Development of a Softpellet Formulation for Inhaled High-Dose Therapy

Tuberculosis is a difficult-to-treat disease caused by mycobacterium tuberculosis, which is one of the top 10 causes of death and the deadliest infectious disease worldwide. In 80 % of the patients, the primary infection occurs in the lungs. The standard treatment for the disease is systemic administration of a combination of different antibiotics in high doses over a period of at least 6 months. In tuberculosis, however, the pathogen may be encapsulated in granulomas which are difficult to access for systemically administered drugs. At the same time, patient compliance is reduced due to the long duration of therapy and frequent side effects. In addition to other factors, these complications can lead to subtherapeutic concentrations in the target tissue, which favors the development of multidrug-resistant pathogens and thus compromises the success of the therapy. One approach to solve this problem is the administration of high-dose antibiotics via the inhalation route. This procedure allows high drug concentrations to be achieved in the target tissue while keeping systemic exposure low, thus minimising the incidence of side effects. To implement this new treatment method, a dry powder formulation for inhalation was developed in this thesis. Powders intended for inhalation must have aerodynamic particle diameters in the micronised range (1 - 5 μm), which makes them exhibit strong cohesive forces and difficult to handle. For this reason, controlled agglomerates, so-called softpellets, were produced from the raw materials by using a continuous process based on vibration. Due to the reduced surface area, softpellets show simplified handling, while the interparticle forces are low enough to allow deagglomeration during inhalation. Since softpellets can be produced from pure active ingredient and thus the amount of powder to be inhaled can be kept to a minimum for the patient, they are ideally suited for high-dose inhalation. By further developing the production device, the yield obtained in this work could be increased from 27 % to 80 %, which corresponds to an increase of almost threefold. The size of the softpellets could be controlled by using sieves with different mesh sizes for pre-agglomeration. The antibiotics used for tuberculosis treatment, rifampicin and isoniazid, were used as starting material. In the Twister, a FPF of 54 % and a FPD of 20 mg could be achieved with rifampicin softpellets, and a FPF of 11 % and a FPD of 4 mg with isoniazid Abstract 149 softpellets. For all experiments, a positive effect on FPF was observed when the dose was divided into several single inhalations. By using coarse lactose particles, the ED in the Twister of rifampicin softpellets could be increased from 65 % to 74 %, resulting in an increase in FPD to 24 mg. In addition, the development of the Micro-Force apparatus made it possible for the first time to determine the energy required to compress a softpellet. Overall, this work has shown that the production method on a vibrating chute represents a continuous process with which softpellets with spherical morphology and high yields can be obtained. The softpellets showed the potential to transport large amounts of active substances in the mg range into the lungs and, therefore, to be suitable for inhaled high-dose therapy.


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