Sanders / Hendren Protein Delivery

Physical Systems
1. Auflage 2005
ISBN: 978-0-306-46803-2
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 10, 447 Seiten

Reihe: Pharmaceutical Biotechnology

Thirteen chapters by industrial and academic authorities in this rapidly evolving field present detailed case histories and reviews of current sophisticated protein-drug delivery technologies. Highlights include a comprehensive overview of insulin delivery and a discussion of the use of biodegradable microspheres.

Autoren/Hrsg.

Sanders, Lynda M.

Hendren, R. Wayne

Inhaltsverzeichnis

1;Contributors;6
2;Preface to the Series;9
3;Preface;11
4;Contents;13
5;Protein Delivery from Biodegradable Microspheres;22
5.1;1. INTRODUCTION;22
5.2;2. COMPONENTS FOR SUCCESSFUL DEVELOPMENT OF MICROSPHERE FORMULATIONS;24
5.2.1;2.1. Polymer Chemistry;24
5.2.2;2.2. Engineering of Microsphere Formulations;29
5.2.3;2.3. Protein Stability;42
5.3;3. CASE STUDIES OF DRUG DELIVERY FROM BIODEGRADABLE MICROSPHERES;45
5.3.1;3.1. LupronDepot;45
5.3.2;3.2. MNrgp120 Controlled Release Vaccine;47
5.4;4. IMMUNOGENICITY AND INJECTION- SITE CONSIDERATIONS;51
5.5;5. REGULATORY REQUIREMENTS FOR DEVELOPMENT OF PROTEIN DELIVERY FROM MICROSPHERES;55
5.5.1;5.1. Toxicology Studies;55
5.5.2;5.2. Residual Solvent Concerns;56
5.5.3;5.3. Manufacturing Issues;57
5.5.4;5.4. Preclinical Animal Models and Clinical Experiments;58
5.6;6. SUMMARY;59
5.7;REFERENCES;60
6;Degradable Controlled Release Systems Useful for Protein Delivery;65
6.1;1. INTRODUCTION;65
6.2;2. DEFINITIONS;68
6.3;3. SYNTHETIC HYDROPHOBIC DEGRADABLE POLYMERS;69
6.3.1;3.1. Poly(lactic acid), Poly(glycolic acid), and Their Copolymers;69
6.3.2;3.2. Polycaprolactone;75
6.3.3;3.3. Poly(hydroxybutyrate), Poly(hydroxyvalerate), and Their Copolymers;76
6.3.4;3.4. Poly(ortho esters);77
6.3.5;3.5. Polyanhydrides;81
6.3.6;3.6. Polyphosphazenes;85
6.3.7;3.7. Delivery of Vaccines;85
6.4;4. HYDROPHILIC POLYMERIC BIOMATERIALS AND HYDROPHOBIC NONPOLYMERIC BIOMATERIALS;90
6.4.1;4.1. General;90
6.4.2;4.2. Specific Hydrophilic Polymeric Biomaterials;91
6.4.3;4.3. Specific Hydrophobic Nonpolymeric Biomaterials;99
6.4.4;4.4. Miscellaneous;101
6.5;5. CONCLUSIONS;102
6.6;REFERENCES;103
7;Delivery of Proteins from a Controlled Release Injectable Implant;113
7.1;1. THE ATRIGEL ™ DRUG DELIVERY SYSTEM;113
7.2;2. EFFECTS OF FORMULATION VARIABLES ON PROTEIN RELEASEKINETICS;115
7.2.1;2.1. Polymer Type;116
7.2.2;2.2. Polymer Concentration;117
7.2.3;2.3. Polymer Molecular Weight;118
7.2.4;2.4. Solvent;119
7.2.5;2.5. Protein Load;120
7.2.6;2.6. Additives;121
7.3;3. CHARACTERIZATION;122
7.3.1;3.1. Protein Quantitation in Different ReleaseMedia;122
7.3.2;3.2. Protein Structure;125
7.3.3;3.3. Enzyme Activity;127
7.3.4;3.4. Cellular Bioactivity;128
7.4;4. IN VIVO EVALUATIONS;130
7.4.1;4.1. Biocompatibility;130
7.4.2;4.2. Protein Release Kinetics;131
7.4.3;4.3. Bioactivity;133
7.5;5. CONCLUSIONS;135
7.6;REFERENCES;136
8;Protein Delivery from Nondegradable Polymer Matrices;138
8.1;1. INTRODUCTION;138
8.1.1;1.1. Biocompatible Polymers Used as Hydrophobic Matrices;139
8.1.2;1.2. Protein Release from Polymer Matrices;141
8.2;2. MECHANISMS AND MODELS FOR PROTEIN RELEASE FROM MATRICES;143
8.2.1;2.1. Macroscopic Models of Diffusion in Porous Polymer Matrices;144
8.2.2;2.2. Microscopic Models of Diffusion in Porous Polymer Matrices;150
8.3;3. APPLICATIONS OF PROTEIN/ POLYMER MATRIX SYSTEMS;151
8.3.1;3.1. Topical Delivery;152
8.3.2;3.2. Targeted Delivery of Proteins to Specific Tissue Regions;152
8.3.3;3.3. Systemic Delivery for Extended Periods;153
8.4;REFERENCES;153
9;Diffusion-Controlled Delivery of Proteins from Hydrogels and Other Hydrophilic Systems;157
9.1;1. INTRODUCTION;157
9.1.1;1.1. Mechanisms of Protein Diffusion;158
9.1.2;1.2. Structure of Hydrophilic Polymers;160
9.1.3;1.3. Methods for Loading Proteins into Hydrogels;162
9.2;2. DIFFUSION- CONTROLLED DELIVERY SYSTEMS;163
9.2.1;2.1. Reservoir Systems;163
9.2.2;2.2. Matrix Systems;165
9.2.3;2.3. Biodegradable Hydrogels;167
9.3;3. FACTORS AFFECTING THE DIFFUSION OF PROTEINS;169
9.3.1;3.1. Environmental Conditions;169
9.3.2;3.2. Hydrogel Structure;170
9.4;4. TECHNIQUES FOR MEASUREMENT OF THE DIFFUSION COEFFICIENT;171
9.4.1;4.1. Membrane Permeation Method;173
9.4.2;4.2. Absorption/Desorption Method;175
9.4.3;4.3. Scanning Electron Microscopy (SEM);178
9.4.4;4.4. Fourier Transform Infrared (FTIR) Spectroscopy;178
9.4.5;4.5. Quasi-Elastic Light Scattering (QELS) Method;179
9.4.6;4.6. Other Techniques;180
9.5;REFERENCES;180
10;Poly(ethyleneglycol)-CoatedNanospheres: Potential Carriers for Intravenous Drug Administration;184
10.1;1. Introduction;184
10.1.1;1.1. Approaches to Increase Particle Blood Circulation Time;186
10.1.2;1.2. PEG Hydrophilic Coatings: Mechanism of Protein Rejection;187
10.2;2. PEG-COATED LONG-CIRCULATING DRUG CARRIERS;188
10.3;3. PEG-COATED BIODEGRADABLE NANOSPHERES POTENTIAL LONG-CIRCULATING DRUG CARRIERS;190
10.3.1;3.1. Biodegradable Polymers Containing PEG Blocks;191
10.3.2;3.2. Preparation of PEG- Coated Nanospheres;193
10.4;4. NANOSPHERE CHARACTERIZATION;194
10.4.1;4.1. Morphology Studies;194
10.4.2;4.2. Size Distribution Measurement;196
10.4.3;4.3. Detection and Stability of the PEG Coating;197
10.4.4;4.4. Surface Hydrophobicity and Charge Determination;198
10.5;5. DRUG ENCAPSULATION IN PEG- COATED NANOSPHERES;200
10.5.1;5.1. Drug Encapsulation and Release Properties;200
10.5.2;5.2. Parameters Influencing Drug Release;201
10.6;6. STUDIES (PHAGOCYTOSIS ASSAY);204
10.7;7. BLOOD HALF-LIFE AND ORGAN DISTRIBUTION OF PEG COATED NANOSPHERES;205
10.8;8. CONCLUSION;209
10.9;REFERENCES;210
11;Multiple Emulsions for the Delivery of Proteins;216
11.1;1. INTRODUCTION;216
11.2;2. METHODS OF PREPARATION;217
11.3;3. STABILITY ISSUES;218
11.3.1;3.1. Background;218
11.3.2;3.2. Surfactant Migration;219
11.3.3;3.3. Osmotic Gradients;219
11.3.4;3.4. Process Denaturation of Protein;219
11.3.5;3.5. Methods to Determine Physical Stability;220
11.4;4. APPLICATIONS;220
11.4.1;4.1. Parenteral Administration;220
11.4.2;4.2. Oral Administration;221
11.5;5. SOLID- STATE EMULSIONS;222
11.5.1;5.1. Method of Preparation;223
11.5.2;5.2. Physical Properties of Solid- state Emulsions;223
11.5.3;5.3. Oral Administration of Vancomycin Solid- state Emulsion;224
11.6;6. MISCELLANEOUS APPLICATIONS;225
11.6.1;6.1. Vaccine Adjuvants;225
11.6.2;6.2. Enzyme Immobilization;225
11.7;7. SUMMARY;226
11.8;REFERENCES;226
12;Transdermal Peptide Delivery Using Electroporation;229
12.1;1. INTRODUCTION;229
12.2;2. RESULTS AND DISCUSSION;233
12.2.1;2.1. In Vitro Transport;233
12.2.2;2.2. Isolated Perfused Porcine Skin Flap;243
12.2.3;2.3. Skin Toxicology following Electroporation;248
12.3;3. CONCLUSION;251
12.4;REFERENCES;251
13;Protein Delivery with Infusion Pumps;255
13.1;1. INTRODUCTION;255
13.1.1;1.1. Rationale for Infusion Therapy;255
13.1.2;1.2. Limitations of Infusion Therapy;258
13.2;2. HISTORY OF INFUSION THERAPY;259
13.3;3. STATIONARY AND PORTABLE INFUSION PUMPS;261
13.3.1;3.1. Stationary Infusion Pumps;262
13.3.2;3.2. Implantable Infusion Pumps;265
13.3.3;3.3. External Infusion Pumps;266
13.4;4. SUMMARY;268
13.5;REFERENCES;269
14;Oral Delivery of Microencapsulated Proteins;271
14.1;1. INTRODUCTION;271
14.2;2. MECHANISMS OF INTESTINAL ABSORPTION OF PROTEINS AND PEPTIDES;273
14.2.1;2.1. Passive Diffusion;273
14.2.2;2.2. Carrier-Mediated Transport;275
14.2.3;2.3. Receptor-Mediated and Non-Receptor-Mediated Endocytosis;277
14.3;3. MECHANISMS OF INTESTINAL ABSORPTION OF MICROPARTICULATES;280
14.3.1;3.1. Transcellular Pathway;281
14.3.2;3.2. Paracellular Transport;283
14.3.3;3.3. Liposome Absorption;284
14.4;4. CASE STUDIES;285
14.4.1;4.1. Introduction;285
14.4.2;4.2. Polyester Microspheres;286
14.4.3;4.3. Zein Microspheres;287
14.4.4;4.4. Proteinoid Microspheres;288
14.4.5;4.5. Polycyanoacrylate Microspheres;289
14.4.6;4.6. Lipid-Based Systems;291
14.5;5. CONCLUSION;293
14.6;REFERENCES;293
15;Controlled Delivery of Somatotropins;305
15.1;1. INTRODUCTION;305
15.2;2. PREFORMULATION DEVELOPMENT;307
15.2.1;2.1. Solution Stability;307
15.2.2;2.2. Molecular Modification;309
15.3;3. IN JECTABLES;311
15.3.1;3.1. Oil-Based Gel Depots;311
15.3.2;3.2. Microsphere Systems;315
15.3.3;3.3. Liposomes;317
15.3.4;3.4 Emulsions;317
15.3.5;3.5. Aqueous Gels and Complexes;318
15.4;4. IMPLANTS;319
15.4.1;4.1. Uncoated Implants;319
15.4.2;4.2. Coated Implants;321
15.5;5. OSMOTIC DEVICES;326
15.6;6. MISCELLANEOUS SYSTEMS;328
15.6.1;6.1. Wound Healing;328
15.6.2;6.2. Nasal Delivery Systems;329
15.7;7. CONCLUSIONS;329
15.8;ACKNOWLEDGMENTS;329
15.9;REFERENCES;329
16;Insulin Iontophoresis;334
16.1;1. INTRODUCTION;334
16.2;2. SPECIFIC DRUG DELIVERY REQUIREMENTS FOR INSULIN;337
16.2.1;2.1. Duplicating the Function of the Pancreas;337
16.2.2;2.2. Candidate Systems for Insulin Delivery;338
16.3;3. CAPABILITIES OF IONTOPHORESIS RELATED TO INSULIN DELIVERY;341
16.3.1;3.1. Noninvasive Delivery of Insulin;342
16.3.2;3.2. Control of Delivery Rate of Insulin;342
16.3.3;3.3. Bolus Administration;342
16.3.4;3.4. Dose Precision;343
16.3.5;3.5. Portal Delivery;343
16.3.6;3.6. Bioavailability;343
16.3.7;3.7. Compliance;344
16.3.8;3.8. Summary of Capabilities Related to Insulin Delivery;345
16.4;4. THEORETICAL LIMITATIONS AND PUBLISHED RESULTS;345
16.4.1;4.1. Published Results of Insulin Iontophoresis;345
16.4.2;4.2. Theoretical and Practical Limitations to Insulin Iontophoresis;348
16.5;5. PHYSICOCHEMICAL PROPERTIES OF INSULIN RELATED TO IONTOPHORESIS;351
16.5.1;5.1. Charge Titration;351
16.5.2;5.2. Solubility;352
16.5.3;5.3. Enzymatic Degradation;353
16.5.4;5.4. Insulin Self-Association;353
16.6;6. FUTURE PROSPECTS FOR IONTOPHORETIC DELIVERY OF INSULIN;354
16.7;REFERENCES;355
17;Insulin Formulation and Delivery;357
17.1;1. INTRODUCTION;357
17.2;2. FORMULATION OF INSULIN;358
17.2.1;2.1. Introduction;358
17.2.2;2.2. Formulation for Parenteral Administration;359
17.2.3;2.3. Formulation for Alternative Routes;365
17.2.4;2.4. Insulin Analogs and Derivatives;366
17.3;3. DELIVERY OF INSULIN;369
17.3.1;3.1. Introduction;369
17.3.2;3.2. Parenteral Insulin Delivery;371
17.3.3;3.3. Alternative Routes of Insulin Delivery;382
17.4;4. SUMMARY AND FUTURE PERSPECTIVES;399
17.5;REFERENCES;400
18;Index;425

Leseproben

Chapter 3
Delivery of Proteins from a Controlled Release Injectable Implant (p. 93-94)

GeraldL. Yewey, Ellen G. Duysen,
S. Mark Cox, and Richard L. Dunn

1. THE ATRIGEL™ DRUG DELIVERY SYSTEM

Development of controlled release systems for the delivery of recombinant proteins remains a critical research challenge for the biotechnology industry. Current therapies with these biopharmaceutical agents require frequent injections or infusion owing to the short half-lives of the proteins (Bodmer et al., 1992). Biodegradable implants and microspheres for parenteral administration could extend the half-life of serum-labile proteins and provide an effective mechanism for localized as well as systemic delivery. Although such sustained release therapies may result in higher formulation costs, they have the potential to reduce overall medical costs by decreasing the frequency of administration. They are also more convenient for the patient to use, with a resulting improvement in compliance. Biodegradable systems that allow repetitive courses of therapy to be administered without the need for a subsequent medical procedure to remove the device contribute even more to lower costs.

Recently, a liquid polymer system (ATRIGEL™) has been developed which has both the simplicity and control of solid biodegradable implants and the injectability of microspheres for delivering drugs (Dunn et al., 1992). This drug delivery system combines a biodegradable polymer with a biocompatible solvent, resulting in a solution that can be injected using standard syringes and needles. When the system contacts physiologic fluid, the polymer precipitates as the solvent diffuses into the surrounding tissues. As a result, a biodegradable polymeric implant is formed. For controlled release applications, a drug can be incorporated into the delivery system. The incorporated drug is physically entrapped within the precipitated polymer matrix and is then slowly released. The polymer type, concentration, and molecular weight as well as the carrier solvent, drug load and formulation additives each influence the release kinetics. Manipulation of these formulation variables provides diverse drug delivery profiles as well as polymer biodegradation rates for specific applications.

Candidate biodegradable polymers for use in the drug delivery system include homopolymers of poly( DL -lactide) (PLA) and copolymers of poly(DL -lactide-co-glycolide) (PLG) and poly(DL-lactide-co-caprolactone) (PLC). These polymers are similar in chemical composition to biodegradable sutures and have been well characterized in the literature (Kulkarni et al., 1971, Cutright et al., 1971, Gourlay et al., 1978, Rice et al., 1978, Nakamura et al., 1989). They are well tolerated in the body and generally accepted as safe by the medical/pharmaceutical community. Biodegradation of the polymers is effected by their hydrolysis to lactic, glycolic, and hydroxycaproic acids, respectively. These are either metabolized by the Krebs (or tricarboxylic acid) cycle to CO2 and H2O (Brady et al., 1973, Gilding, 1981, Woodward et al., 1985, Hollinger and Battistone, 1986) or, in the case of D-lactic acid, are excreted unchanged by the kidney. Biocompatible solvents utilized with the system include N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO). Safety studies conducted with pharmaceutical-grade solvents provide extensive toxicological profiles that support substantial margins of safety for both the neat solvents and ATRIGEL™ formulations prepared with these solvents (Wilson et al., 1965, Jacob and Wood, 1971, David, 1972, Bartsch et al., 1976, Wells and Digenis, 1988, Shirley et al., 1988, Wells et al., 1992, International Specialty Products, unpublished results).