Using Excipients With Biologics

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 acetate.¹

Sophie Chesnoy

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 injectable administration.

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

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.

Nasal delivery

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 enhancers.¹

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.

Ongoing developments

Biologic manufacturers are not really reluctant to use excipients; instead, they are more wary about selecting the right partner with whom to develop the most efficient formulation with reduced frequency administration.

The ideal biomolecule delivery system should improve upon the conventional dosage form. Because of the large sizes of the biomolecules under development, the invasive routes of administration, such as systemic or subcutaneous injections, will remain the most efficient ones. We do, however, believe there is a greater role to be played by very inert excipients acting as simple bulk carriers, such carbohydrates and polyols. Mannitol is well known for its cryoprotective properties and is used for protein's lyophilisation. In fact, one very recent patent emphasises the use of polyols as stabilising factors for highly concentrated antibody liquid formulations for subcutaneous administration.⁴ This interest in polyols is a result of their ability to prevent aggregation of proteins in solution and to provide a viscosity compatible with subcutaneous administration.

We also advise using the latest advances in sustained release excipients to modulate the release of the biomolecule. As mentioned earlier, polymer matrix-based sustained release formulations are of interest for injectable protein lifecycle improvement.

One particular trend in the field of particle engineering technologies is in the development of solutions that would allow biologicals to be administered in standard solid dosage forms.

Dry emulsion formulations can incorporate soluble protein and provides them protection against degradation when in contact with biological fluids.⁵ This dry emulsion can be directly compressed as a tablet⁶ or can first be adsorbed onto a powder with high specific surface area for better compressibility.⁷

As discussed earlier, the key challenges for biologics delivery include stability and achieving the desired targeting once the biomolecules are in the body. As a supplier, we think in terms of designing excipients for specific dosage forms that can be delivered through a specific route of administration.

Most biologics are formulated for delivery via injection. This requires very strict standards for manufacturing endotoxin-free excipients. More recently, studies have been conducted regarding the development of non invasive oral delivery systems for peptides using lipids and film coating technologies for better protection and more precise targeting.^1,2,5,6

Overall, we believe that it is important to continue developing innovative excipient technologies that prolong the lifecycle of biologics inside the body and, consequently, improve their delivery.

References

1. L.R. Brown, Expert Opin. Drug Deliv. 2(1) 2005.

2. M.A. Karsdal, et al., Clin. Pharmacol., 50(7) 2010.

3. B. Yu, et al. The AAPS Journal,11(1) (2009).

4. Stable high protein concentration formulations of human anti TNF alpha antibodies. Patent US2010278822A1.

5. J. Shaji and V. Patole. Indian J Pharm Sci.,70(3) 2008.

6. E. Toorisaka, et al., J. Control. Release,107(1) 2005.

7. R.P. Dixit and M.S. Nagarsenken, Pharm. Dev. Technol., 12(5) 2007.