URSATEC is celebrating its 30th anniversary and looks back on a long success story with application devices for preservative-free formulations. An ideal moment to share the perspectives for future developments that are united under the vision of a preservative-free medical industry, providing customized solutions also for new target sites.

Abstract

Targeted drug delivery is key to exploiting state-of-the-art drug developments to their full potential. To support the targeted drug delivery, application devices combine several characteristics to ensure performance and patient safety: a precise dosage, the technical prerequisite to reach the target of interest, and prolonged patient adherence to the treatment protocol, which goes hand in hand with a device that is easy-to-use and not too explanation extensive.

URSATEC and its partners develop soft mist nebulizers, characterized by a very fine and innovative spray mist embedded in a standard inhalation device or a nasal spray, ensuring an easy and safe usability profile.

The devices are designed to suit different treatment sites. The fine mist nasal spray allows some coverage of the olfactory region and supports nose-to-brain applications, which can be a powerful tool to bypass the blood-brain barrier. Moreover, by using different spray nozzle units in the head of the device, it is possible to generate different droplet sizes, which enables laryngeal and pulmonary deposition. At the same time, no propellants (CFCs, HFAs, or VOCs) are being used. Furthermore, the devices allow innovative drug formulation without the use of preservatives since their sophisticated construction prevents microbiological contamination.

The technology behind URSATEC

URSATEC’s 3K® pumps are specifically designed for preservative-free formulations. Therefore, as seen in Figure 1, a protective design is integrated with the pump’s architecture (turquoise elements in the sectional view of the nasal spray), i.e., a tight valve, an air filter, and the integration of oligodynamic acting metals that provide a bacteriostatic activity, even under challenging conditions.¹

3K® UltraSoft Devices open new doors in drug targeting

Recently, the spray pumps have been combined with a spray nozzle technology, providing a new platform for different inhalation applications. An array of spray nozzles, that entail pores and geometric patterns to generate a slow-moving ultra-fine mist, is used. The principle of Rayleigh break-up (the generated jet breaks up automatically in droplets) generated by mechanical means turns out to be a robust alternative for aerosol generation.

3K® UltraSoft Nasal Spray for targeting the olfactory region

With the ultrasoft mist technology, standard nasal sprays are transformed into targeting devices for the olfactory region.²

The olfactory region lies deep within the nasal cavity and provides access to the brain as a consequence of nerval structures that invade the brain, the so-called trigeminal and olfactory pathways. In terms of drug delivery to the brain, this is interesting because reaching the brain is fundamentally difficult because of the blood-brain barrier (BBB). In contrast to other organs where a vivid exchange of molecules between blood and organs exists, the brain tissue is separated from the blood by the BBB, which consists of different cell types that fuse to an extremely tight barrier.

The BBB’s physiology is such that only very small, lipophilic molecules, or molecules with their own specialized transport systems in the brain epithelium, can overcome it. This means that, on one hand, the BBB can be viewed as an evolutionary marvel, effective at safeguarding the brain against pathogens and toxins and creating a highly specialized environment.

On the other hand, from the point of view of pharmaceutical therapeutics, the BBB can be seen as a barrier in the negative sense, hindering effective drug targeting of brain-associated disorders of the central nervous system (CNS). To open the BBB pharmacologically to facilitate drug uptake is both difficult and dangerous because it is always accompanied by the danger of ingress of toxic plasma proteins and, consequently, neuropathologies. Sometimes, drug design is able to adapt or exploit these special circumstances, but most of the potential neurotherapeutics will not be able to reach their intended target.

This is where the olfactory region and drug delivery via a specialized nasal spray come into play. By circumventing the BBB through the nerves innervating the olfactory region, a higher bioavailability is combined with lower drug dosing and fewer side effects, proving important advantages that have a great influence on drug design.

Figure 2 shows the distribution pattern of an aqueous solution with a fluorescent dye applied with a 3K® Standard Nasal Spray and a 3K® UltraSoft Nasal Spray. The evenly spread spray mist of the 3K® UltraSoft Nasal Spray reaches every compartment of the nasal cavity, including the olfactory region up to 40 %. This is an outstanding result, which may result from the long actuation time (~1 second) in combination with the small droplet size distribution of the spray pump.³

UltraSoft Inhalation device for rehydration of the airways

Whereas the deep lung and the anterior nasal cavity are well-known drug targets, with many different devices on the market, and we already presented in the previous section a solution for the olfactory region, the connection between the nasal cavity and the deep lung (trachea, larynx, voice cord) are not targeted specifically by many devices so far.

The larynx, as part of the conducting zone that is inevitably passed during inhalation, is also worth looking at regarding a potential drug target for some indications. Using the larynx route for rehydration therapy and airway hygiene is a simple and potentially highly effective idea. Some studies show that poor hydration has a negative effect on infection protection, which makes affected individuals more susceptible to COVID-19.^4,5

The underlying mechanism for why airway dehydration has this impact is that inhaled contaminants are not filtered in an ideal way. Dehydration leads to thinning of the upper airway lining fluid, decreases the beat frequency of cilia, and impairs epithelial cells. Of course, this not only holds true for SARS-COV2 – it applies to other airborne infections as well as allergies, asthma, and chronic obstructive pulmonary disease, as well as general air dryness exposure, as in air-conditioned rooms.

To provide hands-on solutions for this need, the ultrasoft mist technology integrated with URSATEC systems is not limited to the use of nasal sprays. The Rayleigh-principle-based technique is also integrated into an inhaler, providing an ultrasoft mist inhalation device with all the usability-associated advantages of a slow-moving mist and the independence of breath actuation and coordination of firing events as is the case for dry powder or pressurized metered dose inhalers. There is even more customizing possible: the generation of various droplet sizes that deposit in different structures of the respiratory tract according to their aerodynamic properties, e.g., the larynx can be specifically targeted for rehydration therapy³ (Figure 3).


Taken together, the 3K® ultrasoft technology provides a platform for targeting different sites of the respiratory tract on the basis of a well-known application device with a good usability profile proven by use over decades. The modern world is demanding easy and affordable solutions for a continuously increasing negative effect dry air exerts by dehydrating the respiratory tract. Since the pathomechanism of dehydration can even be worsened by the effect of preservatives, the 100% preservative-free philosophy of URSATEC adds another unique selling point on the devices presented here.

References
1.  Bagel S, Wiedemann B. Eur J Pharm Biopharm. 2004, 57, 353-358.
2.  M.-C. Klein, R. Kraus, A. Bilstein ONdrugDelivery 2022, 131, 22-26.
3.  M.-C. Klein, A. Bilstein, C. Hoffmann ONdrugDelivery 2023, 145, 56-60.
4.  George CE et al, “COVID-19 symptoms are reduced by targeted hydration of the nose, larynx and trachea”. Sci Rep, 2022, Vol 12(1), p 4599.
5.  Lauc G et al, “Fighting COVID-19 with water”. J Glob Health, 2020, Vol 10(1), p 010344.

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