Refine
Document Type
- Article (1)
- Doctoral Thesis (1)
Language
- English (2) (remove)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- Tuberculosis (2) (remove)
Institute
- Biochemie und Chemie (1)
- Pharmazie (1)
Antibiotic treatment of tuberculosis (TB) is complex, lengthy, and can be associated with various adverse effects. As a result, patient compliance often is poor, thus further enhancing the risk of selecting multi-drug resistant bacteria. Macrophage mannose receptor (MMR)-positive alveolar macrophages (AM) constitute a niche in which Mycobacterium tuberculosis replicates and survives. Therefore, we encapsulated levofloxacin in lipid nanocarriers functionalized with fucosyl residues that interact with the MMR. Indeed, such nanocarriers preferentially targeted
MMR-positive myeloid cells, and in particular, AM. Intracellularly, fucosylated lipid nanocarriers favorably delivered their payload into endosomal compartments, where mycobacteria reside. In an in vitro setting using infected human primary macrophages as well as dendritic cells, the encapsulated antibiotic cleared the pathogen more efficiently than free levofloxacin. In conclusion, our results point towards carbohydrate-functionalized nanocarriers as a promising tool for improving TB treatment by targeted delivery of antibiotics.
The present work comprises different projects within the scope of public health. In detail, they all aim at combating the high-burden diseases HIV/AIDS, malaria and tuberculosis more effectively. Since there was, and still is, no harmonization between the existing biowaiver guidelines, the biowaiver dissolution test conditions by WHO and FDA were compared against each other using drug products, which had already demonstrated BE to the comparator in vivo. Thereby it could be shown that the dissolution conditions proposed by the WHO are more appropriate for granting biowaivers than those of the FDA. Further, the applicability of the WHO dissolution test conditions was investigated using the APIs ethambutol, isoniazid and pyrazinamide (all BCS Class III) as model compounds. These investigations demonstrated that the concept of the biowaiver proved to work properly, i.e. leading to no false positive BE decision and an acceptable incidence of false negative BE decisions. In addition, four new biowaiver monographs were published addressing important APIs in the treatment of HIV/AIDS and malaria. Before these efforts, there were only a very few biowaiver monographs available for antiviral or antimalarial APIs, i.e. the database of biowaiver monographs has been clearly improved. The last part of the present work dealt with the extension of the biowaiver concept to related areas such as the WHO Prequalification of Medicines Programme. Investigations revealed that the biowaiver tools are generally eligible for prequalification of drug products containing ethambutol, isoniazid, pyrazinamide, or lamivudine to prove BE between an appropriate comparator and the test candidate. By contrast, some APIs are excluded from the biowaiver procedure. In conclusion, the implementation of the biowaiver tools for prequalification of biowaivable APIs is, along with BCS-based biowaiver approval of new generics, an important step towards making essential, high-quality drug products more cost-effective and, as a consequence, more accessible for a larger percentage of the population. In that way, the treatment conditions for those in need living in the developing countries can be improved enormously, so that those who are poor do not have to receive poor treatment. The quality standard of essential medicines will increase worldwide, thereby helping to combat the high-burden diseases better and, in turn, lead to an improvement of the global health status.