BioTherapi: Bioinformatics for Therapeutic Peptides and Proteins
|G.P.S. Raghava | Department of Computational Biology | IMTECH | CRDD | Team Members | Contact | FAQ|
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1. Oral delivery: is probably the most natural route to consider for drug delivery. But, digestion hinders researchers attempting to deliver proteins through the gastrointestinal (GI) tract. "The stomach is a bad place for proteins. Several companies have investigated additives that improve absorption in the GI tract. Oral delivery of proteins as the magic bullet, but it's almost mission impossible".
During normal manufacturing processes, the materials absorb large quantities of water, which results in protein degradation during distribution and storage. Other skepticism centers on repeatability and wasted administered proteins. In the case of oral insulin, glucose levels can be lowered for a short time, but "no report in the literature has shown the repeated administration of insulin resulting in effective control of the glucose level and has induced the insulin effect at the right time".
2. Bioavailability: is a main issue. You observe only 10–20% at the most.
A therapeutic drug is mixed with a delivery agent (a synthetic chemical or compound), which temporarily changes the shape of the macromolecule through noncovalent interactions and partially exposes a drug's more lipid-like core. The GI tract membrane (being lipid-based itself) absorbs the delivery agent drug complex and allows it to pass into the bloodstream. Then, the drug and the delivery agent separate, and the carrier is excreted from the body.Because the delivery agent is used as an excipient, nothing unusual is required to manufacture the oral formulations in tablets or capsules.
But, if these challenges can be addressed, oral delivery might offer better options for dosing regimens.
3. Inhalation routes: Because the lung does not destroy proteins, as the stomach does, many groups are looking into inhalation delivery techniques. Various organic and chemical excipients have been investigated to stabilize protein formulations delivered through the nose and the lungs. Unfortunately, these additives are problematic.For example, every attempt to produce nasal insulin has failed, mostly because of unacceptable nasal irritation caused by large amounts of excipients and other factors.
"If you look at the literature, more than 100 mucosal adsorption enhancement agents have been studied, and they all have the same two limitations: either they don't increase bioavailability significantly or they cause irritation of mucosal tissue."
According to Maggio, the excipients do not irritate the lungs and metabolize CO2 in water. "The only atoms involved are carbon, oxygen, and hydrogen. They're very simple structures," he explains. The company has used its technology to stabilize proteins such as a human growth hormone currently being applied in transmucosal systems. "With growth hormones, we can do nasal.
4.Getting under the skin: parenterals
Monoclonal antibodies are engineered to recognize and target specific antigens or cells. Potential therapeutic applications for the proteins could include the delivery of drugs or toxins to treat cancer, rheumatoid arthritis, or autoimmune and infectious diseases. Though they have several advantages, the doses are relatively high.
"If you're going to deliver a large dose, and if you're going to do so parenterally, you must have a concentrated solution. A large dose and low concentration mean large volume, which is very painful"
5. Analytical needs: Demonstrating that two biopharmaceutical products are identical is difficult with current analytical technology. "We want to develop protein products in an absolutely pure form, and for that, we need good analytical methods to support them," "If you don't have a good analytical method, you can't even detect degradation."
Analytical tools are rapidly evolving to help address this need, including protein mass spectrometry, analytical ultracentrifugation, and capillary electrophoresis, which offer better ways of looking at the chemical and physical structures of these biomolecules.