Inhalation | Combination Therapy | Market Opportunity

The lung represents an excellent drug delivery route, but with significant formulation and manufacturing challenges for the drugs in question. The lung structure is ideal for non-invasive, systemic delivery of drugs given the surface area available for absorption, allowing the drugs to easily pass into the bloodstream from the deep lung yielding rapid onset of action; improved efficacy and tolerance.

Deep lung delivery for greater systematic availability or local effect in the deep lung requires particles less than 3 micron in size. The upper respiratory tract is ideal for the treatment of such diseases as asthma and COPD, as well as respiratory infections, requiring particles 1 to 5 micron in size. However, many device, such as MDIs and DPIs are inherently and unnecessarily complicated as they have been designed to compensate for the limitations of the APIs that they deliver.

This means there is a clear need for much improved respiratory APIs that have been designed to be delivered to the lung. To achieve the required formulation performance there are many more characteristics that need to be tailored than just particle size.

Respiratory APIs are in essence high performance products and their size, morphology, surface energy, and critically surface 3D geometry all govern particle performance in inhaled medicines formulation. Prosonix' API particles can be fully engineered via controlled crystallization across all of these important variables leading to drugs that can use much simpler delivery platforms.

It can be difficult to obtain 1-5 micron crystalline particles by conventional technology. The use of jet-milling results in unstable amorphous material, unstable finished powders and multiple performance variability that lead to significant reject rates of final formulated product.

Delivery of drugs via the lungs requires superior particles. Prosonix technologies such as DISCUS^® and UMAX^® uniquely facilitate control of size, shape, surface geometry, surface free energy, and crystallinity. They are also ideally aligned with the new Quality by Design initiative laid out by the US FDA, which is aimed at guiding the pharmaceutical industry to improved invention, development and commercialisation of structured products using technologies that will result in superior product quality.

So what are the ideal respiratory particle requirements? We need high fine particle mass and fraction (FPM and FPF), high emitted dose (ED), dose to dose consistency and uniformity, and this should be achieved independent of the type of device and inhalation flow rate. These can be achieved by having:

•   Correct aerodynamic particle size (mass medium aerodynamic diameter)

•   Right aerodynamic diameter - function of density and dynamic shape factor

•   Narrow particle size distribution

•   Low aerodynamic dispersion forces to aerosolise

•   Good physical and chemical stability - high crystallinity, low amorphous content

Dry Powder Inhalation (DPI)

DPI formulations have two components:

•   The API, ideally 1-5 micron diameter, and

•   An inert carrier, generally micronized lactose, which is used to carry the drug, but much larger at 60 -150
micron diameter.

In these formulations the surface texture and contact geometry plays a crucial role and has a significant effect on the important cohesive-adhesive balance (CAB), which governs the ease (or difficulty) in the drug particles being released from the carrier particles by the force of inspiration.

Through the application of its particle engineering technologies, Prosonix can carefully control the CAB of its engineered API particles and in doing so can develop more useful drug formulations. This can not be achieved by standard jet milling techniques.

Metered Dose Inhalation (MDI)

MDIs contain therapeutically active ingredients dissolved or suspended in a propellant, in a compact pressurised aerosol dispenser. Depending on the product, each actuation may contain from a few micrograms up to milligrams of the API delivered in a volume typically between 25 microliters and 100 microliters.

Prosonix’ interest relates to the development of improved products in suspension based MDIs. As with DPIs, the physiochemical parameters of the API particles are critical to the MDI product performance. By controlling the shape, size, morphology and crystallinity, through the application of Prosonix particle engineering technologies, significantly better product can be achieved than using conventional micronization techniques. Of particular benefit is improved dose content uniformity through life, extended stability, and the potential for dose sparing. Furthermore, the only way to achieve in vitro only substitutable generic monotherapies is to use an engineered particle, all other methods of preparation lead to unstable formulations and result in non equivalence.