| title_exact_search | Biopharmaceutics applications in drug development |
| title_full | Biopharmaceutics applications in drug development ed. by Rajesh Krishna ... |
| title_fullStr | Biopharmaceutics applications in drug development ed. by Rajesh Krishna ... |
| title_full_unstemmed | Biopharmaceutics applications in drug development ed. by Rajesh Krishna ... |
| title_short | Biopharmaceutics applications in drug development |
| title_sort | biopharmaceutics applications in drug development |
| topic | Biopharmaceutics Biopharmaceutics methods Drug Design Drug development Pharmaceutical Preparations |
| topic_facet | Biopharmaceutics Biopharmaceutics methods Drug Design Drug development Pharmaceutical Preparations |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016501093&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT krishnarajesh biopharmaceuticsapplicationsindrugdevelopment |