Preparation and Quality Evaluation of Salvianolic Acids and Tanshinones Dry Powder Inhalation

Salvianolic acids and tanshinones both exhibit efficacy in treating idiopathic pulmonary fibrosis (IPF), but their formulation limits their clinical use. This study aimed to prepare the salvianolic acids and tanshinones dry powder for inhalation (SPI) to achieve pulmonary delivery for the treatment of IPF. The variable quantities of salvianolic acids and tanshinones composite powder were optimized using the central composite design-response surface method. Different carriers with various drug-carrier ratios were optimized to prepare SPI. The final optimized formulation of SPI was as follows: InhaLac 230^® was selected as the carrier with drug:carrier = 1:6, and the milled lactose InhaLac 400^® was added at 5%. The developed SPI characterized with an angle of repose 52.46 ± 1.04°, Carr's index of 34.00 ± 0.50% and showed high lung deposition in vitro, indicating the potential of pulmonary delivery for the treatment of IPF.     

Comparing the efficacy and safety of salmeterol/fluticasone pMDI versus its mono-components,other LABA/ICS pMDIs and salmeterol/fluticasone Diskus in patients with asthma

Introduction: Pressurized metered dose inhalers (pMDIs) are evolving to be a very effective drug delivery option in patients with airway diseases. They offer comparable lung deposition and reduced oropharyngeal deposition similar with the dry powder inhalers. As recommended by the Global Initiative for Asthma guidelines, the ideal maintenance treatment for asthma is a combination of long acting β₂-agonists (LABAs) and inhaled corticosteroids (ICSs). One of the available LABA/ICS combinations is the salmeterol/fluticasone propionate combination (SFC) and a plethora of evidence supports its clinical efficacy and safety.

Areas covered: This article focuses on the SFC hydrofluroalkane pMDI and compares the efficacy and tolerability with salmeterol and fluticasone given individually, and with other fixed-dose combinations namely formoterol/fluticasone, formoterol/beclometasone and formoterol/mometasone furoate, all delivered via pMDI. Also discussed is the efficacy and tolerability of the SFC delivered via a pMDI, as compared to the SFC via Diskus.

Expert opinion: pMDIs play an important role in inhalation therapy given the low price, low maintenance and convenience of use. LABA/ICS combinations are the preferred choice of medication for asthma treatment and will remain the mainstay for the decades to come. In our opinion, pMDI should be the choice of device to administer LABA/ICS maintenance therapy, as it is already being used by the patients for reliever therapy, which may eventually improve patient adherence and compliance.     

Influence of Realistic Inspiratory Flow Profiles on Fine Particle Fractions of Dry Powder Aerosol Formulations

Purpose The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 μm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. Materials and Methods Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63–90 μm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung™ and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler™. Results Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min⁻¹ s⁻¹ although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R ² = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler™, increasing FIR from 120 to 600 l min⁻¹ s⁻¹ for a constant peak flow rate (PFR) of 60 l min⁻¹ increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. Conclusion Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.     

Dose emission and aerodynamic characterization of the terbutaline sulphate dose emitted from a Turbuhaler at low inhalation flow

Previously, dose emission below 30?L min^?1 through DPI has not been routinely determined. However, during routine use some patients do not achieve 30?L min^?1 inhalation flows. Hence, the aim of the present study was to determine dose emission characteristics for low inhalation flows from terbutaline sulphate Turbuhaler.

Total emitted dose (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) of terbutaline sulphate Turbuhaler were determined using inhalation flows of 10–60?L min^?1 and inhaled volume of 4?L.

TED and FPD increase significantly with the increase of inhalation flows (p <0.05). Flows had more pronounced effect on FPD than TED, thus, faster inhalation increases respirable amount more than it increases emitted dose. MMAD increases with decrease of inhalation flow until flow of 20L min^?1 then it decreases.

In vitro flow dependent dose emission has been demonstrated previously for Turbuhaler for flow rates above 30?L min^?1 but is more pronounced below this flow. Minimal FPD below 30?L min^?1 suggests that during routine use at this flow rate most of emitted dose will impact in mouth. Flow dependent dose emission results suggest that Pharmacopoeias should consider the use variety of inhalation flows rather than one that is equivalent to pressure drop of 4 KPa.     

Optimized Inhalation Aerosols. II. Inertial Testing Methods for Particle Size Analysis of Pressurized Inhalers

Pressurized metered dose inhaler (MDI) output from three different albuterol formulations was characterized using three inertial separation devices. Results were compared for the Delron six-stage cascade impactor (DCI6), the Andersen Mark II eight-stage impactor (ACI8), and Copley's twin-stage liquid impinger (LI). None of the devices tested in this study was ideal in all respects. All devices could differentiate between formulations in terms of respirable doses (albuterol amount with aerodynamic diameters <5.5 through 6.4 µm). Only the high-flow rate LI could differentiate among all three formulations when data were presented in terms of respirable percentage (RP) of drug collected. Values for RP were in excellent agreement for the independently calibrated impactors when the same evaporation chamber was used atop the impactors. The LI appeared to overestimate values for RP in vivo. Results are discussed in light of the debate surrounding the revision of USP aerosol testing requirements. Rigorous specifications for evaporation chambers and methodologies are necessary for meaningful inter- and intra-laboratory comparison of results when any of these devices are used.     

吸入装置的演变过程及研究进展

吸入装置通过不同的气溶胶发生原理,结合相应的药物形态形成了现有的药械组合式吸入制剂,目前已广泛应用于吸入治疗领域。但在临床使用过程中也逐渐暴露出一些问题,如患者使用压力定量吸入气雾剂(pressurized metered-dose inhaler,pMDI)时协调性不够,使用干粉吸入剂(dry powder inhaler,DPI)时吸力不足,患者使用依从性差等。新型吸入装置致力于通过装置性能的改善弥补吸入装置目前存在的缺点,并结合智能化和云端管理扩展功能等,提高患者的使用依从性,从而进一步提高临床治疗效果。     

Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos

Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20 μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1–#3 were within the acceptance criteria (80–120%). The emitted doses (ED) were 102.3 ± 11.5%, the fine particle fractions (FPF) were 60.5 ± 5.6% and the mass median aerodynamic diameters (MMAD) were 2.3 ± 0.3 μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1–73.7% after treatment by intravenous injection whereas only a 50.1–58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-value < 0.05). The available sildenafil in the blood vessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was within the range of 751–825 ng/mL which was much higher than that of a sildenafil only pMDI.     

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r² values ranged between 0.46 and 0.90 and the secondary OA increased the r² values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r² 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.     

Aerosol Profile Extracted from Spacers as a Determinant of Actual Dose

No HeadingPurpose. We propose a novel method to evaluate the efficacy of a pressurized metered dose inhaler (pMDI) in combination with a spacer, by not only considering the total dose extractable from the spacer but also the dependence of dose on the volume available for aerosol inhalation.Methods. We studied volume-dependence of aerosol concentration during extraction from two commonly used plastic spacers (150 ml AerochamberPlus; 750 ml Volumatic) after a single puff of a 100 g salbutamol pMDI (HFA-Ventolin), using laser photometric measurements.Results. After a delay of 1s in each spacer, the aerosol peak dose for AerochamberPlus was 2-fold that for Volumatic (p < 0.001), with the peak appearing well within the first 0.5 L even for the largest spacer. The opposite dose relationship is reached when considering total cumulative dose, which was 2-fold higher for Volumatic than for AerochamberPlus (p < 0.001); >95% of total cumulative dose was extracted well within 3 L for the largest spacer. The 2-fold cumulative dose relationship was confirmed by chemical assay on an absolute filter [AerochamberPlus: 21.4 ± 3.2 (SD) g; Volumatic: 43.8 ± 9.1 (SD) g].Conclusions. Actual aerosol dose available to patients during inhalation via spacers can only be done on the basis of a quantification of aerosol peak dose and cumulative dose as a function of extracted volume.     

Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers

Purpose  A novel concept is presented for the formation of stable suspensions composed of low density flocs of high aspect ratio drug particles in hydrofluoroalkane (HFA) propellants, and for subdividing (templating) the flocs with aerosolized HFA droplets to achieve high fine particle fractions with a pressurized metered dose inhaler. Methods  Bovine serum albumin (BSA) nanorods, produced by thin film freezing (TFF), were added to HFA to form a suspension. Particle properties were analyzed with an Anderson cascade impactor (ACI), static and dynamic light scattering and optical microscopy. Results  The space filling flocs in HFA were stable against settling for one year. The pMDI produced high fine particle fractions (38–47%) with an emitted dose of 0.7 mg/actuation. The atomized HFA droplets break apart, that is template, the highly open flocs. Upon evaporation of HFA, capillary forces shrink the templated flocs to produce porous particles with optimal aerodynamic diameters for deep lung delivery. Conclusions  Open flocs composed of nanorods, stable against settling, may be templated during actuation with a pMDI to produce optimal aerodynamic diameters and high fine particle fractions. This concept is applicable to a wide variety of drugs without the need for surfactants or cosolvents to stabilize the primary particles.     

The rejuvenated pressurised metered dose inhaler

The pressurised metered-dose inhaler (pMDI) has now been available for 50 years. Once regarded as an inefficient and difficult-to-use device, the technology has evolved significantly over the last few years, particularly since the introduction of novel formulations containing hydrofluoroalkane (HFA) propellants. Many modern HFA pMDIs deposit drug more efficiently in the lungs, impact less forcefully on the back of the throat and feel less cold than their chlorofluorocarbon pMDI counterparts. An improved understanding of technical factors makes it possible to design HFA pMDIs to have specific spray properties, particularly in terms of fine particle dose and spray velocity. Device technology has also progressed with the introduction of compact and convenient breath-actuated, breath-coordinated and velocity-modifying devices, which help patients to achieve a reliable lung dose. Although it faces competition from dry powder inhalers and possibly from novel soft-mist inhalers containing liquid formulations, the rejuvenated HFA pMDI is a device with a significant future for asthma, chronic obstructive pulmonary disease and wider treatment indications.     

Formulation of novel dry powder inhalation for fluticasone propionate and salmeterol xinafoate with capsule-based device

The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose^® SV003, Respitose^® SV010, and Respitose^® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.     

Identifying the features of an easy-to-use and intuitive dry powder inhaler for asthma and chronic obstructive pulmonary disease therapy: results from a 28-day device handling study,and an airflow resistance study

Background: Many patients with asthma and chronic obstructive pulmonary disease (COPD) symptoms remain insufficiently controlled despite inhalation treatment, with poor inhaler technique recognized as a significant contributor. Dry powder inhalers (DPIs) need less coordination of actuation and inspiration than pressured metered dose inhalers.

Objectives: To assess whether consideration of ‘ideal inhaler’ features during design and development of a new DPI device (Forspiro® Sandoz AG, Switzerland) led to an easy-to-use and reliable inhaler.

Methods: Two studies are reported here: i) 24 adult Accuhaler® users received either limited written instructions (n = 12) or fully illustrated instructions (n = 12) for the Forspiro device; and ii) peak inspiratory flow rates through the Forspiro device were assessed in 30 adult and 10 pediatric patients with asthma and 10 adult patients with COPD.

Results: All subjects understood the correct sequence of actions for the Forspiro device and rated all aspects of handling the device as ‘very easy’ or ‘fairly easy’ (except one uninstructed subject who rated ‘ease of determining number of doses left’ as ‘fairly difficult’). All patients achieved ≥ 35 l/min, thus demonstrating that the Forspiro device provides low-medium airflow resistance.

Conclusions: Inhaler design providing good drug delivery with maximum ease of use may lead to more reliable therapy and improved control of airway diseases.     

Development and Comparison of New High-Efficiency Dry Powder Inhalers for Carrier-Free Formulations

High-efficiency dry powder inhalers (DPIs) were developed and tested for use with carrier-free formulations across a range of different inhalation flow rates. Performance of a previously reported DPI was compared with two new designs in terms of emitted dose (ED) and aerosolization characteristics using in vitro experiments. The two new designs oriented the capsule chamber (CC) at different angles to the main flow passage, which contained a three-dimensional (3D) rod array for aerosol deaggregation. Computational fluid dynamics simulations of a previously developed deaggregation parameter, the nondimensional specific dissipation (NDSD), were used to explain device performance. Orienting the CC at 90° to the mouthpiece, the CC₉₀-3D inhaler provided the best performance with an ED = 73.4%, fine particle fractions (FPFs) less than 5 and 1 μm of 95.1% and 31.4%, respectively, and a mass median aerodynamic diameter (MMAD) = 1.5 μm. For the carrier-free formulation, deaggregation was primarily influenced by capsule aperture position and the NDSD parameter. The new CC-3D inhalers reduced the percent difference in FPF and MMAD between low and high flows by 1–2 orders of magnitude compared with current commercial devices. In conclusion, the new CC-3D inhalers produced extremely high-quality aerosols with little sensitivity to flow rate and are expected to deliver approximately 95% of the ED to the lungs.     

干粉吸入剂的研究进展

干粉吸入剂（DPI）具有独特的吸收方式和药动学特点,与定量气雾剂相比优点突出。粉体工学性质和给药装置设计一直是制约该剂型发展的重要因素。近十几年来随着药物微粉化技术和新型给药装置研究的不断进步,其应用范围越来越广,在国际药物制剂研发方面呈快速发展趋势。现参考国内外研究文献,对DPI给药方式的药物作用特点、DPI药物及载体粉末性质以及目前吸入装置的种类及主要特点等进行综述。     

Inhalation devices: from basic science to practical use,innovative vs generic products

ABSTRACT

Introduction: Inhalation therapy is a convenient method of treating respiratory diseases. The key factors required for inhalation are the preparation of drug carriers (aerosol particles) allowing reproducible dosing during administration. These technical challenges are accomplished with a variety of inhalation devices (inhalers) and medicinal formulations, which are optimized to be easily converted into inhalable aerosols.

Areas covered: This review is focused on the most important, but often overlooked, effects, which are required for the reliable and reproducible inhalable drug administration. The effects of patient-related issues that influence inhalation therapy, such as proper selection of inhalers for specific cases is discussed. We also discuss factors that are the most essential if generic inhalation product should be considered equivalent to the drugs with the clinically confirmed efficacy.

Expert opinion: Proper device selection is crucial in clinical results of inhalation therapy. The patients’ ability to coordinate inhalation with actuation, generation of optimal flow through the device, use of optimal inspiratory volume, all produces crucial effects on disease control. Also the severity of the disease process effects proper use of inhalers. Interchanging of inhalers can produce potentially conflicting problem regarding efficacy and safety of inhalation therapy.     

Challenges and opportunities in respiratory drug delivery devices

Recent reviews conclude that there is a need to improve the management of respiratory diseases treated with inhaled drugs, mainly asthma and chronic obstructive pulmonary disease (COPD). Healthcare professionals – mainly in primary care – seem to lack to some degree the evidence-based information required for the selection of the most appropriate respiratory drug delivery devices (inhalers) for the patients, whereas some of the patients often tend to have poor inhaler technique. This could have an impact on the ability to control the respiratory diseases in question. There are probably several reasons for these apparent challenges in the primary care arena. Owing to the abundance of inhalers available at present, especially for the treatment of asthma and COPD, it is quite a challenge to pick the ‘right’ inhaler for each patient. For an inhaler to be optimal, the patient has to be able to master the inhaler technique required for the specific inhaler. The patient–inhaler interfaces – mouthpieces or facemasks – can add important challenges that further diminish the efficacy of the treatment.     

Protein Deposition from Dry Powder Inhalers: Fine Particle Multiplets as Performance Modifiers

Purpose. To evaluate the use of carrier-based dry powder aerosols for inhalation delivery of proteins and examine the effect of fine particle excipients as potential formulation performance modifiers. Methods. Bovine serum albumin (BSA) was co-processed with malto-dextrin by spray-drying to produce model protein particles. Aerosol formulations were prepared by tumble mixing protein powders with -lactose monohydrate (63–90 m) or modified lactoses containing between 2.5 and 10% w/w fine particle lactose (FPL) or micronised polyethylene glycol 6000. Powder blends were characterised in terms of particle size distribution, morphology and powder flow. Formulation performance in Diskhaler^® and Rotahaler^® devices was investigated using a twin stage impinger operating at 60 1 min^–1. Results. Inhalation performance of binary ordered mixes prepared using BSA-maltodextrin and lactose (63–90 m) was improved by addition of FPL and micronised PEG 6000. For the addition of 5% w/w FPL the protein fine particle fraction (0.5–6.4 m) using the Diskhaler^® was increased from 31.7 ± 2.4% to 47.4 ± 2.2%. Inclusion of FPL and micronised PEG 6000 changed the bulk properties of inhalation powders and reduced powder flow but did not affect device emptying. Unexpectedly, improvements in performance were found to be independent of the order of addition of FPL to the ternary powder formulations. SEM studies revealed that this was probably the result of a redistribution of protein particles between the coarse carrier lactose component and added FPL during mixing. Conclusions. Fine particle excipients can be used to improve the performance of carrier-based protein dry powder aerosols. Mechanistically, enhancement of performance is proposed to result from a redistribution of protein particles from coarse carrier particles to the fine particle component in the ternary mix.     

Highly reproducible powder aerosolisation for lung delivery using powder-specific electromechanical vibration

Dry powder inhalers (DPIs) have been in use since the 1970s, but it is only within the past few years that their use has constituted > ～ 10% of the inhaler units sold worldwide. Similarly, active DPIs have been in development for more than a decade, but no active device has yet been approved. Oriel is developing an active DPI technology that uses a very simple physical design coupled with a complex knowledge of powder flow and dispersion characterisation. The DPI uses electromechanical vibration with frequencies determined through the analysis of powder flow properties. Results so far have shown highly reproducible, efficient performance. The technology lends itself to both unit-dose and multidose platforms in a targeted cost-effective DPI.