Tracking the Potential of Excipients

Excipients are an important part of a formulation, but regulatory hurdles and economics make it difficult to bring new excipients to market. Despite these obstacles, excipient producers see opportunity for innovation and in working more closely with formulators to improve the understanding of excipients in a formulation as well in meeting specific needs when formulating poorly water-soluble drugs and in nanotechnology.

Quality by design offers opportunity

On a developmental basis, excipient makers point to important trends affecting innovation in excipients. "Definition and testing of excipient functionality is an issue as well as the education of formulators in the use of excipients," says Alen Guy, vice-president of research and development at JRS Pharma (Patterson, NY). "Education is an area that is sadly lacking. It has certainly led to repeats of academic work that has been forgotten owing to poor research and reading by formulators. I would also point to quality by design as both a challenge and an opportunity for innovation. If the pharmaceutical companies more fully understand the excipients they use, then perhaps they will work more closely with the excipient manufacturers to develop even better excipients," he says.

Advancing poorly water-soluble drugs

Other producers see opportunity in poorly water-soluble drugs. "New excipients should focus on the very often poor solubility and poor resorption into the body of many new chemical entities coming from active pharmaceutical ingredient (API) research," says Dr. Ralf Widmaier, marketing manager at BASF SE (Ludwigshafen, Germany). "The need for highly efficient, yet versatile solubilizers, and especially polymeric solubilizers is one of the most important topics within the next years."

Brian Koblinski, market development manager of pharmaceutical excipients at Dow Wolff Cellulosics, a business unit of the Dow Chemical Company (Midland, MI) points to several areas for innovation. "For development, there is a focus on excipients that are fully characterized in structure/property relationships and understanding how these properties affect drug-release performance across the spectrum of low- to high-solubility actives and developing dosage forms with in vitro–in vivo correlations, salvaging poorly soluble and poorly absorbed new chemical entities, and enabling oral delivery of large molecules."

Nanotechnology and excipients

As the field of nanotechnology widens, so does the role of excipients. In a recent analysis, BCC Research outlined some key developments in excipients in nanotechnology (1).

One application involves nanocoatings that are used to protect small tablets and assist in the ingestion of high therapeutic doses (600–800 mg). BCC Research offers as an example BASF's ibuprofen DC 85 formulation with a nanolayer that protects against temperature influences and speeds up production (700,000 tablets/h as compared with 200,000 normally) (1, 2). Nanocoatings reduce the amount of lubricants needed and eliminate the need for wet granulation and compacting (1).

In another example, Justin Hanes and a team of Johns Hopkins University scientists discovered that coating nanoparticles with a low-molecular-weight polyethylene glycol excipient allows them to penetrate vagina membranes and serve as sustained-release carriers for therapeutic agents for treating cervical cancer. Also, incorporating nanoparticles into quick-dissolving edible thin strips can improve film properties, reports the BCC study (1).

Nanotechnology is also being applied to human serum albumin (hSA), an approach taken by Abraxis BioScience (Los Angeles, CA) with its "Nab" (nanoparticle albumin-bound) technology platform that combines hSA with an API for delivering protein drugs. "With the European Medicines Agency's 2006 reversal of its decision on transgenic drugs, transgenic albumin could be a future excipient option," reports the BCC study. GTC Biotherapeutic's (Framingham, MA) "ATryn" (recombinant human antithrombin), an anticlotting protein secreted into the milk of transgenic goats, was initially rejected for marketing approval by the European Medicines Agency in February 2006. EMEA later reversed is decision and approved the drug upon further review in August 2006.

Excipients used in nano-sized liposomes also offer opportunity, "The pharmaceutical industry has made overtures toward the use of liposomes (or 60 nanometer-sized emulsion droplets) as delivery systems but has yet to accept them fully," reports the BCC Research study. "That acceptance has been stalled, in part because of the lack of precise scientific data on the exact role of lipid-based excipients (oleochemicals) and their influence on adsorption of the drug." The excipients are used to stabilize the liposomes (1).

In addition, fatty acids, alcohols, esters, and ethers are being considered as excipients for nanoparticle matrices. "Minimal amounts of excipients are being used in vivo nanoparticle formulations with similar or enhanced immunogenicity in comparison to that of alum," according to the BCC Research study (1).

A case in point is the work of researchers at Novartis Vaccines and Diagnostics (Emeryville, CA), who developed a lyophilized nanoparticle formulation that suspends the small amount of excipients used (sucrose and mannitol or dioctyl sodium sulfosuccinate with trehalose and mannitol) in polyvinyl alcohol. The formulation also contains adsorbed protein antigen (1, 3).

Calcium phosphate is also being considered as a replacement for aluminum salts, an US Food and Drug Administration-approved adjuvant for vaccines. BioSante Pharmaceuticals (Lincolnshire, IL) uses the excipient in its "CaP" nanotechnology. The company has completed Phase I of a clinical trial on the technology as a vaccine adjuvant and a delivery system. Preclinical results indicate that the CaP nanotechnology also performs well when injected as a facial-line filler. BioSante plans to initiate clinical tests of the technology in 2008 (1).

References

1. "Excipients in Pharmaceuticals," Report No. PHM010E, BCC Research (Norwalk, CT, 2006).

2. P. Van Arnum, "BASF Advances Nanocoating for Ibuprofen Formulation," Pharm. Technol. 30 (6), 48 (2006).

3. K. O Hagan et al., "A Practical Approach to the Use of Nanoparticles for Vaccine Delivery, J. Pharm. Sci. 95 (12), 2738–2750 (2006).

For analysis and trends in the excipient market, see the article "Measuring Excipient-Market Growth" in the April 2008 issue of Pharmaceutical Technology.