Paediatric drug development of ramipril:reformulation, in vitro and in vivo evaluation

Ramipril is used mainly for the treatment of hypertension and to reduce incidence of fatality following heart attacks in patients who develop indications of congestive heart failure. In the paediatric population it is used most commonly for the treatment of heart failure, hypertension in type 1 diabetes and diabetic nephropathy. Due to the lack of a suitable liquid formulation, the current study evaluates the development of a range of oral liquid formulations of ramipril along with their in vitro and in vivo absorption studies. Three different formulation development approaches were studied: solubilisation using acetic acid as a co-solvent, complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and suspension development using xanthan gum. Systematic optimisation of formulation parameters for the different strategies resulted in the development of products stable for twelve months at long term stability conditions. In vivo evaluation showed CMAX of 10.48 µg/mL for co-solvent, 13.04µg/ml for the suspension and 29.58µg/mL for the cyclodextrin based ramipril solution. Interestingly, both ramipril solution (co-solvent) and the suspension showed a TMAX of 2.5h, however, cyclodextrin based ramipril produced TMAX at 0.75h following administration. The results presented in this study provide translatable products for oral liquid ramipril which offer preferential paediatric use over existing alternatives.

Uncertainty evaluation of an axi-symmetric measurement machine

This paper describes a method of uncertainty evaluation for axi-symmetric measurement machines which is compliant with GUM and PUMA methodologies. Specialized measuring machines for the inspection of axisymmetric components enable the measurement of properties such as roundness (radial runout), axial runout and coning. These machines typically consist of a rotary table and a number of contact measurement probes located on slideways. Sources of uncertainty include the probe calibration process, probe repeatability, probe alignment, geometric errors in the rotary table, the dimensional stability of the structure holding the probes and form errors in the reference hemisphere which is used to calibrate the system. The generic method is described and an evaluation of an industrial machine is described as a worked example. Type A uncertainties were obtained from a repeatability study of the probe calibration process, a repeatability study of the actual measurement process, a system stability test and an elastic deformation test. Type B uncertainties were obtained from calibration certificates and estimates. Expanded uncertainties, at 95% confidence, were then calculated for the measurement of; radial runout (1.2 µm with a plunger probe or 1.7 µm with a lever probe); axial runout (1.2 µm with a plunger probe or 1.5 µm with a lever probe); and coning/swash (0.44 arc seconds with a plunger probe or 0.60 arc seconds with a lever probe).