Advances in soft mist inhalers.

INTRODUCTION: Soft mist inhalers (SMIs) are propellant-free inhalers that utilize mechanical power to deliver single or multiple doses of inhalable drug aerosols in the form of a slow mist to patients. Compared to traditional inhalers, SMIs allow for a longer and slower release of aerosol with a smaller ballistic effect, leading to a limited loss in the oropharyngeal area, whilst requiring little coordination of actuation and inhalation by patients. Currently, the Respimat® is the only commercially available SMI, with several others in different stages of preclinical and clinical development. AREAS COVERED: The primary purpose of this review is to critically assess recent advances in SMIs for the delivery of inhaled therapeutics. EXPERT OPINION: Advanced particle formulations, such as nanoparticles which target specific areas of the lung, Biologics, such as vaccines, proteins, and antibodies (which are sensitive to aerosolization), are expected to be generally delivered by SMIs. Furthermore, repurposed drugs are expected to constitute a large share of future formulations to be delivered by SMIs. SMIs can also be employed for the delivery of formulations that target systemic diseases. Finally, digitalizing SMIs would improve patient adherence and provide clinicians with fundamental insights into patients' treatment progress.

Micronized drug powders in binary mixtures and the effect of physical properties on aerosolization from combination drug dry powder inhalers.

OBJECTIVES: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. METHODS: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. RESULTS: The median SS particle diameter was larger than BDP (4.33 ± 0.37 µm compared to 2.99 ± 0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. CONCLUSIONS: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.

Combining experimental and computational techniques to understand and improve dry powder inhalers.

INTRODUCTION: Dry Powder Inhalers (DPIs) continue to be developed to deliver an expanding range of drugs to treat an ever-increasing range of medical conditions; with each drug and device combination needing a specifically designed inhaler. Fast regulatory approval is essential to be first to market, ensuring commercial profitability. AREAS COVERED: In vitro deposition, particle image velocimetry, and computational modeling using the physiological geometry and representative anatomy can be combined to give complementary information to determine the suitability of a proposed inhaler design and to optimize its formulation performance. In combination, they allow the entire range of questions to be addressed cost-effectively and rapidly. EXPERT OPINION: Experimental techniques and computational methods are improving rapidly, but each needs a skilled user to maximize results obtained from these techniques. Multidisciplinary teams are therefore key to making optimal use of these methods and such qualified teams can provide enormous benefits to pharmaceutical companies to improve device efficacy and thus time to market. There is already a move to integrate the benefits of Industry 4.0 into inhaler design and usage, a trend that will accelerate.

Investigation into the influence of polymeric stabilizing excipients on inter-particulate forces in pressurised metered dose inhalers.

Colloid probe atomic force microscopy (AFM) was utilised to quantify the cohesive forces of salbutamol sulphate in a model non-pressurised fluorinated liquid (mHFA), in the presence of increasing concentrations of poly(ethylene glycol) (PEG; molecular weight (MW) 200, 400 and 600). In addition, samples of PEG 400 (0.05-0.5%, v/w), were analysed in the presence of 0.001% (w/w) of poly(vinyl pyrrolidone) (PVP). In the absence of any stabilizing agents, strong attractive forces were present between particles. Increasing the concentration of the different MW PEG solutions in the mHFA system (up to 0.5%, v/w), significantly decreased the force of interaction (ANOVA, p<0.05). The decrease in cohesion was particularly evident at very low concentrations of PEG (0.05-0.1%, v/w). Further data analysis (p<0.05) suggested that the reduction in the force of cohesion was dependent on the concentration and molecular weight of PEG. The addition of low concentration of PVP to the PEG 400-mHFA system had the most significant influence on drug particle cohesion. In the presence of PVP, increasing addition of PEG 400 (0.05-0.5%, v/w) to the mHFA, resulted in no significant reduction in the force of cohesion (p>0.05). Clearly, an understanding of the conformation of polymer molecules at interfaces is of vital importance when controlling the stability/flocculation behaviour of sterically stabilized pMDI suspensions. In this context, the use of the colloid probe AFM technique has provided a quantitative insight into the interactions of these complex systems and may be an invaluable asset during the early phase of formulation product development.

Exploring the impact of sample flowrate on in vitro measurements of metered dose inhaler performance.

Pharmacopoeial methods for measurement of the aerodynamic particle size distribution (APSD) of metered dose inhalers (MDIs) by cascade impaction specify a sampling flow rate of 28.3L/min. However, there is little data within the literature to rationalize this figure, or to support its clinical relevance. In addition, the standard United States Pharmacopoeia Induction Port (USP IP) used for testing is known to inaccurately reflect deposition behavior in the upper airway, further compromising the relevance of testing, for product development. This article describes experimental studies of the effect of sampling flow rate on APSD data gathered using an Andersen Cascade Impactor (ACI). Tests were carried out using two different formulations to assess the influence of formulation composition. In addition, comparative testing with an Alberta Idealised Throat, in place of the USP IP, to ensure more realistic representation of the upper airway. The results show how measured APSD and fine particle dose, the dose than on the basis of size would be expected to deposit in the lung, vary as a function of test methodology, providing insight as to how the testing can be modified towards greater clinical relevance.

Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient.

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4µm±0.1 and 2.5µm±0.2), fine particle dose (⩽5µm; 66µg±6 and 68µg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.

Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro.

Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (∼1000ng or ∼2000ng of the formulation) or equivalent particle number (1000ng of BDP in the glycerol-containing versus 2000ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2h was faster when delivered in glycerol-free particles, 465.01ng±95.12ng of the total drug (20.99±4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17ng±3.07ng (6.07±0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.