Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 2: Evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols

Abstract

Three in vitro methodologies were evaluated as models for the analysis of drug release from controlled release (CR) microparticulates for inhalation. USP Apparatus 2 (dissolution model), USP Apparatus 4 (flow through model) and a modified Franz cell (diffusion model), were investigated using identical sink volumes and temperatures (1000 ml and 37 °C). Microparticulates containing DSCG and different percentages of PVA (0%, 30%, 50%, 70% and 90%) were used as model CR formulations. Evaluation of the release profiles of DSCG from the modified PVA formulations, suggested that all data fitted a Weibull distribution model with R² ⩾ 0.942. Statistical analysis of the t_d (time for 63.2% drug release) indicated that all methodologies could distinguish between microparticles that did or did not contain PVA (Students t-test, p < 0.05). However, only the diffusion model could differentiate between samples containing different PVA percentages. Similar results were observed when analysing the data using similarity and difference factors. Furthermore, analysis of the release kinetic profiles for all samples suggested the data fitted the Higuchi diffusion model (R² ⩾ 0.862 for the diffusion methodology data set). Due to the relatively low water content in the respiratory tract and the lack of differentiation between formulations for USP Apparatus 2 and 4, it is concluded that the diffusion model is more applicable for the evaluation of CR inhalation medicines.

Introduction

Pulmonary administration of drugs has been employed for many years for the treatment of localized disease states such as asthma. Furthermore, with the high surface area and permeability of the lung, the 21st century has seen a paradigm shift to inhaled therapy for systemic use. Although, many compounds are either in use or under investigation as potential respiratory medicines, little thought has gone into controlling the rate at which drugs are absorbed and metabolized. Local disease states, infectious respiratory pathogens and systemic delivery systems would benefit from control over release rate of the active pharmaceutical ingredient (API). For example, asthma, which in many cases has exacerbated effects overnight, would benefit from a treatment that would result in controlled release delivery, for instance of a β₂-agonist, over an 8-h period. Moreover, the treatment of chronic infections with local antibiotics would benefit from an increased API residence time in the lung, improving the antimicrobial activity whilst potentially reducing the high dosing regime that is commonly required for these rapidly metabolized molecules.

To date, there is no controlled release (CR) product for inhalation on the market, however, recently there has been a research focus within the field [1]. One of the potential hurdles in developing CR inhalation formulations is the use of suitable methodologies for in vitro evaluation. Particulate systems for inhalation are regularly tested in terms of particle size and aerodynamic diameter, using pharmacopoeia methodologies that are well established. For example, the deposition pattern of a particular formulation in the respiratory tract can be estimated using inertial impactor testing. However, for a CR inhalation system it becomes essential to evaluate the release of an API molecule from the formulation matrix as a function of time. Currently, no pharmacopoeia methodology exists for the evaluation of the in vitro release rates from CR respiratory medicines. Subsequently, the evaluation of release from these novel systems has been conducted using a variety of methods, which are based on different principles, rely on certain assumptions and allow little comparison between different CR approaches.

A range of pharmacopoeia methodologies exist for the testing of conventional solid dosage formulations, however, these systems generally are designed to mimic the GI tract and as such are based on ‘sink’ conditions. The most common apparatus used are United States Pharmacopoeia (USP) apparatus 1 and 2, which monitor the dissolution of a solid dosage form in a 900–1000 ml solution, either suspended in a rotating basket (apparatus 1) or resting below a rotating paddle (Apparatus 2) [2]. This methodology has recently been adopted by many researchers for the assessment of drug release from microparticulate formulations. For example, carbamazepine-loaded enteric microparticles [3] and spray dried CR sodium diclofenac microparticles [4] were recently investigated using USP Apparatus 2. In these cases, however, the microparticulates were not of respiratory size range (e.g. ⩽6 μm [5]) and had mean diameters of the order 9.1–34.8 μm. This method was also recently used to test microparticles intended for pulmonary delivery by Huang et al., to assess the in vitro release of betamethasone from spray dried microparticles with different release modifiers [6], and by Asada et al. for the testing of co-spray dried theophylline-chitosan microparticles [7]. Interestingly, in the former study, dissolution measurements were performed in a smaller volume (300 ml). The approach of modifying a conventional dissolution apparatus for evaluating inhalation medicines was further investigated by McConville et al., where a conventional twin stage impinger was modified, to incorporate a dissolution compartment. Subsequently, using this apparatus, the aerosol properties and dissolution rates of CR inhalation formulations could be measured simultaneously [8].

An alternative to USP apparatus 1 and 2 is USP apparatus 4. Based on a continuous flow system published in 1972 [9], the USP apparatus 4 utilizes a reciprocal housing that contains a formulation, housed between two filters. A liquid flow is past through the housing and the output concentration monitored as a function of time [2]. Apparatus 4 has been successfully used to evaluate the dissolution profiles of poorly soluble and extended release powder formulations [10] and has been regarded as the method of choice for novel dosage forms including microspheres, liposome formulations and stents [11]. Recently, this method has been utilized to evaluate the in vitro dissolution rate of poorly soluble glucocorticoids, administered as aerosols [12]. In this study, it was concluded that a modified USP Apparatus 4 could be successfully used to examine aerosol formulations, which are intended to have extended residence time in the respiratory tract. Both methods described above are based on the evaluation of particle dissolution, in a media where the formulation is exposed to a volume-flow and sink conditions. Other studies investigating the dissolution of aerosol particles have utilized much smaller volumes. For example, volumes as small as 2 ml have been used to assess release rates of drug from microparticles under continuous stirring (150 rpm) or in a shaking water bath [13], [14].

The respiratory tract has a large surface area (>100 m²) [5] and contains approximately ∼1 μl cm² of liquid (generally endogenous phospholipids and mucus), present as a 10-μm layer [15]. Subsequently, evaluation of the dissolution profile of a CR drug particulate in a large volume may not be representative of the in vivo release rate. An alternative approach is to treat the release mechanism of drug from CR inhalation particles as analogous to a diffusion process, where the formulation is merely wetted and will diffuse out into the surrounding media. Recently, this approach was investigated by Cook et al., who used a custom built horizontal diffusion cell to determine variations in release rates of terbutaline sulphate from microparticles prepared by spray-drying the API with different concentrations of hydrophobic excipients [16].

Direct comparison between the various methodological approaches is difficult to make, since current literature is based on different CR formulation methods. Furthermore, the literature in this field is generally very barren and information is very limited about in vitro testing of release from particulate systems. Subsequently, the focus of this paper is to evaluate three methods for the measurement of drug release from inhalation CR formulations. The methods studied are (1) the conventional USP Apparatus 2 paddle method [2], (2) the modified USP apparatus 4 flow through system [10] and (3) a diffusion model based on a transdermal diffusion Franz cell [17].

To study these methods, a series of model CR inhalation formulations were prepared. Disodium cromoglycate (DSCG), a prophylaxis drug used for severe bronchial asthma, was chosen as model compound. DSCG is water-soluble and has low molecular weight. The CR component of the formulation was polyvinyl alcohol (PVA). PVA was chosen as a model polymer since it was recently reported that viscous solutions containing only 1% w/w PVA altered the in vivo release of 5(6)-carboxyfluorescein in an in vivo rat model [18].