Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30 s in 2-6 ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30 min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

Vasopeptidase-activated latent ligands of the histamine receptor-1.

Whether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H1 receptor (H1R). First, a peptide consisting of the antihistamine cetirizine (CTZ) condensed at the N-terminus of ε-aminocaproyl-bradykinin (εACA-BK) was evaluated for an antihistamine activity that could be revealed by degradation of the peptide part of the molecule. CTZ-εACA-BK had a submicromolar affinity for the BK B2 receptor (B2R; IC50 of 590 nM, [(3)H]BK binding competition), but a non-negligible affinity for the human H1 receptor (H1R; IC50 of 11 µM for [(3)H]pyrilamine binding). In the human isolated umbilical vein, a system where both endogenous B2R and H1R mediate strong contractions, CTZ-εACA-BK exerted mild antagonist effects on histamine-induced contraction that were not modified by omapatrilat or by a B2R antagonist that prevents endocytosis of the BK conjugate. Cells expressing recombinant ACE or B2R incubated with CTZ-εACA-BK did not release a competitor of [(3)H]pyrilamine binding to H1Rs. Thus, there is no evidence that CTZ-εACA-BK can release free cetirizine in biological environments. The second prodrug was a blocked agonist, L-alanyl-histamine, potentially activated by aminopeptidase N (APN). This compound did not compete for [(3)H]pyrilamine binding to H1Rs. The human umbilical vein contractility assay responded to L-alanyl-histamine (EC50 54.7 µM), but the APN inhibitor amastatin massively (17-fold) reduced its apparent potency. Amastatin did not influence the potency of histamine as a contractile agent. One of the 2 tested latent H1R ligands, L-alanyl-histamine, supported the feasibility of pro-drug activation by vascular ectopeptidases.

Stereoselective and multiple carrier-mediated transport of cetirizine across Caco-2 cell monolayers with potential drug interaction.

The aim of this study was to explore potential transport mechanisms of cetirizine enantiomers across Caco-2 cells. Cetirizine displayed polarized transport at concentrations ranging from 4.0 to 80.0 microM, with the permeability in the secretory direction being 1.4- to 4.0-fold higher than that in the absorptive direction. Cetirizine enantiomers were transported distinctively different from each other. In the presence of inhibitors of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), the absorptive transport was enhanced and secretory efflux was diminished. When verapamil, indomethacin, or probenecid were present, the difference in the absorptive permeability of R-cetirizine and S-cetirizine substantially intensified, whereas quinidine could eliminate. R-cetirizine significantly increased the efflux ratio of rhodamine-123 and doxorubicin in a fashion indicative of the upregulation of P-gp and MRP activities. However, S-cetirizine played a role of an inhibitor for P-gp and MRP. Ranitidine modified the absorption of cetirizine enantiomers, suggesting that the potential drug-drug interaction would significantly change the cetirizine pharmacokinetics. In conclusion, the results indicated that there are several efflux transporters including P-gp and MRP participating the absorption and efflux of cetirizine, which showed enantioselectivity in the transmembrane process. In addition, both P-gp and MRP functions could be modulated by cetirizine in chiral discriminative ways.