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Protein Delivery Systems

N. Peppas, C. Donini
Published 2006 · Chemistry

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More effective and tailored drug delivery systems (DDS) are continuously investigated, tested, and, eventually, marketed. In the last 30 yr, the pharmaceutical industry has made substantial steps in this direction. Drug products containing proteins and peptides, as therapeutic agents, are a perfect example of these two intimately correlated aspects: route of administration and quality of life. In the past 60 yr, hormones, serum proteins, and enzymes have been extensively used in therapy as active ingredients. But recently, molecular biology and, especially, recombinant deoxyribonucleic acid (DNA) technology have made tremendous progress resulting in the availability of a wide variety of peptideand protein-based therapeutics for poorly controlled diseases. For this class of drugs, however, the parenteral route represents today the predominant route of administration, as the bioavailability of alternative routes is extremely low and variable. The development of a successful nonparenteral delivery system for proteins implies challenges including the protection of the therapeutic agent from hostile physiological conditions, otherwise detrimental for the biological activity, and gentle manufacturing conditions to maintain the original molecular conformation of the protein. One such agent widely studied as model protein is insulin, a 51 amino acid polypeptide, used in therapy for the treatment of diabetes mellitus. Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia that affects a sizeable portion of the population worldwide, estimated to increase in the next 20 yr of more than 30% reaching the size of an epidemic. Furthermore, the complications coupled with it are debilitating and at times fatal. For these reasons, a chronic therapy is required. To maintain normal glucose levels in the blood and mimic the physiological profile of the secretion of the protein, frequent daily injections (up to four) of insulin are needed. One of the most promising new methods of nonparenteral protein delivery is oral delivery. For this process, various types of specialized polymeric carriers are used. For example, hydrogels have been studied as suitable candidates for oral drug delivery of peptides. Particularly the complexing hydrogels that respond to pH changes in the surrounding environment have been extensively studied. For example, we developed new cross-linked copolymers composed of poly(ethylene glycol) (PEG) grafted on poly(methacrylic acid) (PMAA) backbone, henceforth designated as P(MAA-g-EG), by UV-initiated bulk-free radical polymerization. They possess the unique characteristic to form interpolymer complexes in response to changes in pH of the environmental fluids. The interpolymer complexes are formed owing to hydrogen bonding between the protonated carboxylic acid group of PMAA and the ether group of the PEG chain. In particular, they remain in the collapsed state at low pH values, similar to those found in the stomach. Therefore, the release of the protein is impeded, and the protein entrapped in the network can be protected from the undesirable conditions found in the stomach. When the pH rises up to approximately 6, the network swells. This unusual behavior seems very promising for an oral formulation that would be able to release the labile therapeutic agent only in a more favorable environment such as that encountered in the upper small intestine. The expansion of the system would allow the polymeric chains to interact with the mucosal lining, causing the tight junctions to slightly separate, thus enhancing the transport of the protein into the systemic circulation.
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