The challenges of protein formulation

By Gregory Roumeliotis

- Last updated on GMT

Related tags Protein Pharmacology

Even with the most advanced analytical equipment, elucidating the
complete conformational characteristics of proteins still
represents mission impossible, often making their formulation
problematic, yet there are always ways to improve their
pharmacokinetic properties, according to Octoplus's chief
scientific officer.

Daan Crommelin, a renowned guru of pharmaceutical chemistry, used his speech at the Controlled Release Society's annual meeting in Vienna to illustrate the problems that a protein's fragile structure poses to achieving controlled release in drug delivery and how some of the problems can be overcome.

Proteins are sensitive molecules held together by weak physical interactions and disulfide bonds. Their three-dimensional structure can be disrupted by a number of factors including the presence of hydrophobic surfaces, high shear, the removal of water and a change in temperature or pH.

A change in a protein's structure can not only negatively impact its therapeutic effect but can also trigger adverse immune reactions to the drug.

Any effective controlled release technology therefore must safeguard a protein's integrity while achieving the desired pharmacokinetic profile. In order to extend a protein's plasma half life, the formulation developed must be resistant both to physical degradation, such as aggregation and denaturation, as well as chemical degradation, such as oxidation and deamination.

Controlled release formulations reduce injection frequency and increase patient comfort and compliance. They can also improve safety and efficacy of a drug by avoiding peak concentrations and achieving prolonged high concentrations in target organs and tissues.

Many protein formulations use polylactic-polyglycolic acid (PLGA), a biodegradable and biocompatible polymer, to create microspheres with mainly hydrophobic characteristics.

Although it is difficult to avoid a burst release with this technique, a selection of polymers and production processes allows the release of proteins over two to three weeks.

However, the use of organic solvents and the gradual drop of pH inside the microspheres may affect the integrity of the protein.

A more protein-friendly technology involves the use of hydrogels, which are hydrophilic polymeric networks capable of imbibing large quantities of water. These can avoid organic solvents and pH drops do not occur during release.

Protein release from hydrogels is controlled by bulk degradation of the material rather than by surface erosion in other systems.

"Proteins want to have fun, they like to have water around to swim in,"​ said Crommelin.

"However, every protein has a life of its own and even if you do everything by the book you still cannot be sure your formulation will work until you try it."

Crommellin has applied hydrogel-based microspheres to proprietary technologies for the company he co-founded, Octoplus. In PolyActive technology, hydrophilic poly(ethylene glycol)-terephtalate segments are coupled to more hydrophobic poly(butylene terephtalate) segments, while OctoDEX technology uses cross-linked dextran microspheres.

One of the main advantages of the OctoDEX drug delivery system is that it shows no burst effect and the release profile can be completely controlled. It also represents an alternative to PEGylation, where a protein is chemically modified.

Octoplus is currently working on "one-off vaccines" using OctoDEX technology, hoping to develop a vaccine whose dose is released gradually, stimulating the body's immune system over a longer time and allowing full protection to be achieved with a single injection.

Despite an emphasis on non-injectable delivery technologies for biologics, particularly pulmonary, hydrogel-based techniques are likely to continue to dominate research as scientists seek to minimise injection frequency and boost patient compliance.

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