Multidimensional analysis of human intestinal fluid composition.

The oral administration of solid dosage forms is the commonest method to achieve systemic therapy and relies on the drug's solubility in human intestinal fluid (HIF), a key factor that influences bioavailability and biopharmaceutical classification. However, HIF is difficult to obtain and is known to be variable, which has led to the development of a range of simulated intestinal fluid (SIF) systems to determine drug solubility in vitro. In this study we have applied a novel multidimensional approach to analyse and characterise HIF composition using a published data set in both fasted and fed states with a view to refining the existing SIF approaches. The data set provided 152 and 172 measurements of five variables (total bile salt, phospholipid, total free fatty acid, cholesterol and pH) in time-dependent HIF samples from 20 volunteers in the fasted and fed state, respectively. The variable data sets for both fasted state and fed state are complex, do not follow normal distributions but the amphiphilic variable concentrations are correlated. When plotted 2-dimensionally a generally ellipsoid shaped data cloud with a positive slope is revealed with boundaries that enclose published fasted or fed HIF compositions. The data cloud also encloses the majority of fasted state and fed state SIF recipes and illustrates that the structured nature of design of experiment (DoE) approaches does not optimally cover the variable space and may examine media compositions that are not biorelevant. A principal component analysis in either fasted or fed state in combination with fitting an ellipsoid shape to enclose the data results in 8 points that capture over 95% of the compositional variability of HIF. The variable's average rate of concentration change in both fasted state and fed state over a short time scale (10 min) is zero and a Euclidean analysis highlights differences between the fasted and fed states and among individual volunteers. The results indicate that a 9-point DoE (8 + 1 central point) could be applied to investigate drug solubility in vitro and provide statistical solubility limits. In addition, a single point could provide a worst-case solubility measurement to define the lowest biopharmaceutical classification boundary or for use during drug development. This study has provided a novel description of HIF composition. The approach could be expanded in multiple ways by incorporation of further data sets to improve the statistical coverage or to cover specific patient groups (e.g., paediatric). Further development might also be possible to analyse information on the time dependent behaviour of HIF and to guide HIF sampling and analysis protocols.

Transdermal scopolamine attenuates methacholine-induced bronchospasm.

Anticholinergic agents have been widely used in the management of asthma. The use of scopolamine has been limited by significant side effects. Transdermal delivery of scopolamine (TS) has, however, been used successfully for the prevention of motion sickness. The purpose of this study was to determine if TS would decrease methacholine-induced bronchospasm in a group of subjects with mild asthma. Bronchoprovocational challenges with inhaled methacholine were performed on three separate occasions in 10 male subjects who each had a past history of asthma. After a baseline challenge, each subject received, in a double-blinded fashion, either a placebo patch or TS patch. The challenge was then repeated after at least 36 hours, and the alternate patch was then dispensed. The provocative dose producing a fall in FEV1 by 20% from baseline was then calculated by linear regression analysis. No significant change in baseline pulmonary function was noted with placebo patch or TS. With the use of TS, there was a small but significant increase in the provocative dose producing a fall in FEV1 by 20% from baseline for the group (p less than 0.05). In conclusion, we were able to demonstrate that a TS patch worn for a short period of time, can significantly decrease airway reactivity to methacholine in some patients with hyperactive airways.