In vitro and in vivo antitubercular activity of benzothiazinone-loaded human serum albumin nanocarriers designed for inhalation

New Insight into Dearomatization and Decarbonylation of Antitubercular 4H‐Benzo[e][1,3]thiazinones: Stable 5H‐ and 7H‐Benzo[e][1,3]thiazines

“…Identification of possible reaction pathways of BTZs is important for understanding and optimization of absorption, distribution, metabolism and excretion (ADME) characteristics and of particular interest with regard to the ongoing investigation of this compound class in medicinal chemistry, [10] pharmaceutics [11] and clinical development. [3a] …”

“…A very recent study proved the importance of electron-deficient (nitro-)aromatic pharmacophores in covalent DprE1 inhibitors, which showed comparable reactivity towards NaBH 4 . [9] Identification of possible reaction pathways of BTZs is important for understanding and optimization of absorption, distribution, metabolism and excretion (ADME) characteristics and of particular interest with regard to the ongoing investigation of this compound class in medicinal chemistry, [10] pharmaceutics [11] and clinical development. [3a] We have now (re)investigated reactions of BTZs…”

Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages

“…Hydrophilic anti-TB drugs like aminoglycosides and INH have been encapsulated in micro-carriers and have displayed improved intracellular delivery [54,55]. Albumin microcarriers have been used to improve solubility and bioavailability of antimycobacterial benzothiazinone compounds [56]. Ligands such as mannose and fucose were used for targeted intracellular delivery into AMs that express high levels of mannose receptors [57][58][59][60].…”

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines

“…However, to overcome the hydrophobicity of PLGA or modulate the drug release, hydrophilic polymers such as PEG, PVA, HA can be employed to modify PLGA in the inhaled formulations 108 , 109 , 110 . Various polymeric excipients used in inhaled sustained-release formulations are summarized in Table 1 99 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 .…”

“… Polymer The property of polymer MW of polymer API Aerosol form D a Performance in in vitro release profiles /in vivo PK studies Ref. Natural polymers Albumin Naturally present at the lungs, non-immunogenic, biocompatible, biodegradable ∼66 kDa Benzothiazinones Dry powders 2.2–2.7 μm (geometric diameters) The drug release was triggered by proteases, causing more than 50% of drug being released within 4 h, which was followed by a slower and sustained release profile lasting for 48 h. 111 Alginate Biodegradable, biocompatible, mucoadhesive – Isoniazid, rifampicin Dry powders 1–2 μm The formulations exhibited an initial burst release (30%–40% within the first 4 h) followed by a sustained release pattern (90% within 60 h). 112 CS Biocompatible, biodegradable, non-immunogenic, antimicrobial activity, mucoadhesive – Levofloxacin Dry powders Less than 5 μm A sustained in vitro release profile was observed (cumulative release of 80%–90% over 24 h) 113 Gelatin Biodegradable, biocompatible <300 kDa Methotrexate Dry powders 2.2–2.9 μm Only 35% of the loaded drug was released from the methotrexate conjugated gelatin particles within 72 h in the presence of trypsin, while the unconjugated entirely released the drug within 36 h. 114 HA Naturally present at the lungs, non-immunogenic, biodegradable, mucoadhesive ∼2000 kDa Insulin Dry powders 1–4 μm As compared to spray-dried pure insulin powders, the formulations had no immediate blood concentration peak and displayed a slower in vivo clearance phenomenon.…”