The pharmaceutical industry has to tackle the explosion of high amounts of poorly soluble APIs. This phenomenon leads to numerous sophisticated solutions. These include the use of multifactorial data analysis identifying correlations between the components and dosage form properties, laboratory and production process parameters with respect to the API liberation Example of such API is bicalutamide. Improved liberation is achieved by particle size reduction. Laboratory batches, with different PSD of API, were filled into gelatinous capsules and consequently granulated for tablet compression. Comparative dissolution profiles with Casodex 150 mg (Astra Zeneca) were performed. The component analysis was used for the statistical evaluation of f1 and f2 factors and D(v,0.9) and D[4,3] parameters of PSD to identify optimal PSD values. Suitable PSD limits for API were statistically confirmed in laboratory and in commercial scale with respect to optimized tablet properties. The tablets were bioequivalent with originator (n = 20; 90% CI for ln AUC0-120: 99.8-111.9%; 90% CI for ln cmax: 101.1-112.9%). In conclusion, the micronisation of the API is still an efficient and inexpensive method improving the bioavailability, although there are more complicated and expensive methods available. Statistical multifactorial methods improved the safety and reproducibility of production.

• MeSH
• anilidy chemická syntéza   metabolismus   MeSH
• biologická dostupnost MeSH
• chemie farmaceutická metody   MeSH
• multivariační analýza MeSH
• nitrily chemická syntéza   metabolismus   MeSH
• tablety MeSH
• terapeutická ekvivalence MeSH
• tosylové sloučeniny chemická syntéza   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

The G protein-coupled cysteinyl leukotriene receptor CysLT1R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT1R antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLT1R bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue-coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.

• MeSH
• antagonisté leukotrienů chemie   metabolismus   MeSH
• antiastmatika chemie   metabolismus   MeSH
• chromony chemie   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• ligandy MeSH
• receptory leukotrienů chemie   genetika   metabolismus   MeSH
• rekombinantní proteiny biosyntéza   chemie   izolace a purifikace   MeSH
• simulace molekulového dockingu MeSH
• sodík chemie   metabolismus   MeSH
• terciární struktura proteinů MeSH
• tosylové sloučeniny chemie   metabolismus   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH