Traditionally mere vessels, functional excipients are now present in nearly all marketed drugs and perform many different roles. Often, more excipient is present than active pharmaceutical ingredient (API) and it now provides the ‘therapeutic enhancement’ of ingredients, helping to increase their effectiveness.

Excipients can enable a substance to be absorbed more easily or slowly depending on the patient’s needs, for example, and they come in many forms, ranging from simple colours and flavours to lubricants, anti-adherants and binding products. They are commonly made from sugars, starches, minerals, cellulose, fats, oils and solvents, with synthetic or semisynthetic substances becoming more popular. Ensuring a product has a shelf life competitive with similar drugs, by keeping the active ingredient intact, is also a primary purpose of excipients.

A spokesperson for the International Pharmaceutical Excipients Council (IPEC) Europe tells World Pharmaceutical Frontiers: “Historically, an excipient was defined as an inert ingredient, a pharmacologically inactive additive formulated with the API of a medication.

“IPEC defines an excipient as any substance other than the active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form. This reflects the growing tendency to recognise the important role excipients play in drug delivery, regarding what they can impart to a pharmaceutical dosage form rather than simply acting as ‘filler’. The right choice of excipients and their properties contribute greatly to meeting a product’s design requirements and patient acceptability.”

Mass effect

“The ideal excipients are stable, cost-effective and physiologically inert with no interaction with active drugs,” the spokesperson continues. “Excipients are subdivided into various functional classifications depending on the role they are to play in the formulation.

The right choice of excipients and their properties contribute greatly to meeting a product’s design requirements and patient acceptability.

“Excipients usually also fill out the mass of a tablet or capsule (fillers), making it practical to produce and convenient for the consumer to use. The excipient adds volume and/or mass to a drug, enabling precise metering and handling in the preparation of low-dosage forms. Other excipients hold the ingredients in a tablet together (binders), or facilitate disintegration of tablets and contents of capsules into smaller particles for quick dissolution when coming in contact with water (disintegrants). Coating agents protect the API from the environment, mask the bad taste of the drug and help with identification for patients.”

According to research by IPEC, excipients can help specifically with solid oral dose formulations by adding bulk. They can also help with drug absorption or solubility, as well as other pharmacokinetic considerations; many active pharmaceutical ingredients under development have less than ideal physicochemical and absorption properties, resulting in poor bioavailability. Excipients also help with the handling of APIs during manufacturing, and provide stability and protection from denaturation.

The costs involved in developing new excipients are high as the timescale can be 12 years or longer, as is the case with any new drug product. Excipients also tend to be far less lucrative than drugs, so companies are reluctant to share their development notes with other firms that might then use them to their own advantage. Products can be patented, with all the dangers of a patent cliff, or are often just kept as confidential company information.

Formulation development

A major development in this field is coprocessed excipients, which are proving to be an effective way to shorten approval times in some cases, as two existing products are combined.

The IPEC Europe spokesperson says, “Drug formulation scientists have recognised that single-component excipients do not always provide the required performance to allow certain active pharmaceutical ingredients to be formulated or manufactured adequately. Consequently, new combinations of existing excipients are an option for improving functionality.

In so-called coprocessed excipients, the particle engineering of individual or combined excipients using techniques such as spray drying has created highly functional products perfectly suited to modern tablet manufacturing. The combination acts synergistically, takes advantage of its individual material properties and can overcome the limitation of existing excipients. “While coprocessed excipients are not chemically combined, the creation of excipient ‘new chemical entities’ is possible,” reveals IPEC Europe.

An open door for coprocessed exipients

According to the ‘Coprocessed Excipients – An Alternative to Novel Chemical Entities’ review, carried out by the Modern College of Pharmacy in India in 2012, “The particular phenomenon of coprocessed excipients is a field with vast scope for development of excipients with desirable properties for direct compression, as well as for specific method and formulation. The limitation of the existing excipients for new rapidly developing APIs can be overcome. The process also opens opportunity for the development and use of single multifunctional excipients, rather than multiple excipients in formulation.

“Many excipients are also now being coprocessed directly with APIs to develop compositions that are ready for direct compression,” the review continues. “Drug formulation scientists have recognised that single-component excipients do not always provide the requisite performance to allow certain active pharmaceutical ingredients to be formulated or manufactured adequately. In addition to this, the cost involved in the development of new chemical excipients with improved properties is quite high. In response to these deficiencies, drug formulation scientists have relied on increasing numbers of combination excipients introduced by excipient manufacturers into the commercial market.

“In order to justify the high rise in new drug development and high industrial output demand, new excipients with purpose-satisfying characteristics are the need of the hour. New combinations of existing excipients are an interesting option for improving excipient functionality.

“Excipient mixtures or coprocessed excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the marketplace. The success of any pharmaceutical excipient depends on quality, safety and functionality. Although the first two parameters have remained constant, significant improvements in functionality open the door for the increased use of coprocessed excipients.

“The advantages of these excipients are numerous,” concludes the document, “but further scientific exploration is required to understand the mechanisms underlying their performance. With the number of new chemical entities rising by the day, there is huge scope for further development and use of these excipients. Exploring material property of natural polymers and coprocessing them with the existing ones will create a large inventory of new excipients.

“Rather than developing an entirely new excipient, which would have to undergo a full safety evaluation and would be enormously expensive, it is better to develop the physicomechanical properties of an established product.”

The market today

The scope for coprocessed excipients is still limited to some extent, and the demand for novel products remains strong. Cost factors are, of course, crucial. According to IPEC Europe, “Excipients that impart the correct functional characteristics to a medicine can contribute greatly to productivity and cost margins. If excipients can allow a solid oral product to be manufactured by a direct compression method rather than classic wet granulation techniques, the savings could be considerable.”

Competition from generic drugs and counterfeit products is also a factor confronting companies, which see their development costs rising all the time. The markets in China and India are a growing feature of the global drugs scene, with trends towards cheaper excipients that have not been as rigorously tested as comparable products in the West.

The real role of excipients is often underestimated. The functionality of an excipient can help determine whether a drug succeeds or fails.

Excipients used in European and US-produced drugs must use raw materials from approved suppliers under the European Medicine Agency’s (EMA) good manufacturing practice (GMP). But Indian and Chinese companies are not bound by the same rules, and can cut their costs and prices as a result. Excipients produced in Europe or the US are also often expected to be certified under the EXCiPACT scheme.

IPEC Europe says, “The correct choice of excipient can lead to the success or failure of a drug product with the consequent impact on drug development timelines and commercialisation. The real role of excipients is often underestimated. The functionality of an excipient can help determine whether a drug succeeds or fails.

“The potential consequences of not wisely selecting the best excipients for formulation comprise manufacturing complications, low stability and poor bioavailability of the API,” the spokesperson continues. “To avoid these adverse consequences, it is important to select the right excipient for the formulation and guarantee its quality.”

New scientific developments in excipient production may help with their future use on a large scale. We may see further development of pharmaceutical excipients dedicated to paediatrics, and oral dispersible films and tablets. Multi-unit particulate systems (MUPS) are also being developed that have the advantages of reduced risk of toxicity and local irritation, while providing additional functions such as taste masking.

So, we know that functional excipients can and do play a critical role in the development and delivery of modern drugs. They will surely continue to perform extremely useful functions in the production of the most important varieties.

New developments such as coprocessed excipients help pharmaceutical firms keep their costs at a reasonable level at which they can compete with global companies that have less stringent regulatory regimes to deal with. The use of coprocessed excipients is likely to grow as manufacturers search for products that meet modern expectations of multipurpose medicines with few or no side-effects.