ABSTRACT
The loss of active substance, both small and large molecules, from sterile liquid drug products after contact with an administration kit has been extensively reported in the literature. This loss has been reported to be caused by incompatibility of the active substances with the contact surfaces of the administration kit and adsorption or sticking of the active substance to the surfaces of the administration kit. This paper investigates the mechanism for loss of a highly potent active substance based on the type and design of the administration kit. Two administration kits (syringe/Insyte Catheter and syringe/Nexiva Catheter) of different designs were used to administer a solution formulation of an ultra-low dose (nanograms) of a model hydrophobic active substance Compound X. The Nexiva Catheter was longer with tubing and Y connectors while the Insyte Catheter was shorter with no split septum tubing. Dose recovery from both administration kits was determined using high pressure liquid chromatography. The results indicated that the full dose was recovered from the syringes and Insyte Catheter. However, there was a significant loss of active substance from the Nexiva Catheter configuration even after post administration flush, which was due to holdup volume of the formulation within dead spaces of the Nexiva Catheter. It was also demonstrated that the dose recovery from the Nexiva Catheter can be significantly increased with increase in the post administration flush volume, which further confirms that the observed loss of active substance was not due to incompatibility or surface adsorption. The significance of this work is to provide awareness to formulation scientists that closed system Catheter design with Y connectors can be the main contributor for the loss in active substance, especially at ultra-low doses, and therefore dose recovery experiments should be expanded to include proper flushing of the Y connectors to expel any holdup volume from the Catheter.
Subject(s)
Syringes , Administration, Intravenous , Infusions, IntravenousABSTRACT
There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality-by-design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Chemistry, Pharmaceutical/methods , Dietary Fats/metabolism , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/metabolism , Isotope Labeling/methods , Administration, Oral , Adult , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Humans , Male , TabletsABSTRACT
Over the past several years, vacuum-assisted closure has been used as an adjunctive treatment in the management of many chronic and acute wounds. A chart review of chronic wounds in the authors' wound care practice was conducted to ascertain and document the effect of vacuum-assisted closure on the healing of chronic wounds. Over a 30-month period, 70 patients with chronic, nonhealing wounds were treated with vacuum-assisted closure. Of those, 50 had vacuum-assisted closure treatment following skin graft procedures. Using vacuum-assisted closure in addition to a protocol of general supportive and local wound care resulted in a high rate of closure during an average of 48 days. All (100%) of the skin grafts healed. These clinical results suggest that vacuum-assisted closure can be a useful adjunctive treatment in the management of open and grafted wounds and that additional research and documentation are warranted.
