Journal of pharmaceutical sciences
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The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. ⋯ The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration-time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.
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The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a child's weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. ⋯ The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age.
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Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PK-PD/clinical response models offer critical insight in guiding biologics development at various stages. ⋯ Examples of using TMDD, PK-PD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PK-PD models most used.
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Aerosolized medicine is one of the fastest growing areas in the pharmaceutical industry. Dry powder aerosols of pharmaceutical compounds are particularly attractive for the prevention and treatment of respiratory diseases but are also emerging as a treatment option for systemic diseases. Engineering particles in dry powder formulations can overcome many of the limitations of traditional inhaled pharmaceuticals. ⋯ Parameters such as milling time and drug concentration were investigated, and the aerosol performance of dried budesonide NanoClusters was characterized. The wet milling process was able to produce aerosol particles composed entirely of budesonide. High emitted fraction and a large fine particle fraction suggested that the NanoCluster budesonide formulation would offer highly efficient delivery of drug throughout the lung.
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The biopharmaceutical and physicochemical properties of two new cyclic prodrugs (CA-[cychexalanine (Cha(4)), D-Leu(5) ]-Enkephalin (Enk) and coumarinic acid (CA)-[Cha(4), D-Ala(5)]-Enk) of opioid peptides that were designed to be stable to oxidative metabolism by cytochrome P-450 enzymes in the intestinal mucosa are described in this paper. Two-dimensional nuclear magnetic resonance studies and molecular dynamics simulations showed that these cyclic prodrugs exhibit unique solution conformations (i.e., type I β-turns), which are favorable for transcellular permeation. ⋯ Permeability studies using an in situ rat intestinal perfusion model confirmed the poor intestinal permeation characteristics of CA-[Cha(4), D-Leu(5) ]-Enk and CA-[Cha(4), D-Ala(5)]-Enk as well as the stability of these two new cyclic prodrugs of opioid peptides to oxidative metabolism. In conclusion, these data clearly show that oral absorption of cyclic prodrugs of opioid peptides can only be achieved by designing molecules devoid of substrate activity for both cytochrome P-450 enzymes and efflux transporters in the intestinal mucosa.