More than a walk-on part: how excipients play a role in making a drug successful
14 Feb 201813min read
Senior Consultant Applied Scientist
We take medication because of the benefits it offers, benefits which are delivered by the active pharmaceutical ingredient (API). However, the tablets, capsules, injections, liquids or suppositories we use typically contain less than 10% of the API. What makes up the bulk of the medicines we take is the inactive ingredients, also known as excipients. Whilst the API may be the “star of the show”, the excipients play a strong supporting role: to make sure that the medicine is able to do its job. It is an important role; so much so, in fact, that an excipent can often make or break the API’s performance.
An ideal role
Research conducted by Rutesh Dave,at Long Island University, looked at the excipients used in the top 200 most commonly prescribed tablets1. Over 94 excipients were used in this list of most frequently prescribed medicines. The most prolific excipient, magnesium stearate (used as a lubricant to stop the API sticking to the industrial machines during manufacture), appears in 108 of the top 200 prescribed medicines.
Excipient roles are wide-ranging; a cast list including not only lubricants, but coatings, preservatives and antioxidants. Improving the API by providing a better taste or texture, stabilising the formulation, or extending the drug’s shelf-life, are further roles. The nature of excipients means that they must also be non-toxic, stable, able to avoid being rapidly cleared by the kidneys and non-reactive in the body. Although they are often referred to as inactive components, it is these properties and behaviours of excipients that have a significant impact on the success of a medicinal product. In short, the ideal excipient must provide a cost effective and unobtrusive supporting role, ensuring the API is able to perform effectively and efficiently. A number of interesting applications are explored in this article.
“Excipient roles are wide-ranging; a cast list including not only lubricants, but coatings, preservatives and antioxidants.”
Coming out of the cold
Maintaining the cold-chain, from a vaccine’s point of origin to where it is needed, is a significant barrier to global vaccination campaigns. The cold-chain process accounts for up to 80% of vaccine campaign costs and is tricky to sustain in remote and low-resource settings2. Keeping a vaccine at its optimum storage temperature – usually lower than the ambient temperature – is an ongoing challenge when targeting human papillomavirus (HPV), the antigen responsible for most of the cases of cervical cancer. For example, around 80% of all cervical cancer patients reside in developing countries and, despite the availability of several liquid vaccine formulations (Gardasil, Cervarix), it is difficult to get the vaccines to where they are needed and at the right temperature. The vaccines are thermalsensitive and need to be kept under tightly controlled temperature conditions (between 2°C and 8°C) – from production to administration – in order to keep their long-term potency.
Developing formulations with enhanced resistance to freezing and heating could significantly increase the reach of these vaccines. This is where excipients can help. Current strategies to prolong vaccine shelflife and their thermostability involve adding excipients to both liquid and dry formulations, either to protect against freezing damage, or to remove the need for a cold-chain by enhancing the heat resistance of the product (using stabilising and buffering excipients)3.
Adjuvanted vaccines*, for example, containing aluminium salts, are particularly sensitive to freezing, as the vaccine adjuvant-antigen protein bond is susceptible to damage by the formation of ice crystals during the freezing process. Excipients, such as polyethylene glycol (PEG) or sucrose, are therefore added to preparations for their cryo-protective properties2. Nonliquid formats, such as freeze-foam and spray-dried, are generally preferred as they can greatly improve the vaccine’s long-term stability compared to a liquid format3 (although it is still difficult to produce non-liquid, thermostable adjuvanted vaccines).
Non-liquid forms do not always need to be reconstituted before use and offer alternative routes to parenteral, such as oral, dermal and pulmonary. Excipients used to stabilise the dry formulations include sugars, polyols (e.g. PEG) and even silk fibres4. For the HPV vaccine, a spray-dried, virus-like particle formulation containing an excipient combination of three sugars (mannitol, trehalose and dextran) and the amino acid leucine was shown to retain high levels of potency (i.e. immunogenicity) after being stored for more than a year at 37°C5. The increased robustness offered by this excipient-supported formulation has the potential to reduce the number of cases of cervical cancer in areas such as sub-Saharan Africa.
A Trojan Horse approach
The role of drug carrier is a powerful example of where excipients come into their own. Take the case of paclitaxel, which belongs to a group of compounds known as taxanes, produced by plants belonging to the yew family. Taxanes are widely used as chemotherapy agents, as they inhibit the process of cell division in tumours. In an alternative to the “taxane in solution” formulation, paclitaxel is bound to albumin nanoparticles6. As the most abundant plasma protein in human blood, albumin is a good choice for the role of ‘carrier excipient’.
Acting rather like a Trojan Horse, it is able to navigate inside the body without challenge or rejection, to deliver its therapeutic (though toxic) payload where it is needed. Early indications from clinical trials7 for treatment of bladder cancer suggest that using a nanoparticle carrier method of administration, delivered directly to the tumour site, improves the therapeutic benefits of paclitaxel (compared with the usual systemic treatment) due to better specificity and reduction in toxicity, as there is less uptake by other organs via systemic distribution. Another possible benefit in receiving taxane via albumin nanocarrier and administered in solution, is that it may mean faster uptake. Treatment duration reduces to 30 minutes per session, compared to up to 3 hours via the usual method (the volume of medication varying from patient to patient).
“Treatment duration reduces to 30 minutes per session, compared to up to 3 hours via the usual method”
US biotech company Ceregene uses an unusual method to improve delivery of growth factor treatment (via gene therapy) for a range of neurodegenerative diseases, such as Parkinson’s, Alzheimer’s and Huntington’s diseases, age-related macular degeneration, and glaucoma: not just an excipient, but something far smarter – a disabled virus.
Neural growth factor treatments are potentially able to halt the degeneration and restore the function and vitality of damaged or failing neural cells in the brain or eyes. However, the growth factors are large proteins, which are difficult to deliver to the target tissues using conventional methods. To circumvent this problem, Ceregene has developed adeno-associated virus (AAV) vectors – a harmless version of a virus that infects humans – for delivering the genes for the growth factor to the site where they are needed, i.e. the degenerative or failing neurons 8,9.
The modified AAV, containing genes for specific disease targeting, reaches its specific target cell destination and releases its genetic payload into the cell nucleus (Figure 1). Now permanently incorporated into the targeted cells, the genes signal the production of the required growth factors on a sustained basis. Using the fiendish ability of a virus to survive and get to its target, and modifying the AAV to ensure it cannot replicate or reproduce itself, a usually unwelcome visitor in the human body makes successful delivery of a therapy possible.
“The role of drug carrier is a powerful example of where excipients come into their own”
Recent research suggests that the effects of statins in lowering cholesterol levels may also have a beneficial role in Alzheimer’s disease, rheumatoid arthritis, and other neurodegenerative disorders10. Using an intranasal route for delivery of drugs to the brain has been investigated for specific neurodegenerative diseases. There are benefits in the nose-to-brain route, such as avoiding the GI tract and the risk of irritation of the stomach, intestine and liver, where the drug may be broken down too rapidly. However, the amount of drug transported directly from the nose to the brain is generally very low, with normally less than 0.1% getting to its target. This is where nanoparticles consisting of chitosan, lecithin, and different oil excipients encapsulating the statin may be the answer to improved delivery. These nanoparticle excipients are picked for their desirable characteristics, i.e. their small particle size, positive surface charge, long-term stability, and their ability to improve nose-to-brain transport, whilst lowering the toxicity of the statin. Early results from simulated studies show that a statin dose can be delivered nasally, using this safe, biocompatible, biodegradable delivery system.
Getting under your skin
One of the challenges of biopharmaceutical drugs (also known as biologics) is their instability due to their large molecular size and high viscosity, making drug delivery tricky – particularly when the API is delivered subcutaneously. As a result, biologics (such as the best-selling drug, Humira, used in the treatment of auto-immune conditions) are typically delivered intravenously, or as a cycle of multiple injections.
Research with Halozyme’s ENHANZE technology is focused on overcoming these challenges to create a better patient experience. ENHANZE is based on Halozyme’s proprietary recombinant† human enzyme, rHuPH20. This enzyme excipient temporarily degrades hyaluronan, a chain of natural sugars in the body, and increases interstitial space for the injected API. Rather like opening up a “temporary door” in the body, the result may allow biologics and other compounds that are administered intravenously to be delivered subcutaneously. Once the medication is delivered, the body acts to reinstate the hyaluronan “door” again. Whilst regulating a therapeutic action like this will no doubt prove challenging, it opens up a potentially useful mechanism for delivering biologic therapies. Should it prove successful, the result for the patient and the healthcare giver could be a reduction in the need for multiple injections (due to the improved dispersion and absorption) and a shorter time for drug administration.
Excipients moving upstage
What will the excipients of the future look like? How far can the boundaries of the so-called ‘inactive’ ingredient be extended? Looking to the future, we may see personalised medicine in which the API is invariant and it is the excipient which is customised – tailored to the patient’s physiology and specific genetic mutations, to provide optimum delivery of the drug. Electrochemical ‘sensor’ excipients may emerge which bolster supply-chain compliance, by detecting when the API has exceeded its shelf-life, has not been stored appropriately or has been tampered with in some way – maybe even deactivating the API or at least providing a visual indication that it is no longer safe or active. What is clear is that whilst the API will continue to take centre stage, the role of the excipient is still important in therapeutics, sometimes determining the success of as new medicinal product. Excipients may not be right in the spotlight, but their place in patient treatments continues to be vital.
* Adjuvanted vaccines contain added substances to increase the body’s immune response to the vaccine.
† Produced when segments of DNA derived from different sources are joined together.
Dave R. Overview of pharmaceutical excipients used in tablets and capsules. Drug Topics. October 24, 2008. Available at: http://drugtopics.modernmedicine.com/drug-topics/news/modernmedicine/modern-medicinenews/overview-pharmaceutical-excipients-usedtablets
Bishop KM, Hofer EK, Mehta A, et al. Therapeutic Potential of CERE-110 (AAV2-NGF): Targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons. Experimental neurology 2008: 211; 574–584.
Wooder S, et al. Alzheimer’s Disease – ST3 Drug Discovery II. M.Phil. in Bioscience Enterprise, Institute of Biotechnology, University of Cambridge. 6th December, 2011.
Clementino A, Batger M, Garrastazu G, Sonvico F. The nasal delivery of nanoencapsulated statins – an approach for brain delivery. Int J Nanomedicine 2016: 11; 6575–6590.
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