Protein Delivery
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Lynda M. Sanders, R. Wayne Hendren (Eds.)
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Protein Delivery
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Kluwer Academic Publishers
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9780306468032
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1
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CHF 134.90
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Naturwissenschaft
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English
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447
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DRM
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PC/MAC/eReader/Tablet
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PDF
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.
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).
Contributors
6
Preface to the Series
9
Preface
11
Contents
13
Protein Delivery from Biodegradable Microspheres
22
1. INTRODUCTION
22
2. COMPONENTS FOR SUCCESSFUL DEVELOPMENT OF MICROSPHERE FORMULATIONS
24
2.1. Polymer Chemistry
24
2.2. Engineering of Microsphere Formulations
29
2.3. Protein Stability
42
3. CASE STUDIES OF DRUG DELIVERY FROM BIODEGRADABLE MICROSPHERES
45
3.1. LupronDepot
45
3.2. MNrgp120 Controlled Release Vaccine
47
4. IMMUNOGENICITY AND INJECTION- SITE CONSIDERATIONS
51
5. REGULATORY REQUIREMENTS FOR DEVELOPMENT OF PROTEIN DELIVERY FROM MICROSPHERES
55
5.1. Toxicology Studies
55
5.2. Residual Solvent Concerns
56
5.3. Manufacturing Issues
57
5.4. Preclinical Animal Models and Clinical Experiments
58
6. SUMMARY
59
REFERENCES
60
Degradable Controlled Release Systems Useful for Protein Delivery
65
1. INTRODUCTION
65
2. DEFINITIONS
68
3. SYNTHETIC HYDROPHOBIC DEGRADABLE POLYMERS
69
3.1. Poly(lactic acid), Poly(glycolic acid), and Their Copolymers
69
3.2. Polycaprolactone
75
3.3. Poly(hydroxybutyrate), Poly(hydroxyvalerate), and Their Copolymers
76
3.4. Poly(ortho esters)
77
3.5. Polyanhydrides
81
3.6. Polyphosphazenes
85
3.7. Delivery of Vaccines
85
4. HYDROPHILIC POLYMERIC BIOMATERIALS AND HYDROPHOBIC NONPOLYMERIC BIOMATERIALS
90
4.1. General
90
4.2. Specific Hydrophilic Polymeric Biomaterials
91
4.3. Specific Hydrophobic Nonpolymeric Biomaterials
99
4.4. Miscellaneous
101
5. CONCLUSIONS
102
REFERENCES
103
Delivery of Proteins from a Controlled Release Injectable Implant
113
1. THE ATRIGEL ™ DRUG DELIVERY SYSTEM
113
2. EFFECTS OF FORMULATION VARIABLES ON PROTEIN RELEASEKINETICS
115
2.1. Polymer Type
116
2.2. Polymer Concentration
117
2.3. Polymer Molecular Weight
118
2.4. Solvent
119
2.5. Protein Load
120
2.6. Additives
121
3. CHARACTERIZATION
122
3.1. Protein Quantitation in Different ReleaseMedia
122
3.2. Protein Structure
125
3.3. Enzyme Activity
127
3.4. Cellular Bioactivity
128
4. IN VIVO EVALUATIONS
130
4.1. Biocompatibility
130
4.2. Protein Release Kinetics
131
4.3. Bioactivity
133
5. CONCLUSIONS
135
REFERENCES
136
Protein Delivery from Nondegradable Polymer Matrices
138
1. INTRODUCTION
138
1.1. Biocompatible Polymers Used as Hydrophobic Matrices
139
1.2. Protein Release from Polymer Matrices
141
2. MECHANISMS AND MODELS FOR PROTEIN RELEASE FROM MATRICES
143
2.1. Macroscopic Models of Diffusion in Porous Polymer Matrices
144
2.2. Microscopic Models of Diffusion in Porous Polymer Matrices
150
3. APP
