The field of biologic drug delivery has evolved from low to high-concentration liquid formulations. Dr Kerstin Walke, head of global pharmaceutical development, biopharmaceuticals at Boehringer Ingelheim, explains how this has had an impact not only upon development, but also upon primary packaging and devices.
Innovation in syringes and auto-injectors has become necessary in recent years as the field for biologics has widened, but the proportion of people who are able to take oral dosages remains largely the same. Developers of the future will therefore have to excel in pharmaceuticals as well as engineering.
The fact that chronic diseases are the main therapy targets for biologics means that the limitations of invasive delivery will become even more pronounced, but does this mean we will soon see tablets, nasal sprays or a host of other options becoming widely available? Although the first products were mostly insulin-related, proteins and peptides are increasingly appearing in research laboratories.
Biologics, according the US FDA, can be composed of sugars, proteins or nucleic acids – or complex combinations of these substances – or they may be living entities such as cells and tissues. They are usually isolated from a variety of natural sources, and may be produced by biotechnology methods. Gene-based and cellular biologics, for example, are often at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.
Biologics are also the fastest growing segment of the pharma market. There are many new benefits that the current generation of biologics can bring to patients in need of treatment.
The development
New ways of delivering biologics are vital. The industry is moving quickly as more companies try to move towards oral solutions, but there are some consequential issues that developers and patients must yet overcome.
“The benefits of biologics are that there are many therapy areas and diseases that are simply not treatable with small molecules, so it’s ultimately a question of which particle modality works for a disease,” Dr Kerstin Walke, head of pharma development at Boehringer Ingelheim, explains. “Small molecules have their benefits, but they cannot reach many entities.”
The biologics expert believes that protein therapeutics offer a highly specific – and rather complex – set of functions, plus limited interference with the normal biological processes, low immunogenicity, the potential to replace gene therapy, and from an industrial point of view, faster clinical development and approval time, as well as better patent protection. But what issues might current parenteral methods of administration present in terms of delivering required dosages or with regard to patients?
“What matters about parenterals, independent of whether we are talking about biological or an new chemical entity (NCE), is who will give the medication,” explains Walke. “Is it the caregiver, the patient themselves or a parent providing a dose to a child?”
“These are the most important topics to deal with when developing a parenteral,” she continues, “and then it is a case of overcoming the challenges. If you have a patient who has difficulty grabbing things, you have to design the auto-injector to ensure that they are able to deliver the dose in 100% of cases.”
The effects of such motor issues and the task of giving medicine create a hugely complex emotional and practical problem that encompasses patient safety and compliance with all regulatory advice. This sits on top of the challenge of making a device that delivers a drug as effectively as possible in the first place.
“For a parent, it should be easy and not frightening to have that medication in hand,” says Walke, “The caregiver should be able to use it efficiently and not take too much time. In most cases, you are dealing with all ages and must find something that works best for everybody.”
Parenterals
In a report from the Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø, Dr Nataša Škalko-Basnet described the development of oral formulations as a challenge awaiting a solution. “To improve the delivery of biologics via the commonly used parenteral route, two main strategies have been employed,” she stated. “Namely, post-translational modification/conjugation and genetic fusion, and the development of depot-sustained-release formulations of unmodified proteins with specific pharmacokinetic features.”
Within this environment, advances in auto-injections and pens are being made, and the industry is positive these will lead to more effective drug delivery.
“If we are looking at state-of-the-art ideas,” Walke explains, “on one hand, we have the needle safety systems – which are important, especially in hospitals, to ensure that the caregivers do not suffer any needlestick injuries – and on the other, we have the auto-injectors.
“If you look at insulin, and how this whole field has developed, it is 15–20 years ahead of typical biologics. First of all it was in vials, and was given by syringes. Then, later on, pens came, and application became much more convenient for patients.
“The same is happening now in typical biologics. Launched a few years ago, they are becoming more user-friendly. If someone is going to take a drug themselves, at home, you have to provide them with something that is easy to use, and the auto-injector is one such thing.”
This corresponds with what is going on in the field. From a population point of view, everything is getting more highly concentrated, which has lead to viscosities increasing, and now auto-injectors must overcome the challenges of being able to quickly deliver subcutaneous doses quickly, even when dealing with consistencies that are close to that of honey.
“This is where the industry is now looking for solutions,” says Walke. “High-volume devices and auto-injectors bigger than typical pens are being developed right now.”
Other options
Some non-invasive methods are also being explored. Attempts have been made with nasal or respiratory inhalation, but do these hold much promise in the near future?
“It’s all speculation,” says Walke, “but a successful pulmonary delivery of insulin was brought to market, so if we’re stating that insulin isn’t biologic – and, in my opinion, it is – the possibility of delivering biologics via respiratory means exists.”
Unfortunately, Walke concedes, lukewarm industry support means the amount that must be administered for the insulin to be effective remains unclear. The advantage of delivering something subcutaneously is that the dose goes straight into the patient and is absorbed.
“Between 2008 and today, 50% of what is going on has been in the parenteral space,” reveals Walke. “Even for NCE projects, if you go through the research and development pipelines, you’ll find a lot of parenterals, so that route of administration is no more unusual now than compared with 10–15 years ago.”
Oral administration has always been the most coveted goal, particularly for insulin. This has proven particularly difficult, though, with many methods failing early in trials, and Walke doubts that an effective formulation is even possible. “The nature of a biological is that it is degraded, so you will have to get it into the blood as a whole,” she says. “You have to make sure that it survives the intestine on its way to delivery.
“Much depends on the drug in question, but you are dealing with quite high amounts, and from an NCE perspective, if only 10% is finally absorbed, you are giving away 90% of a biologic for nothing.
“In addition, experiments have been unsuccessful in routinely delivering consistent amounts of drugs, and the therapeutic windows of biologics are often not that broad.”
Future prospects
Because biologics are such sensitive and complex drugs, designing delivery methods requires multidisciplinary expertise, not just in biopharmaceuticals, but also engineering as well as other disciplines.
“It’s important that you have all the expertise under one roof, which means somebody looking into the biologics activity and into the molecule itself, and thinking about pharmacokinetics and how to prolong the half-life,” stresses Walke. “Then you have to bring in engineering and risk management very early on, because if a drug takes a certain amount of time to dissolve, an engineer will wonder how to ensure that the patient isn’t only getting part of the substance.”
Despite encouraging developmental progress, high-volume and auto-injector devices, and oral administration for biologics are unlikely to become commercially viable prospects in the next decade. “The cross-functional parts of devices, and the formulation and biologic behind them are really important, and cannot be rushed out separately,” concludes Walke. Biologics will eventually be the norm, but the questions of when and in what form are still a long way away from being answered.