Generation excipients

The global excipients market is growing fast. According to research by Markets and Markets, it will reach $9.7 billion in 2025, up from $6.9 billion in 2019. This growth, which mirrors the growth of the pharmaceuticals market in general, is spurred by advancements in functional excipients, rising adoption of orphan drugs and increased uptake of biopharmaceuticals.

While the market is still dominated by oral formulations, parenterally administered drugs are catching up. Many of the new molecules in the pipeline (especially biologics and targeted oncology drugs) are poorly soluble and difficult to formulate as oral solids. This is fuelling demand for parenteralgrade excipients, a segment that is growing more quickly than the market overall.

In essence, parenteral formulations can include any preparation that will be administered directly into the systemic circulation. According to the market intelligence company Kline, there are three main types of parenteral formulations: liquid solutions, lyophilised (freeze-dried) products and suspensions. Liquid injectable solutions comprise 72% of the market.

In the past, most of these liquid solutions were supplied in single-dose glass or plastic containers, but today the sector is moving towards prefilled pens or syringes. These are generally plastic and disposable, and make injections much easier to administer.

Development challenges

Compared with other administration routes, parenteral formulations pose a unique set of challenges for the drug developer. On one hand, they are more easily absorbed than oral formulations and do not suffer the pitfalls of first-pass metabolism. This means a parenteral excipient, compared with an oral excipient, may not need to work quite so hard at enhancing bioavailability.

On the other hand, there can be issues associated with drug stability and poor solubility. If the API and excipient are not fully compatible, the API can be degraded and impurities can form. On top of that, while an excipient may work synergistically with the API, there is also a risk of unwanted reactions with the packaging components.

As Rajsekhar Paul, fellow at Novartis explains, there are a few main considerations drug developers need to bear in mind when selecting the right parenteral-grade excipient.

“The main consideration would be that the degradation of the drug product needs to be stopped, or controlled to a certain level, as well as particle formation,” he says. “It can definitely be a challenge to make the molecules stable, because aggregation, degradation and association between molecules all play a big role.”

As he points out, the excipients in a parenteral formulation need to fulfil several key functions. These include enhancing the solubility of the API, increasing shelf life, and controlling pH and tonicity. Above all, they need to promote stability. Since protein therapeutics (such as monoclonal antibodies) are inherently unstable, excipients are tasked with suppressing protein aggregation and other forms of physical degradation.

Paul says he tests the stability of the formulation by using accelerated stability tests, in which the product is stored at elevated stress conditions.

“I’ll do 25°C and 40°C stability chamber studies with 40% and 60% relative humidity, and look at the protein aggregation level,” he says. “This can be soluble aggregates, insoluble aggregates or particle matter. I think the main aim is to have a purer compound, quality-wise, so depending on the molecule we need to feel like the final formulation shows the least aggregates.”

While there is a huge range of excipients on the market, such as sugars, salts, lipids and polymers, not all of these are suitable for parenteral formulations. For instance, given the high-sterility requirements, the excipient must be able to withstand terminal sterilisation or aseptic processing. Parenteral preparations need to be pyrogen-free and (in the case of a liquid solution) remain soluble throughout the entire shelf life of the product.

Depending on the formulation, some potential additives may include antimicrobials, bulking agents, chelating agents, solubilising agents, tonicityadjusting agents, antimicrobials and protectants. These will be added to a vehicle such as water, oil or a water-miscible solvent.

Many parenteral formulations also include a buffer system that protects the product against degradation and controls the pH. Buffers commonly used for the purpose include citrates, acetates and phosphates, along with certain amino acids.

72%
Liquid injectable solutions comprise a large portion of the market.
Kline

“The buffer system is always targeted to the physiological pH, but since different buffers can also exert an effect on the pH, the concentration of the buffer is very important,” says Paul. “Sometimes the buffer concentration plays a very big role in the pH shift, and other times it actually hinders the pH shift that is intended.”

He remarks that no one excipient is suitable across the board. While some common parenteralgrade excipients include PEF-polysorbates and sugars like sucrose and trehalose, each of these has its own potential pitfalls.

“The problem with trehalose is that it crystallises in many different conditions,” he says. “It can crystallise upon storage, and in the case of lyophilised products it can also crystallise during the lyophilisation. So in these cases I think trehalose is not suitable. Sucrose is also very commonly used commercially, and I have seen galactose and glucose used in other cases. Polysorbate is very widely used for parenteral drug administration for injectables, but you have to take care with how it degrades with regard to oxidation.”

Given these challenges, some new molecules may require excipients to be used in novel ways, or they may require new excipients altogether. Excipient manufacturers have various ways of achieving this end: they might modify an existing excipient, or create an entirely new chemical entity.

Slow innovation

Unfortunately, innovation in this field is progressing less quickly than one might expect, thanks in no small part to the associated legislative requirements. As novel excipients are regarded as new substances, the regulatory pathways are longer and more complicated (not to mention more expensive) than they would be in the case of established excipients. It does not help that excipients can only be approved as part of a formulation, rather than as products in their own right. This means, if the final product failed, the new excipients within would also fail to gain approval.

The International Pharmaceutical Excipients Council (IPEC) works hard to develop and harmonise standards in this field, as well as promoting the development of new excipients and creating guidance about best practice.

“You need to have a compliant excipient, so you need to have things that don’t exert any kinds of side effects as well as guaranteeing stability for the shelf life of the product,” says Paul. “There should not be any new excipient that is not pharmacopoeiacompliant, so there is very stringent regulation there. There should be toxicological data that shows that the excipient is safe and efficacious and there are also dose limits guiding how much of the excipient you can use.”

It is easy to see, then, why a drug developer might prefer to play it safe and stick with what they know. That said, it seems clear that some of tomorrow’s medicines will require next-generation excipients. Particularly as drug delivery systems change (think nanotechnology-enabled drug delivery systems and liposomal drug delivery systems) the pharmaceutical industry will be on the lookout for novel excipients that are multifunctional, high-tech and safe to use.

Failing that, they will be looking to develop new and creative formulations. As Paul points out, we are currently seeing a research trend towards nonionic excipients, as well as formulation systems that are less viscous than what has gone before.

“More and more people are talking about the limitations of injectables with regard to injection course and increased viscosity,” he says. “This means there is a trend to look for viscosity reducing agents; for example, where you have a charged basis that creates a responsive force and a negatively or positively impulsive force.”

While Paul works with more traditional excipients, he believes the industry in general could be about to fork out into some interesting new directions.

“We are seeing a shift towards different kinds of formats of the API itself, so these days the monoclonal antibody isn’t being considered only as a parenteral product, as it was when I started my career,” he says. “So I think the complexity is increasing and the need for novel excipients is definitely there.”

“The organic chemicals segment is to dominate the pharmaceutical excipients market in 2019.”

On the basis of product, the pharmaceutical excipients market is segmented into three major categories— organic chemicals, inorganic chemicals, and other chemicals. In 2018, the organic chemicals segment accounted for the largest share of the pharmaceutical excipients market. The large share of this segment can be attributed to the use of these chemicals in the majority of pharmaceutical formulations available in the pharmaceutical market.

“By functionality, the fillers and diluents segment is expected to account for the largest share of the pharmaceutical excipients market in 2019.”

On the basis of functionality, pharmaceutical excipients are categorised into fillers and diluents, binders, suspending and viscosity agents, flavouring agents and sweeteners, coating agents, colorants, disintegrants, lubricants and glidants, preservatives, emulsifying agents and other functionalities. The fillers and diluents segment accounted for the largest share of the pharmaceutical excipients market in 2018. The large share of this segment is attributed to the increased use of fillers and diluents in the development and production of solid oral drugs, and the advantages they offer to manufacturers and patients.

“By formulation, the oral formulations segment is estimated to account for the largest share of this market in 2019; however, the topical formulations segment is estimated to be the fastest-growing segment.”

Based on formulation, the pharmaceutical excipients market is segmented into oral, topical, parenteral, and other formulations. In 2018, oral formulations accounted for a major share of the pharmaceutical excipients market, mainly because oral formulations are the most common route of drug delivery.

The market for topical formulations is expected to witness the highest growth during the forecast period. Growth in this segment is majorly due to better assimilation of topical excipients with liquid APIs and increased patient compliance due to sensorial effects.

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Growth of the pharmaceutical excipients market

• The pharmaceutical excipients market is projected to reach $9.7 billion by 2025 from $6.9 billion in 2019, at a CAGR of 5.8% during the forecast period.
• The key factors driving market growth include the growth of the pharmaceuticals market backed by functional excipients, a surge in the generics market, increasing uptake of biopharmaceuticals and the rising adoption of orphan drugs.
• The emergence of multifunctional excipients, shifting focus of pharmaceutical manufacturing to emerging markets and the growing biosimilars industry are expected to offer significant growth opportunities for market players during the forecast period.