Hybrid insulin cocrystals for controlled release delivery
| Autor: | Amy L. Cox, Ronald E. Chance, David S. McClellan, Sharon R. Myers, Mark L. Brader, Allen H. Pekar, David B. Flora, Lynnie A. Irwin, Muppalla Sukumar |
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| Rok vydání: | 2002 |
| Předmět: |
Blood Glucose
Time Factors Chemistry Pharmaceutical medicine.medical_treatment Biomedical Engineering Bioengineering Pharmacology Applied Microbiology and Biotechnology Cocrystal Absorption Dogs In vivo Diabetes Mellitus medicine Animals Humans Insulin biology Chemistry Biological activity Controlled release Protamine Peptide Fragments Solutions Protein Subunits Solubility Basal (medicine) Delayed-Action Preparations Pharmacodynamics Biophysics biology.protein Molecular Medicine Crystallization Somatostatin Biotechnology |
| Zdroj: | Nature Biotechnology. 20:800-804 |
| ISSN: | 1546-1696 1087-0156 |
| Popis: | The ability to tailor the release profile of a drug by manipulating its formulation matrix offers important therapeutic advantages. We show here that human insulin can be cocrystallized at preselected ratios with the fully active lipophilically modified insulin derivative octanoyl-N(epsilon)-LysB29-human insulin (C8-HI). The cocrystal is analogous to the NPH (neutral protamine Hagedorn) crystalline complex formed with human insulin, which is commonly used as the long-acting insulin component of diabetes therapy. The in vitro and in vivo release rates of the cocrystal can be controlled by adjusting the relative proportions of the two insulin components. We identified a cocrystal composition comprising 75% C8-HI and 25% human insulin that exhibits near-ideal basal pharmacodynamics in somatostatin-treated beagle dogs. The dependence of release rate on cocrystal ratio provides a robust mechanism for modulating insulin pharmacodynamics. These findings show that a crystalline protein matrix may accommodate a chemical modification that alters the dissolution rate of the crystal in a therapeutically useful way, yet that is structurally innocuous enough to preserve the pharmaceutical integrity of the original microcrystalline entity and the pharmacological activity of the parent molecule. |
| Databáze: | OpenAIRE |
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