Ben Locwin, Consultant05.09.17
For all the advancements in solid dosage medications, excipients are relatively unchanged. But as billions of medication doses are taken, we learn more and more about excipients, including ones we thought we knew all about.
What is an excipient?
Many people nod their heads in the industry as though they know what excipients are, but just a cursory probing demonstrates a near-complete lack of knowledge in the nuances of this segment of the pharma manufacturing landscape. Excipients are agents used in the drug manufacturing process alongside the active ingredient to control the properties of the final product. By the etymology of its name, ‘excipient’—from excipiens—means something that is an exception. It’s also in the bottom 30% of word popularity according to Merriam-Webster, so congratulations on reading this far! But don’t worry, it gets better below.
Here’s where it gets interesting. They’re not totally inert carriers, and in fact, recent research has demonstrated that male and female rats metabolize the same excipient differently.2 Researchers looked at the effects of polyethylene glycol 400, an excipient used very frequently to enhance the solubility and bioavailability of poorly-water-soluble drugs, on ranitidine (antacid/antihistamine). The excipient led to enhanced bioavailability of ranitidine in the male rats, but not in the female rats. The authors conclude, “the unusual and clinically significant phenomenon that an excipient can influence drug bioavailability in one gender and not the other.” Therefore the drug does not perform the same way. Would it be the same in humans in men as compared to women? How widespread is this? Should we be concerned? Typically excipients are considered “non-active,” but this is clearly not the case.
The future of the market: Drug chemical trends
With solid dose tablets and capsules still making up a tremendous portion of all medications taken around the world, interest in excipients will necessarily continue for the foreseeable future. Various mergers, acquisitions, and plant closures continue to influence the drug chemical sourcing market, and most notably in the areas of contingency planning, business continuity and innovation.
When supplier diversity collapses too much, geopolitical issues and global events can severely hamper production and/or distribution of the necessary intermediates and ingredients to reliably produce drug therapies.
Innovation in excipients also hasn’t been as robust as in some other facets of the drug manufacturing industry. Likely because they are thought to be simply ‘there’ (the disinterest of inertness). Their relative silence and invisibility relegates their development to the back burner—way back burner. But as with every substantive commodity in the world, doing the fundamental things right is a big key to success. Nobody really thinks about their car or truck tires, until they need to. And guess what? Tire innovative technologies have grown leaps and bounds in just the past 2-3 decades.
So to keep excipients as something that perform flawlessly and don’t draw the ire of the public and the attention of FDA, EMA, and other regulatory agencies due to safety surveillance signals, the technology must indeed advance. As we start to understand more and more about these differential in vivo effects that I describe above, we need proactive responses in the development and refinement of excipients to ensure that a potential pharmacokinetic or pharmacodynamic signal isn’t ignored and allowed to continue to persist across formulations and drug indications.
We can’t just assume that current oral drug doses are good enough because that can leave a big unaddressed variable in the dissolution and absorption/metabolism side of the equation. By understanding the root causes of some of these differences, whether it’s pharmacogenomic or otherwise, allows us to understand more about the drugs that we manufacture, and the ability to better help patients with refinements in excipients for selected treatments in the future.
References
Ben Locwin
Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.
What is an excipient?
Many people nod their heads in the industry as though they know what excipients are, but just a cursory probing demonstrates a near-complete lack of knowledge in the nuances of this segment of the pharma manufacturing landscape. Excipients are agents used in the drug manufacturing process alongside the active ingredient to control the properties of the final product. By the etymology of its name, ‘excipient’—from excipiens—means something that is an exception. It’s also in the bottom 30% of word popularity according to Merriam-Webster, so congratulations on reading this far! But don’t worry, it gets better below.
Here’s where it gets interesting. They’re not totally inert carriers, and in fact, recent research has demonstrated that male and female rats metabolize the same excipient differently.2 Researchers looked at the effects of polyethylene glycol 400, an excipient used very frequently to enhance the solubility and bioavailability of poorly-water-soluble drugs, on ranitidine (antacid/antihistamine). The excipient led to enhanced bioavailability of ranitidine in the male rats, but not in the female rats. The authors conclude, “the unusual and clinically significant phenomenon that an excipient can influence drug bioavailability in one gender and not the other.” Therefore the drug does not perform the same way. Would it be the same in humans in men as compared to women? How widespread is this? Should we be concerned? Typically excipients are considered “non-active,” but this is clearly not the case.
The future of the market: Drug chemical trends
With solid dose tablets and capsules still making up a tremendous portion of all medications taken around the world, interest in excipients will necessarily continue for the foreseeable future. Various mergers, acquisitions, and plant closures continue to influence the drug chemical sourcing market, and most notably in the areas of contingency planning, business continuity and innovation.
When supplier diversity collapses too much, geopolitical issues and global events can severely hamper production and/or distribution of the necessary intermediates and ingredients to reliably produce drug therapies.
Innovation in excipients also hasn’t been as robust as in some other facets of the drug manufacturing industry. Likely because they are thought to be simply ‘there’ (the disinterest of inertness). Their relative silence and invisibility relegates their development to the back burner—way back burner. But as with every substantive commodity in the world, doing the fundamental things right is a big key to success. Nobody really thinks about their car or truck tires, until they need to. And guess what? Tire innovative technologies have grown leaps and bounds in just the past 2-3 decades.
So to keep excipients as something that perform flawlessly and don’t draw the ire of the public and the attention of FDA, EMA, and other regulatory agencies due to safety surveillance signals, the technology must indeed advance. As we start to understand more and more about these differential in vivo effects that I describe above, we need proactive responses in the development and refinement of excipients to ensure that a potential pharmacokinetic or pharmacodynamic signal isn’t ignored and allowed to continue to persist across formulations and drug indications.
We can’t just assume that current oral drug doses are good enough because that can leave a big unaddressed variable in the dissolution and absorption/metabolism side of the equation. By understanding the root causes of some of these differences, whether it’s pharmacogenomic or otherwise, allows us to understand more about the drugs that we manufacture, and the ability to better help patients with refinements in excipients for selected treatments in the future.
References
- Bhattacharyya, Lokesh; Schuber, Stefan; Sheehan, Catherine; William, Roger (2006). Excipients: Background/Introduction. In Katdare, A; Chaubal, M. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. CRC Press.
- Lesko, L.J. (1999). Mechanistic understanding of subject-by-formulation interactions. Advisory Committee for Pharmaceutical Science. Rockville, MD.
- Afonso-Pereira, F., Murdan, S., Sousa, J., Veiga, F., Basit, AW. (2016). Sex differences in excipient effects: Enhancement in ranitidine bioavailability in the presence of polytheylene glycol in male, but not female, rats. International Journal of Pharmaceutics, (1-2), 237-241.
Ben Locwin
Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.
