Delivering Biologics

Recombinant biologics have been mainstream therapeutics since the 1990s. This success was largely initiated through replacement proteins (such as insulin), and biologics now generate around $70 billion in worldwide revenues. After the very first generation of biologics, originating from animal or human body fluids, protein and peptide drugs are now available from recombinant technologies, either as copies or Due to the chemical nature and size of biologics, even the most modern representatives of this drug class are still large molecules with secondary and tertiary structures, making them more sensitive to external factors (such as temperature, shear stress and interfaces) compared to small molecules. They are also still sensitive to digestive enzymes and are either not easily or not at all permeable through biological membranes. Therefore, they still need to be administered mainly via the parenteral route. An approach such as inhaled insulin worked technically, but was not successful commercially, had some safety concerns, and was withdrawn from the market after a brief commercialisation phase. So, innovative delivery or new strategies to improve the effects of biologics upon their targets are still needed to make full use of this interesting and innovative class of therapeutics.

DEVICES

Besides the dream of applications of biologics not requiring injections, real and already marketed improvements in the delivery of biologics were achieved mainly through two means. Devices and modifications of the therapeutic proteins leading to improved, pain-reduced injections and reduced injection frequencies was the first. Also, devices like prefilled syringes, double chamber syringes or cartridges, and injection systems such as pens or auto injectors allow improved application by the patient or the healthcare professional. Modern subcutaneous application systems provide small needles (29G/30G), siliconised, where no or only very little pain at the injection site is associated with the treatment, thus improving patient compliance. Protein formulations therefore need to tolerate the high shear forces associated to this thin needle passage and higher protein concentration formulations may be required, since subcutaneous application volumes are limited to about 1ml. Changes from vial to double chamber syringes or prefilled syringes will have the form of microparticles, implants and in situ forming implants (see Table 1) are established, but are only applicable for small peptide drugs (1). Novel delivery systems are under development, using different matrix materials and claiming superior properties, as listed in Table 2 (2).

Chemical modification of the therapeutics is a means to obtaining a reduction in injection frequency, which is especially beneficial for intravenous drugs like cytokines used for hepatitis treatment.

In some cases, structural modifications may even lead to a change in the application route from intravenous to subcutaneous, which will come as a relief for patients who are, in most cases, chronically ill. Subcutaneous injections can now be facilitated by co-administration of an enzyme (hyaluronidase), temporarily breaking the structure of the collagen network in the skin. This breakdown is claimed to be fully reversible, and allows on the one hand the application of larger volumes of subcutaneous drug solution (subcutaneous infusions), and may also allow bioavailability of subcutaneous drugs which are normally not administrable via that route of administration (for example, due to their high molecular weight). At present, collaborations between halozyme and several other companies have been published, studying, for example, subcutaneous application of antibody drugs (Herceptin) and immunoglobulins (Gammagard).