Glass Matrix to Preserve Proteins and Biopolymers
This glass-like matrix preserves proteins without refrigeration or freezing. Appropriately plasticizing carbohydrate or polymeric glasses yields a biopreservation matrix that can provide stability enhancement for encapsulated biological agent of as much as 100-fold over current best-practice formulations.
Biopreservation Glasses - Appropriately plasticizing carbohydrate or polymeric glasses yields a biopreservation matrix that can provide stability enhancement for encapsulated biological agent of as much as 100-fold over current best-practice formulations.
Protein therapeutic agents are becoming increasingly common, and this trend shows no sign of abating. However, these agents are intrinsically unstable, especially under room-temperature storage, or in the body after injection, and must be stabilized. They are typically sequestered in carbohydrate glass (sucrose, trehalose, et cetera) or in controlled release vehicles that are made of partially amorphous biodegradable polymers.
Research by Dr. Cicerone has afforded a dramatic stability enhancement for proteins in carbohydrate or polymer glasses, which is brought about by the addition of a partially hydrophilic plasticizer to the glass. His work, and that of his collaborators shows that the stabilizing effect is general (neither protein- nor material-specific) and that it has its origins in the very well documented plasticization / antiplasticization phenomenon seen in both polymeric and carbohydrate glasses.
In 1999, therapeutic protein sales were approximately $17 billion worldwide. Insulin and Erythropoietin, both therapeutic proteins, are among the top revenue generating pharmaceuticals in the world, each with multibillion-dollar sales annually. Because proteins make ideal therapeutic agents due to generally low levels of toxicity when compared to their chemical counterparts, and due to the recent growth in the field of proteomics, the therapeutic protein sector is expected to experience sustained and significant growth over the next few decades.
Already, this sector is among the fastest growing in the pharmaceutical industry with a growth rate of 10 to 15% annually. However, with all of this advancement and new drugs, there are significant limitations. A short shelf life is a problem with many of the biopharmaceutical products currently on the market and will undoubtedly plague newly developed proteinaceous drugs as well.
Carbohydrate and polymer glasses are commonly used as stabilizers for therapeutic proteins, but it is often difficult to obtain good room-temperature stabilization. There exists a need for a formulation approach that is general in its efficacy and safe for human use. Our approach is at once novel, effective, general, and innocuous to human patients (uses materials approved by the FDA for injection).
The technology recently developed at Brigham Young University incorporates plasticizing agents into carbohydrate or polymer glasses to dramatically improve the stabilizing effect of the glass. The plasticizing agents act by suppressing high frequency motions within the glass, and thus retard processes that depend on these motions, such as diffusion of small reactive species, and protein conformational changes (that lead to aggregation upon rehydration). We have developed general approaches to formulation wherein glasses made either of simple carbohydrates or polymers may be appropriately plasticized to obtain the beneficial effect. In the polymer case, a "dynamic linker" is typically used.
By virtue of the present discovery, glasses with bioprotective capability better than the best single-component glasses can be made, and at a considerably smaller materials cost. In one example of a polymeric glass shown below, an extrapolated enzyme activity lifetime of 10 years at room temperature is obtained. This represents a 1000-fold stability increase over the unplasticized polymeric glass, and a 100-fold increase over the 38-day stability we obtain for the same enzyme in an unplasticized trehalose formulation that is identical other than the glassformer.
US 7,101,693 [MORE INFO
Dr. Marcus T. Cicerone Ph.D.
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