Carvedilol Phosphate

A tunable modular design (TMD) as a new approach was proposed to tailor the dose and drug release profile of poorly water-soluble drugs from hydroxypropyl methylcellulose (HPMC)-based solid foams by combining two manufacturing principles: (1) freeze-drying aqueous HPMC-based gels to yield porous sturdy modules with specific doses of an active pharmaceutical ingredient (API) with the step size of 3 mg, and (2) fine-tuning the desired dose of the API with the step size of 0.1 mg by inkjet printing of the API-loaded ink onto the modules. Carvedilol (CAR) was used as a model poorly water-soluble API that requires frequent dose adjustment. The limitation of poor CAR solubility was overcome by designing pharmaceutically approved co-solvent systems. This approach ensured printable inks of a high drug content, and sturdy and flexible modules with uniform distribution of CAR to achieve effective and accurate doses of CAR. The tailored release rate of CAR from TMD products was succeeded by varying the composition, particularly, the content and grade of HPMC, and physical dimensions of modules. The TMD approach holds potential for designing bespoke high-quality products, containing hydrophilic cellulose ethers such as HPMC and poorly water-soluble APIs.

Tamoxifen, a selective estrogen receptor modulator (SERM) used in breast cancer therapy, requires metabolic activation by CYP3A4 to exert its biological effects. This study evaluated the effects of calcium channel blockers nimodipine, nitrendipine and felodipine on tamoxifen metabolism by studying their interactions with tamoxifen in vitro and in vivo. Rat liver microsomes (RLM) and human liver microsomes (HLM) were used in this study to evaluate the inhibitory potential of nimodipine, nitrendipine and felodipine on tamoxifen metabolism in vitro. A total of 28 cardiovascular drugs, including calcium channel blockers, were screened in an RLM incubation system in vitro. In RLM, nimodipine, nitrendipine and felodipine had half-maximum inhibitory concentration (IC₅₀) values of 5.55 µM, 11.86 µM and 7.71 µM, respectively. In HLM, the IC₅₀ values were increased to 20.38 µM, 30.06 µM, and 44.45 µM for nimodipine, nitrendipine and felodipine, respectively. The kinetic assays indicated that nimodipine and felodipine inhibited the metabolism of tamoxifen in a competitive way, whereas nitrendipine showed non-competitive inhibition in RLM. However, felodipine exhibited non-competitive inhibition, and nimodipine and nitrendipine showed competitive inhibition in HLM. Pharmacokinetic studies in rats revealed that pretreatment with nimodipine and nitrendipine significantly increased the systemic exposure of tamoxifen, as demonstrated by increasing the area under the curve (AUC), the maximum concentration (C_max) and decreasing the clearance (CL_z/F). Finally, molecular docking studies supported these findings, showing potential interactions at the active site of CYP3A4. These results suggested the necessity for careful monitoring and possible dose adjustments of tamoxifen when co-administered with calcium channel blockers in clinic.