A novel method for assessing dissolution of aerosol inhaler products

Abstract

Glucocorticoids administered by inhalation remain a first-line treatment of patients with asthma allergic rhinitis and advanced chronic obstructive pulmonary disease. Budesonide (BD), fluticasone propionate (FP) and triamcinolone acetonide (TA) have high hepatic first-pass inactivation of the swallowed fraction of the inhaled dose, whereas there is no first-pass metabolism in the lung. Hence, the lung bioavailability will determine the overall systemic absorption and the systemic bioactivity. Efficacy of inhaled agents in the respiratory tract depends on the site of deposition and physicochemical properties of the drug, which dictates rate of dissolution, absorption, metabolism and elimination. However, to date no official method exists for testing dissolution rates from inhalation aerosols. An in vitro flow through dissolution method may be useful to provide information on rate of release and determine formulation differences between products or in product development. After administration of three glucocorticoids into a cascade impactor they underwent dissolution in a flow through cell utilising water, simulated lung fluid (SLF) and modified SLF with l-α-phosphatidylcholine (DPPC) as a dissolution medium, at constant flow and temperature. Modified SLF significantly increased the dissolution rate compared with SLF alone. This novel technique appears to be a useful method of evaluating dissolution of these glucocorticoids and may also be applied to other respiratory products administered via aerosols.

Introduction

Glucocorticoids administered by inhalation are effective and widely used as anti-inflammatory agents for treatment of patients with asthma allergic rhinitis and advanced chronic obstructive pulmonary disease. Budesonide (BD), triamcinolone acetonide (TA) and fluticasone propionate (FP) all have a high degree of hepatic first-pass inactivation of the swallowed fraction of the inhaled dose, whereas there is no evidence of first-pass metabolism of these drugs in the lung. (Brogden and Tavish, 1992, Falcoz et al., 1996). Hence, the lung bioavailability of glucocorticoids is likely to determine the overall systemic exposure. Efficacy of inhaled agents in the respiratory tract depends on the site of deposition and on the physicochemical properties of the drug. The latter dictates the rate of dissolution and subsequent systemic absorption, metabolism and elimination of the drug. If the drug particles are deposited at the upper airway, mucociliary clearance take place prior to dissolution and absorption. The mucocilary clearance rate of a normal person’s lungs is about 1–2% per min, i.e. half-life is about 1–2 h. If the drug particles are deposited at the lower airways the drug would be cleared by macrophages via phagoyctosis. The clearance rate by macrophages, however, is significantly slower compared with mucociliary clearance. Insoluble particles in the alveoli can, therefore, reside for days before being completely removed by phagocytosis depending on particle size, shape and load (Daviskas et al., 1995).

Dissolution is defined as the process by which a solid substance enters into a solvent to yield a solution and is controlled by the affinity between the solid substance and the solvent. Dissolution testing is an official test in the Pharmacopoeias for evaluating solid and semi-solid dosage forms. Furthermore, dissolution testing allows the investigation of the dissolution behaviour of pharmaceutical dosage forms in vitro to provide some predictive estimates of their behaviour in vivo.

The flow through cell method has been officially approved in the British Pharmacopoeia (2000) for the assessment of the dissolution of drugs from different dosage forms. Dissolution testing is a sensitive and reliable predictor of bioavailability for some drugs and is one of the most important quality control tests performed on pharmaceutical dosage forms.

The aerosol particles of the inhaled drug which enters the pulmonary region in the non-ciliated area undergo dissolution in the lung fluids, and the dissolved fraction of the dose will be available for absorption across the alveolar membrane (Dolovich et al., 1987). The dissolution rate for drug particles is determined by the rate at which solvent–solid forces of attraction overcome the cohesive forces present in the solid. The dissolution process is most frequently described in the form of a dissolution profile of cumulative percent of drug dissolved over time. Although this is the most exact representation, it is useful in practice to summarise and quantify dissolution kinetics in terms of one or more parameters, including dissolution rate constant or dissolution rate coefficient.

Following administration of a drug substance by an inhalation aerosol, it is generally accepted that less than 20% of the emitted dose reaches the respiratory tract (Barnes, 1995). A narrow particle size range (typically 1–5 μm) reaches the respiratory tract and may undergo dissolution. Drug particles greater than >5 μm may impact in the mouth and throat. The fate of the inhaled drug particles depends on the physicochemical and physical properties of the drug substance and the site of deposition in the respiratory tract.

Particles that deposit in the ciliated airways are cleared primarily by mucociliary clearance (Dolovich et al., 1987). Drug particles that penetrate deep into the lungs and deposit in the peripheral non-ciliated areas of the lungs can be cleared by many mechanisms, including dissolution (Dolovich et al., 1987).

Medications for managing respiratory diseases are generally delivered using metered-dose inhalers or dry powder inhalers. These devices deliver solid particles to the respiratory tract, and those particles that deposit in the non-ciliated regions of the respiratory tract need to be in solution in order to facilitate their local and systemic effects. Aerosol particles from the emitted dose that reach the non-ciliated regions of the lung have very small particle size and the dissolution rate of a drug is expected to be very high because of the large surface area to weight ratio of the particles. However, glucocorticoids are poorly water-soluble compounds, and hence the dissolution process is likely to be a rate-limiting step in glucocorticoid’s action and systemic absorption.

Glucocorticoids are very hydrophobic compounds with lipophilicity in rank order: FP>BD>TA (Rohdewald et al., 1990). The fate of particles deposited in the pulmonary region can be described as in Fig. 1. The insoluble particles will probably be engulfed by alveolar macrophages and transported to the mucociliary clearance system. Subsequently, drug particles will be carried up to the pharyngeal region where they may be expectorated or swallowed. If a particle is swallowed, it may be solubilised upon passage through the gastrointestinal tract and enter the blood stream. Finally, systemic effects may be elicited with subsequent metabolism and excretion of the drugs (or their metabolites) via the urine or bile. Particles that do not undergo disintegration and dissolution would be excreted in the faeces. Insoluble particles in the alveolar region which are not phagocytised may become sequestered in pulmonary tissue (Clark, 1974). If sequestered for a long period, some solublisation may occur and, depending on the chemical nature of the material adverse tissue reactions, may lead to fibrotic response. Alternatively, benign pneumoconiosis may result with no immediate adverse response seen. Soluble particles which reach the pulmonary region will dissolve in the lung fluid and may exert local toxic, irritant or pharmacological effects. Xenobiotics can also enter the blood stream and exert systemic effects and ultimately be subject to excretory mechanisms.

To date no single in vitro test system has yet emerged as the ideal choice for performing dissolution measurements as a tool to estimate in vivo solubility in the lung fluids. The objective of these studies is to study the dissolution of three inhaled glucocorticoids. Specifically, this study will examine the dissolution profile of BD in water, and different types of simulated lung fluids (SLFs). In addition, the dissolution profiles of TA and FP are investigated in different SLFs using a new flow through dissolution system.

The four experimental aims of this study were to investigate: (1) baseline solubility and partition coefficient (K) of the different glucocorticoids. The solubility of TA, BD and FP was studied in various dissolution media which include water, SLF (Table 1) and SLF modified with various concentrations of l-α-phosphatidylcholine (DPPC) (0.01, 0.02 and 0.05%). (2) The influence of the dissolution media, including water, SLF, SLF modified with DPPC (0.1, 0.02 and 0.05%), acidic and alkaline SLFs on the dissolution profile of BD in water. (3) The influence of the dissolution media flow rate on the dissolution profile of BD. (4) The influence of 0.02% DPPC on the dissolution profile of TA and FP compared to SLF alone.