We generally consider biologics as large molecular weight molecules such as proteins, peptides and plasmid DNAs, which are
primarily formulated for parenteral administration — the preferred route of administration for these biomolecules. For these
larger molecular weight molecules, salts, surfactants, glycerol and/or polyols are the most commonly used excipients. However,
there are some smaller biomolecules that have been formulated for oral use, for example, Aventis' hormone analogue drug desmopressin
Most development-stage and promising, recently marketed biologicals are monoclonal antibodies, which again have high molecular
weights and therefore are unlikely to be good candidates for non invasive delivery. Thus they are currently formulated for
Based on our experience, the desired route of administration will drive the search for novel excipients. A number of different
administration routes are available for biologicals, but each has challenges that must be overcome.
Oral administration requires delivery systems that prevent degradation and enhance the absorption of biologics in the gastrointestinal
tract. Enteric coatings and capsules can be used to protect biologics but for the biggest molecular sizes, their oral bioavailabilty
still remains very low and thus oral delivery is very challenging.1
Delivery through the skin
This method of drug delivery bypasses the gastrointestinal tract; however, the skin is a strong barrier that prevents the
passage of big molecules. Encapsulation of biomolecules with the use of nanotechnologies can enhance their transdermal passage.
Transdermal iontophoresis is one such technique, based on active permeation using an electric field, which has shown promise
in the controlled and enhanced delivery of peptides and proteins across the skin.
This is a non-invasive method that avoids first pass metabolism in the liver and provides fast exposure to systemic circulation.
The key challenge here is to obtain a stabilised solution or suspension of biomolecules. Further, because of the large size
of these molecules, their bioavailability through the nasal mucosa can be very poor and would require the use of permeation
The ideal excipients should be the ones that are going to stabilise a high concentration of proteins in water. The search
for new penetration enhancer with very good tolerance could be another way to improve their bioavailability.
With all administration routes, the most challenging issues are:
- overcoming the physical and chemical instabilities of biomolecules in contact with biological fluids or in liquid forms
- efficiently delivering/targeting biomolecules.
The most recent research studies have attempted to address these two issues by designing innovative excipient technologies.
Some of them were aimed at finding physical ways to protect the biologics from aggregation and precipitation using enteric-coated
capsules or tablets,2 thus protecting the biomolecule until it reaches the target site.
Another set of technologies use chemical means to extend the lifecycle and/or the transmembrane delivery of the biomolecule
once administered. This works by chemically linking the biomolecule to the excipient and therefore the resulting compound
could be considered as a prodrug. For instance, oligonucleotides have been conjugated to cholesterol or a fatty acid to enhance
their transmembrane delivery.3
The stability of proteins can be enhanced by chemically coupling a PEG molecule to the protein.1 In this scenario, the protein's surface is modified in order to prevent the stimulation of the immune system. Enzon Pharmaceuticals'
Adagen was the first pegylated protein to gain FDA approval in 1990.1 Excipients can also enhance biomolecule stability by associating them with protease inhibitors.
Other solutions, such as encapsulation and nanotechnologies, are also of great interest for improving the stability and effective
delivery of biomolecules. These solutions can protect biomolecules from proteolytic cleavage, as well enhance their transdermal
passage or facilitate long systemic circulation.
Ipsen and Debiopharm have recently launched a 6 month peptide sustained delivery system using lactide / glycolide copolymers
under the name of Decapeptyl LP (triptorelin LHRH agonist). This innovation allows only two annual injections of this peptide.
This is a marked improvement on the original "long acting release" dosage form, which gradually released peptide over the
course of 3 months.