Understanding the mechanism of drug delivery from thickened fluids to aid swallowing of medications

Abstract

Medications are often crushed and mixed with foods or fluids to aid drug delivery for those who cannot or prefer not to swallow whole tablets or capsules. Dysphagic patients have the added problem of being unable to safely swallow fluids, so thickeners are added to ensure safe swallowing. These thickened fluids are then also used to deliver crushed medications in replacement of water. This thesis explores the influence of thickened water co-administration on drug release in gastric fluid, the effect of rheological properties of these agents and their contribution to describing the mechanism of release. The literature review (Chapter 1) examines oral dosage form administration, rheological properties of these agents as a means to ensure medication delivery and mechanisms of drug release. It is highlighted that thickened fluids have the potential to alter drug release but prediction of the effect of co-administration is not currently reported.Chapter 2 investigates the delivery of medications with thickened fluids as an indicator for potential compromise of drug bioavailability. In vitro dissolution in simulated gastric fluid is investigated for crushed atenolol immediate release tablets mixed with thickened fluids. Five commercial viscosityincreasing agents of varied polysaccharide composition are used at three thickness levels prescribed for dysphagic patients (levels 150, 400, 900). All types of thickening agents are non-Newtonian shear thinning fluids. The greatest thickness (level 900) significantly restricts dissolution, and products that are primarily based on xanthan gum also significantly delay dissolution at the intermediate thickness level (level 400). The interactions of the polysaccharide chains, particularly the rigid rod type conformation of xanthan gum, traps drug molecules within it resulting in impaired dissolution. Under the conditions of this experiment, the higher concentrations of thickening agents remain in large lumps rather than disintegrating into the media. Drug release is generally affected to a greater extent by high-viscosity fluids than low-viscosity fluids at 50 s -1 , but viscosity at this single shear rate of 50 s -1 is not a good indicator for effect on drug dissolution because viscosity changes with shear rate. The determination of other rheological parameters such as viscoelasticity and the effect of breaking up of the structures may be required.To investigate whether it is possible to improve drug release from thickened fluids, in Chapter 3 the effect of the state of aggregation of the active ingredient with thickened fluids is investigated.Paracetamol is the model drug because it is available in a range of formulations with the drug in solution (elixir, dissolved effervescent tablet) or dispersion (suspension). Xanthan gum, which causes the greatest restriction on dissolution (Chapter 2), is used at level 900 as the thickener.ii Crushed tablets with thickener are prepared using manual (i.e. the standard method in clinical practice) or mechanical mixing. The unthickene...

Medication Lubricants for Oral Delivery of Drugs: Oral Processing Reduces Thickness, Changes Characteristics, and Improves Dissolution Profile

“…The in vivo absorption of crushed paracetamol tablets mixed with xanthan gum-based dysphagia-oriented thickeners was substantially faster than what was predicted from in vitro dissolution tests [21]. It has been suggested that this is associated with changes that occur to the bolus structure during deglutition that change the form of the bolus by the time it reaches the stomach, which, in turn, might increase drug release [11,22].…”