Search

Leachables derived from multi-component drug-device syringe systems can result in changes to the quality of drug products. Diphenylguanidine (DPG), a leachable released from styrene butadiene rubber syringe plungers, interacts with Oxytocin to form protein-adducts. This study investigated the mechanism and kinetics of this interaction in both solid and solution states through in-vitro tests and spectroscopic methods For solid state interaction, the protein-adducts with DPG were characterized using SEM, XRD, DSC, FTIR, 13 C ss NMR, and dissolution analysis. For solution state interaction, LC-HRMS was used to assess stability of Oxytocin solutions in presence of various concentrations of DPG at 25°C and 40°C for 4 weeks. Moreover, molecular docking analysis was used to identify possible molecular configurations of the interaction.Results were consistent with the formation of a new solid state with distorted surface morphology for oxytocin-DPG adducts, in which the oxytocin carbonyl group(s) and the secondary amine groups of DPG interact. This interaction was also confirmed by molecular docking analysis through hydrogen bonding (2.31Å) and Van der Waal attraction (3.14Å). Moreover, LC-HRMS analysis revealed an increase in Oxytocin stability and suppression of Oxytocin dimerization by DPG. A potential reduction in the rate of Oxytocin dissolution from the formed adducts was indicative of its strong association with DPG. Hence, the leaching potential of DPG from rubber closures and plungers should be monitored and controlled to maintain the quality and stability of the pharmaceutical product., (Published by Elsevier B.V.)

The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.

The delivery dose uniformity is one of the most critical requirements of dry powder inhaler and metered dose inhaler products. In 1998, the U.S. Food and Drug Administration recommended a two-tier acceptance sampling plan in the Draft Guidance of Metered Dose Inhaler and Dry Powder Inhaler Drug Products Chemistry, Manufacturing and Controls. The two-tier procedure is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity. It employed a zero tolerance criterion. In addition, it has a near-zero probability acceptance at the second tier. In this article, a two-tier sequential tolerance interval approach is proposed that is equivalent to a two-tier two one-sided testing procedure. It controls the probability of the product delivering below a prespecified effective dose and the probability of the product delivering over a prespecified safety dose.

Purpose: Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA)., Experimental Design: The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized., Results: Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes., Conclusions: FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.

The purpose of this study was to develop a new design for transdermal system that provides a nearly constant drug delivery rate for the desired period of time in the absence of a large excess of drug in the donor reservoir. Simultaneous drug diffusion and aqueous binary vehicle evaporation has been investigated as a means of maintaining constant drug delivery from minidose reservoirs. Benzocaine was used as the model drug and water-ethanol mixtures as the binary vehicles. Benzocaine is much more soluble in ethanol than in water. Simultaneous diffusion-evaporation experiments were conducted using the water-ethanol mixture saturated with benzocaine as the minidose-reservoir. The reservoir vehicle was allowed to evaporate through a permselective membrane so as to maintain drug saturation in the vehicle even though the drug mass in the donor reservoir was constantly decreasing. Saturation activity of drug is maintained during donor depletion of drug by the selective loss of alcohol from the donor solvent, which concomitantly lowers the solubility. The superiority of the evaporable binary vehicle over a conventional sealed system was demonstrated by achieving near zero-order drug delivery with minimum drug remaining. A theoretical model was developed to predict drug flux, drug amount delivered, reservoir solvent volume and composition, and drug solubility during the two simultaneous processes of drug release and preferential solvent evaporation. Experimental data are in good agreement with theoretical calculations.

The effect of polar solvents and polar cosolvent mixtures on the transport properties of benzocaine in polydimethylsiloxane (PDMS) was studied. Methanol, ethanol, n-propanol, and n-butanol, as well as aqueous cosolvent mixtures of each n-alkanol, were used as vehicles for benzocaine. A constant activity gradient was maintained in all diffusion studies, with the membrane exposed to saturated donor suspensions of drug, and sink conditions maintained in the receiver. In spite of the constant activity gradient, steady-state benzocaine flux was substantially enhanced with increasing n-alkanol volume fraction and reached a maximum for the pure n-alkanol in each case. At any given composition, the degree of benzocaine flux enhancement generally increased with n-alkanol carbon number. In terms of the appropriate Fick's first law expression for this system, these observations were attributed to simultaneous changes in benzocaine concentration within the PDMS membrane, the diffusion coefficient of benzocaine in PDMS, fillerless membrane volume fraction, tortuosity, and the membrane thickness. These parameters were in turn correlated with the cosolvent composition in contact with the membrane. Both membrane solubility and diffusion coefficient were found to increase substantially, but decreases in tortuosity and increases in fillerless membrane volume fraction and membrane thickness were minor.