Looking to the Future – The Route for Inhaled Medications and Inhalation Technology

• Envigo

Formulations, devices and strategy through non-clinical development

Up until recently, inhaled drugs have been used to deliver medicines that have been specifically targeted at the most prominent of respiratory diseases – these being chronic obstructive pulmonary disease (COPD) and asthma. At present, it is estimated that around 235 million people across the globe are suffering from asthma and that in excess of 200 million people have COPD - with the startling rates set to increase further in developing countries (see Figure 1).¹ As a consequence, a major focus for international research remains finding efficacious medications for these incurable diseases.

Figure 1. Respiratory Disease facts^1,3-6

Taking a look at the figures in totality, the combined inhalation drugs market alone for idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF) as well as COPD and asthma amounted to $28.1 billion in 2015 – with predictions that it will expand further by at least 50% by the year 2022 (see Figure 1).⁴

The worldwide health burden also needs to address other respiratory diseases, such as tuberculosis, lung cancer and infections. At present, there is no fast or easy solution to meet this future global challenge. An obvious advantage of inhalation formulations is delivering respiratory medications directly to their site of action in the respiratory system. However, there are other significant benefits as well, and it is these additional benefits (see Figure 2) that are responsible for driving research into inhalation treatments for systemic diseases across the globe.

Figure 2. Benefits of inhalation delivery⁷

Pfizer’s Exubera was one of the first well publicized inhalation products for systemic disease treatment. Exubera, an inhaled form of insulin for treating diabetes, was withdrawn in 2008 due to weak sales - in part blamed on the bulky and inconvenient inhaler device. However, though this was obviously an initial setback to innovation in this sector, Exubera’s failure actually led to other companies actively reconsidering similar product developments. In 2014, the FDA approved an inhaled insulin product - Mankind’s Afrezza.⁷ To date, the market success of this product appears limited, but this may relate to product pricing and the need for specific patient screening rather than the efficacy of, or preferences for, the inhaled medication concerned.⁸

The interest in inhalation delivery has continued to increase significantly and has not been hindered by the withdrawal of Exubera. In fact over the course of the past four years, 1,350 active inhalation studies - for new, combination, and existing products, encompassing 802 different diseases and 105 rare diseases - have so far been logged with the U.S. FDA clinical trial register. Over half of these inhalation studies are for systemic conditions.⁷

Inhaled Formulations and Devices

Drug formulation and the inhaler device itself are two key considerations that determine the success of inhaled medications – as was previously shown to be the case with the Exubera inhaled insulin device. The onset of innovation in both these aspects of design are leading to more effective drugs - new, combination, route switching and generic - although improved powder formulations may be more cost-effectively developed than the use of new, sophisticated inhalers.⁹

Inhalation devices

A substantial amount of development time, effort, and resources is required for the production of any inhalation device – especially as it has the very real potential to contribute to a drug’s success regardless of how effective and beneficial a drug may be to patients. When compared to other routes of administration, the inhalation delivery device technique offers something highly unique and beneficial. When used in combination, it can provide extended protection to patients.

Consequently, taking a specific example from the US, GSK’s Advair (seretide) came off patent in 2010, although the Diskus delivery device remained in patent through 2016.¹⁰ An inhalation device will only be effective if it is matched to the patient and target patient population and if it is easy to use and apply, forgiving of poor techniques, and able to provide feedback to the user concerning technique and dose emission (see Table 1).

Table 1. Desired physical characteristics of devices¹¹

The scope is enormous and the size of the market for respiratory inhaler devices continues to expand rapidly, with current estimates suggesting that it could reach $43 billion by the end 2025 - representing a compound annual growth (CAGR) of 4.3%¹² at current projections.

Inhalation formulations

Conventionally, a process of mechanical micronization has been used to create the fine drug particles needed for delivery in dry powder inhaler (DPI) devices. Scientists often then combine these fine particles with a lactose carrier to improve drug stability and dose control - depending on the drug type or compound class concerned. More recently, though, future drug formulations look set to be transformed by particle engineering techniques (see Figure 3).⁹ Essentially, these new techniques have the potential to provide a more efficacious drug, enabling lower dosages to be used and reduced potential for side effects on patients.

Figure 3. Examples of some particle engineering techniques⁹

Strategy for Inhalation Technology - Through Discovery and Regulatory Non-Clinical Development

Regardless of formulation, dose delivery methodology and the reproducibility of effective dosing are two of the most important considerations to address when planning efficacy and toxicology studies using inhalation technologies. Intratracheal and inhalation dosing are the two principle methodologies for drug delivery in nonclinical studies. In-tratracheal dosing - which is principally used for early screening studies - involves anesthesia and intubation, with the drug delivered via bolus through the intubation tube. This methodology is simple, uses minimal quantities of drug, and the delivered dose is easily quantifiable. The disadvantage with this method is that it is prone to artefactual toxicological and pharmacological results, and the particle size used in testing often differs from that which will be used non-clinically. In contract, inhalation dosing, delivers compounds to conscious animals by the clinical route of administration - namely via the lung - negates the risk of intratracheal artefacts. A critical requirement of this particular method is the necessity for specialist inhalation technology experience and capabilities. The ability to reproducibly control the aerosol during both intra- and inter-exposures is pivotal to ensuring the maintenance of study integrity. Failing to achieve reproducible control can compromise a study’s end-points, leading to poorer data interpretation and reducing the study’s scientific impact. In the worse case scenario, the study may need to be repeated if there is no effective control of the aerosol.

Almost 2,000 inhalation studies have been conducted by Envigo over the course of the last nine years – including in excess of 100 inhalation studies (where the information has been known) on drugs formulated using unique and novel formulation techniques. Our scientists’ experience with these formulations is that the aerosol concentration is more consistent, reproducible, and aerostable than standard, lactose-based carrier formulations - improving study conduct, decreasing possible animal-to-animal variation, and reducing the overall quantity of drug that is needed to conduct the study concerned.

A key topic for discussion with inhalation studies is always compound requirements as larger amounts of drug are required compared to other routes of administration - although there are a significant number of novel techniques that can be put to use to minimize the usage.¹⁴ Consequently, we have worked collaboratively with a number of customers to develop more efficient methods for inhalation delivery of powders, including a capsulebased aerosol generator (CBAG) with GSK that offers significant cost savings compared to commercially available instruments on the market.¹⁵

A major consideration to have in mind is that the FDA assumes 100% deposition of delivered dosages in humans, 10% in rodents, and 25% in non-rodents.¹⁴ As a consequence, it is very important to take this into account when planning dosing experiments in order to ensure that adequate dose coverage is provided.

Conclusion

Companies are increasingly looking at alternative solutions to historic methods of drug discovery in order to find a competitive advantage that gives them an edge in the marketplace. These include de-risking drugs earlier in the product-development timescale by incorporating additional endpoints into early in vivo studies, route switching of established products to extend the product’s value proposition, and further innovative approaches and techniques for particle engineering and reformulation.

We predict that inhalation delivery will continue to be put to effective use for drugs targeted at both systemic and respiratory diseases – with application of the techniques and methods continuing to expand even when cures for these diseases can be discovered.

References

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