Optimised Inhaled Therapies

Inhalation can offer significant advantages over alternative routes of administration, and can be used to treat respiratory conditions (e.g. COPD, Asthma, respiratory infections), as well as to target rapid systemic uptake and avoid first pass metabolism. The development of medicines with efficient delivery to the lung can prove challenging, however, with the benefits provided by accessing the large surface area of the alveoli and opportunities to develop non-invasive treatments with reduced dose and fewer side effects, pulmonary delivery remains a highly attractive option for many therapeutics.

There are several factors to consider when developing inhaled therapies. These include Active Pharmaceutical Ingredient (API) properties (e.g. particle size, shape and surface properties, propensity to agglomerate and solid-state purity), product formulation (e.g. carriers, lubricants) and inhaler device (e.g. dry powder, metered dose).

Crystec’s mSAS® (modified supercritical anti-solvent) technology provides a range of strategies for the development of inhaled therapies, optimising particle properties to enable simple formulations to be rapidly developed and administered from readily available, off-the-shelf devices.

Targeted particle size
Optimal surface properties
Maximise deep lung delivery
Synergistic delivery of combination therapies
With or without carrier
Effective in simple devices
Rapid development

mSAS^® strategies for addressing poor drug solubility

Targeted particle size

The optimal particle size for inhaled therapeutics is 1 – 5µm. If particles are too large, the drug will not reach the deep lung, too small and it will be exhaled. Crystec’s mSAS^® technology allows particle size to be tuned to meet a Target Product Profile, often targeting the low micron range, with a very high level of control over Particle Size Distribution (PSD). Data shown below represent mSAS® respirable particles with a particle size of D90 = 3.4µm and narrow PSD.

Scanning Electron Micrograph and Particle Size Analysis (Sympatec – 2 bar aerosolisation pressure) for an inhaled mSAS® product.

Optimal surface properties

mSAS^® is a single-step, bottom up process, where particles are precipitated directly from solution with no need for subsequent size reduction. As a result, mSAS^® particles have smooth, low energy surfaces, promoting strong aerosolisation properties.

For a visual representation of aerosolisation, comparing mSAS® particles with a micronised equivalent, watch our video below:

Maximise deep lung delivery

The inherent aerodynamic advantages of mSAS^® particles, coupled with control of particle size and shape, provide impressive levels of lung deposition. A recent example of data generated at Crystec (below) comparing micronised to mSAS^® powders show the potential to achieve a 68% Fine Particle Fraction (FPF) as a percentage of the Total Emitted Dose (TED) using mSAS^® technology, compared to just 26% for micronised product.

Andersen Cascade Impactor data comparing an inhaled mSAS® with a micronised equivalent.

Synergistic delivery of combination therapies

Combination products are of increasing importance in the pharmaceutical industry, particularly in the treatment of complex respiratory diseases such as COPD. However, the ratio of a blended product is often not reflected in the lung deposition profile of the individual components. This is because the different API particles will have differing aerosolisation performance (stemming from each API’s particle size, shape and surface properties). Using mSAS^®, Crystec are able to generate composite particles in a highly reproducible, single-step process. Combinations of APIs (or API plus enhancers) can be incorporated within each particle in a precise ratio, ensuring uniform deposition of each component in the lung.

With or without carrier

Because mSAS^® particles are designed for performance, impressive levels of lung deposition can be achieved without subsequent formulation. In many cases, excipients that are typically required to overcome the challenges of conventionally prepared powders can be eliminated. Furthermore, mSAS^® particles perform well even in the absence of a carrier (e.g. lactose). As a result, pure mSAS^® powders can be filled directly into capsules or inhaler reservoirs and administered at relatively large doses (up to 40mg per actuation), providing opportunities for a wider range of products to reach therapeutic levels through inhalation.

Effective in simple devices

By building performance into particles, mSAS^® enables the development of products that perform well in simple, off-the-shelf devices. As a result, the need for complex device development programmes can be eliminated, meaning inexpensive, non-IP encumbered inhalers can be used, while achieving optimal product performance.

Rapid development

Crystec focus on designing particles to meet a Target Product Profile, taking a ‘right first time’ approach. Through mSAS^®, Crystec develop a reproducible and scalable process to generate particles with the correct solid-state form, particle size/shape and composition, specifically designed to meet the requirements for targeted delivery. As a result, formulations can be kept simple, accelerating the route from concept product to GMP manufacture, to commercialisation.

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Improving Dissolution

40% of marketed drugs and up to 90% of those in development exhibit poor solubility1. mSAS® provides different ways to address this challenge, including through increasing surface area, reducing agglomeration, new solid-state forms, co-crystals or stabilised amorphous forms of drug molecules.