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For our most recent EPM Magazine, Rob Anderton sat down with Michael Shultz, Group Lead, Inhalation, Lonza to discuss all things inhalation.
Rob Anderton:
With lung cancer accounting for 25% of total cancer deaths in the US and worldwide, what benefits does spray drying for inhaled delivery offer for lung cancer treatments?
Michael Shultz:
Lung cancer remains a significant unmet medical need. One way in which treatment might be improved could be to deliver anticancer drugs directly to the surface of the lungs. Local delivery that targets therapy to the site of action would reduce the dosage burden in comparison with systemic delivery, while also bypassing the first pass metabolism of the liver.
In order to create inhaled formulations delivered via a dry powder inhaler, particles with consistent shape and size need to be created. By using spray drying with careful tailoring of the process conditions, both particle size and morphology can be controlled to achieve targeted delivery to various levels of the lung – including the deep lung. The formulation of inhalable powders for spray drying is not limited to small molecules, but can be achieved for complex biologics such as monoclonal antibodies that are frequently used as cancer treatments.
Other advantages of formulating as a dry powder include the possibility of a longer shelf life, and it could, potentially, eliminate the need for cold chain storage and distribution (which is particularly limiting for many biologics). This would facilitate access to life-saving therapies. Additionally, DPIs are small, portable, and the treatments are simple for most patients to self-administer. Therefore, formulating as a dry powder can offer significant advantages over liquid formulations that require a nebuliser, and all the limitations associated with these devices. Spray drying is a powerful technology that can make a DPI formulation a reality for both small molecule therapies and biotherapeutics for the treatment of lung cancer.
Rob Anderton:
How efficient is inhaled drug delivery of dry powder in reaching the lungs?
Michael Shultz:
If the shape and size of the particles fall within the correct parameters, then it can be extremely efficient to deliver drugs to targeted regions within the lung – the bronchi, bronchioles and alveoli – via a dry powder inhaler. Particles can be engineered to have a narrow, targeted aerodynamic size for deposition in the deep lung – minimising the number of fine particles that are so small that they are simply exhaled, and particles so large that they do not reach the target tissue.
Inhalable powders are generally contained within a capsule or blister, and once pierced within the inhaler device are dispersed by the patient’s breath upon inhalation. An important consideration is the potential of the powder to agglomerate, which would significantly impact delivery to the desired target in the lung. Cohesive or poorly dispersible powders may remain within the device, or catch on the patient’s throat. Spray-dried powders can be engineered to have good dispersibility properties, ensuring minimal particle aggregation, and resulting in efficient powder delivery.
Rob Anderton:
What challenges would you encounter within the spray drying process?
Michael Shultz:
The parameters employed during a spray drying process will have a direct impact on the behaviour of the powders that are made. The challenges faced can vary, depending on the nature of the API and excipients required for the formulation. Important parameters include how the solution to be spray dried is prepared, its atomisation, the kinetics of the drying process, and the collection of particles. A number of variables are involved, such as inlet and outlet temperatures, both gas and liquid flow rates, liquid pressure, the liquid-to-gas ratio, solids loading, and even the selection of the nozzle. All of these parameters are carefully tuned during process development to achieve the desired powder properties.
The solubility of the API and excipients are key parameters that need to be considered, and if solubility is low this can cause problems that will need to be overcome. Another challenge comes when scaling up the manufacturing process, and this needs to be considered early on during development. If processing times are prolonged, there will be inevitable cost implications. A number of methods can be employed to overcome these challenges, such as using temperature shift processes or including volatile processing aids to improve solubility and shorten processing times. Biologics, in particular, can pose significant challenges because of the inherent sensitivity of these complex molecules to the physical stresses of the spray drying process. A careful and thorough risk assessment, and mitigation strategies to address any risks, are key for successful process development.
Rob Anderton:
Along with L-leucine are there other promising excipients that are helping to improve inhalation efficiency?
Michael Shultz:
The number of excipients with FDA approval for inclusion in inhaled formulations is decidedly limited. However, as amorphous powders have a tendency to be cohesive, it is important to incorporate dispersibility enhancers to help reduce the adhesion between particles. While L-leucine is not yet on the approved list, it is expected that it will be added in the near future.
There are, however, a number of excipients that are already on the approved list that can improve properties such as flowability (and thus give better aerosolisation), as well as potentially acting as stabilisers, binders and enhancing bioadhesion. These include magnesium stearate, which can also act as a dispersant, plus carrageenan, HPMC, gelatin and glycine. The carriers lactose and mannitol can also improve aerosolisation. And including ingredients such as trisodium citrate, sodium lauryl sulfate and silicon dioxide in the spray dried solution may also have an impact on delivery efficiency.
Trehalose is another ingredient that, like leucine, is yet to be included in the approved list for respiratory dosage forms. This sugar – a disaccharide comprising two glucose units – is commonly used in injectable drug formulations where it confers stabilising properties, and has shown promise for biologics during formulation development for inhalable dry powders.
Rob Anderton:
What alternative approaches to spray drying are available, and what are their benefits/drawbacks?
Michael Shultz:
When developing a new inhalable dry powder, it is important to assess the many possible manufacturing methods that are available. Of course, compatibility of the API with the manufacturing process is paramount in that decision. Additionally, factors such as development and manufacturing costs, reproducibility, and scalability need to be considered if the product is to be both robust and economically viable.
In addition to spray drying, there are various well-established methods that can be used to manufacture dry powders for inhalation, including milling, spray-freeze drying, and supercritical fluid drying. Additionally, there are emerging technologies such as particle replication in non-wetting templates, inkjet printing, and thin-film freezing. All technologies have their benefits and drawbacks, and these can vary depending on the individual API or the API class. Milling, for example, is a simple and inexpensive method for producing dry powders for inhalation. It can, however, produce particles with poor flow characteristics as a result of high surface energy and the irregular size and shape of the particles. It is also unsuitable for most biotherapeutics, as their fragile nature is not compatible with the high force required.
In contrast, spray-freeze drying and thin-film freezing can produce inhalable low-density, porous powders under conditions that are suitable for heat-sensitive formulations such as biotherapeutics. But while they are compatible with many such molecules, the techniques are complex, time intensive, and comparatively costly. And formulations sensitive to cryogenic stress would not be compatible with these methods. Another technique, supercritical fluid drying, can produce uniform spherical powders in a relatively rapid manufacturing process, and is suitable for many APIs, including biological formulations. Significant drawbacks can arise, though, from solubility issues in supercritical CO2, as well as the high cost of implementing this technology.
Rob Anderton:
What are the main considerations when formulating an inhaled dry powder product?
Michael Shultz:
When considering whether to formulate and deliver a drug as a dry powder, patient need is first and foremost. Would a DPI improve their treatment in some way, whether because of faster onset of action, reduced side effects, ease of use, or even improved compliance? An additional consideration is whether it is feasible to make the appropriate powders reliably, reproducibly, and at scale, as this is key for developing a practical and cost-effective manufacturing process. This can be assessed during process and formulation development, considering factors such as the desired particle aerodynamic properties, the desired deployment strategy for the final product, API and excipient solubility, and stability during processing and storage. The development process can be complex, and is highly dependent on the chemical properties of each individual API, and also the desired properties of the final powder. In addition, for more complex biologic APIs, functional activity of the molecule must be retained, and special attention must be placed on controlling parameters that affect the physical three-dimensional conformation of the API during the manufacturing process, and after delivery to the lung.