Comparative pharmacokinetics of salbutamol inhaled from a pressurized metered dose inhaler either alone or connected to a newly enhanced spacer design

Abstract

Background

Coordination between actuation of a pressurized metered dose inhaler (pMDI) and inhalation is a critical manoeuvre that many patients fail to perform correctly. pMDIs connected to spacers do not require hand-lung coordination. This study evaluated the relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol post-inhalation from Ventolin® Evohaler® (GlaxoSmithKline) either alone following verbal inhaler technique counselling (VC) or connected to a newly improved Able Spacer® (AS).

Methods

In a two-period, randomized crossover study, 16 healthy adults inhaled 2 × 100 µg salbutamol puffs (1 min gap) from Ventolin using VC or AS. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition (OD) determination. Urine samples were collected 0.5 h (pre-) and 0.5, 1.0 and 2.0 h post-inhalation. Urine was then pooled 2–24 h post-inhalation. The relative lung bioavailability (0–0.5 h urinary salbutamol excretion – USAL0.5) and systemic bioavailability (0–24 h urinary excretion of salbutamol and its metabolite – USALMET24) were determined. A one week washout separated VC and AS use.

Results

The mean (SD) USAL0.5 of VC and AS was 5.36 (4.48) and 12.80 (10.83) µg, respectively. The mean (SD) OD was 11.35 (3.37) and 0.48 (0.30) µg, respectively. VC and AS were significantly different in USAL0.5 and OD (p<0.001). USALMET24 was comparable (p>0.05).

Conclusions

Compared with VC, AS doubled the inhaled salbutamol lung dose and minimised its precipitation in the oral cavity. The results suggest this inhalation aid can add therapeutic and safety benefits particularly in patients with continued pMDI technique issues despite repeated VC.

Introduction

The inhaled products’ market has expanded enormously over time. Pressurized metered dose inhalers (pMDIs) and dry powder inhalers of various design and pharmaceutical formulation have been introduced [1]. However, the pMDI remains a fundamental inhaler for patients with obstructive lung conditions [2]. Many patients, however, do not get the maximal therapeutic benefit from their inhaled medicines because they fail to use their pMDIs correctly [3], [4], [5]. Up to 93% of patients have a hand-lung coordination issue which is expressed as an inability to press the canister at or instantly after the start of a slow inhalation through their pressurized inhaler [6]. This poor pMDI technique reduces lung deposition and maximises unwanted oropharyngeal deposition of inhaled medicines [2].

Verbal inhaler technique counselling (VC) improves patients’ pMDI use [7, 8]. Despite repeated VC, many patients continue to misuse their pMDIs [9, 10]. Accordingly, these patients are usually prescribed spacer devices, also known as valved holding chambers (VHCs), to use with their pMDIs to overcome coordination and improper inhalation flow problems [3]. These add-on chambers slow the speed of the emitted aerosol particles giving more time for the patient to inhale the puff slowly and deeply. Additionally, spacers allow more evaporation of the aerosol propellant reducing the size of the drug particles and thus their impaction in the mouth and throat [11], [12], [13]. Available spacers differ in size, shape and engineering design. It has been reported that aerosol emission and particle size distribution vary between different spacers, and within a particular spacer when used with different active pharmaceutical ingredients and formulations [14], [15], [16]. Able Spacer® (AS) (Clement Clarke International Limited, UK) is a small-size VHC that has recently been improved with the use of a special transparent polymer that incorporates silver ion anti-microbial technology to protect from contamination and inhibit microbial growth. The Spacer valve has been improved to operate at the low inhalation rates typical of the tidal flows of younger patients, combined with a visible valve movement that allows healthcare professionals to observe and confirm correct pMDI actuation and inhalation.

Various pharmacokinetic and gamma scintigraphy methods have been developed to determine the amount of a drug delivered to the lungs post-inhalation [17]. A urinary pharmacokinetic approach has shown that unchanged salbutamol excreted in urine within the first 30 min following dose inhalation (USAL0.5) represents the therapeutically effective lung dose (or relative lung bioavailability). Whilst, the cumulative renally-excreted salbutamol and its sulphate ester metabolite 0 to 24 h post dose inhalation (USALMET24) identifies the relative bioavailability of salbutamol to the body (the systemic exposure through both pulmonary and gastrointestinal tract (GIT) gates) [18]. This urinary salbutamol excretion pharmacokinetic approach has been applied to assess different pMDI inhalation methods [19, 20], VHCs [21, 22] and inhaler devices [23], [24], [25]. The current study evaluated and compared the relative lung (USAL0.5) and systemic (USALMET24) bioavailability of salbutamol inhaled by healthy adults from Ventolin® Evohaler® (GlaxoSmithKline) either alone following VC or connected to AS. The oropharyngeal deposition of salbutamol was also determined immediately post VC and AS inhalation.