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Possible treatment of brain tuberculosis by methyl-β-cyclodextrin–assisted trans-nasal delivery of anti-tuberculosis drugs

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Tuberculosis (TB) is prevalent worldwide. One of the most life-threatening manifestation of extrapulmonary tuberculosis is the involvement of central nervous system (CNS), which can present as either tubercular meningitis, CNS-tuberculoma, or spinal arachnoiditis. Although CNS-tuberculosis only accounts for approximately 1 %–2 % of all active tuberculosis, 15%–40 % of CNS-TB patients unfortunately die or become disabled even after active anti-TB treatments.

Recently, a paper was published with promising results of the treatment of CNS-TB by methyl-β-cyclodextrin (RAMEB)–assisted trans-nasal delivery of anti-tuberculosis drug actives. (1)

As mentioned above, central nervous system tuberculosis is the most severe extra-pulmonary form of tuberculosis, facing significant challenges due to the limited penetration of anti-tuberculosis drugs across the blood-brain barrier and their insufficient concentrations at the site of infection.

The study published by Indian scientists aimed at the enhancement of the efficacy of anti-TB drugs by encapsulating them in methyl-β-cyclodextrin (M-β-CD) microparticles using spray-drying technology, to create such intranasally applicable micropraticulate drug delivery system, which can manage this serious CNS disease. Two antituberculotic APIs were involved in the study: isoniazid (INH) and rifampicin (Fig 1).

Fig. 1 Structure of two antituberculotic APIs: isoniazide (left) and rifampicine (right)

The spray-dried isoniazide and rifampicin exhibited spherical shapes with slightly deflated surfaces and had average particle sizes of 6.24 ± 0.77 μm and 5.97 ± 0.50 μm, respectively. Methyl-β-CD complexation improved the permeation of these two APIs through in vitro RPMI-2650 cell monolayers, while reducing drug cytotoxicity. Pharmaco-kinetic and biodistribution analysis demonstrated that intranasal administration of methyl-β-cyclodextrin enabled two antituberculotic drugs, resulted in significantly enhanced the trans-nasal brain delivery of APIs and their distribution in the brain, achieving the necessary MIC, minimum inhibitory concentration. In a murine model of CNS-tuberculosis, intranasal insufflation of methyl-β-cyclodextrin complexed drugs for four weeks led to a significant reduction (∼0.78 Log10 CFU) in Mycobacterial burden in the brain, compared to the untreated group (∼3.60 Log10 CFU).  (See Fig 2)

Fig. 2. Graphical abstract of paper by Jadhav et al J.Control. Release (1)

These preclinical results underscore the potential of intranasal administration of methyl-β-cyclodextrin enabled drug microparticles as an effective therapeutic strategy for combating brain inflammation in CNS-tuberculosis.

The above encouraging preliminary results on treatment of brain tuberculosis by methyl-β-cyclodextrin–assisted trans-nasal delivery of anti-tuberculotic drug actives, can be considered as one of the first promising experimental proof of cyclodextrin-assisted nose to brain drug delivery concept described earlier in detail by the group of professor Giunchedi at University of Sassari, Sardinia. (2) Giunchedi’s group described that CDs can be useful both as pharmaceutical excipients (solubilizer and absorption promoter) and even actives (antiviral, antiparasitic, anti-atherosclerotic, and neuroprotective agents), considering their safety profiles, non-toxicity based on clinical data. The use of CDs in nasal formulations allowed researchers to obtain versatile drug delivery systems intended for local and systemic effects, as well as to achieve therapeutic drug concentrations in CNS. In general, CDs contribute to increase the drug solubility in water and modulate their permeability across the nasal mucosa. In terms of the systemic effects, the presence of CDs in nasal formulations has been demonstrated to increase the bioavailability of sedatives and drugs against hypercalcemia. As far as the central effects are concerned, different types of CDs in nasal formulations appeared to induce an increase in drug uptake in different regions of the brain. In vitro and in vivo models are currently suitable to analyze the effects produced by the presence of CDs in nasal formulations. Therefore, CDs are versatile pharmaceutical materials with potential biological activities, and their nasal application could represent an interesting and fruitful research field in the coming years.

References

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