Development Of Dry Powder Inhalers Research Articles

Quality by Design in Pulmonary Drug Delivery: A Review on Dry Powder Inhaler Development, Nanotherapy Approaches, and Regulatory Considerations.

Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.

Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.

Preclinical evaluation of novel synthesised nanoparticles based on tyrosine poly(ester amide) for improved targeted pulmonary delivery

Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines—fluticasone propionate (FP) and salmeterol xinafoate (SAL)—for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency– > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.

Advancements in the Design and Development of Dry Powder Inhalers and Potential Implications for Generic Development.

Dry powder inhalers (DPIs) are drug-device combination products where the complexity of the formulation, its interaction with the device, and input from users play important roles in the drug delivery. As the landscape of DPI products advances with new powder formulations and novel device designs, understanding how these advancements impact performance can aid in developing generics that are therapeutically equivalent to the reference listed drug (RLD) products. This review details the current understanding of the formulation and device related principles driving DPI performance, past and present research efforts to characterize these performance factors, and the implications that advances in formulation and device design may present for evaluating bioequivalence (BE) for generic development.

Systematic development and characterization of inhalable dry powder containing Polymeric Lipid Hybrid Nanocarriers co-loaded with ABCB1 shRNA and docetaxel using QbD approach

The main objective of this research work was to extend the principles of the Quality by Design approach in optimization and development of dry powder inhalers containing hybrid nanocarriers for effective treatment of multidrug-resistant lung cancer. Two statistical designs were used to justify the feasibility and advantages of the Qbd approach for the development of PLHNCs (Polymeric Lipid Hybrid Nanocarriers). The particle size and encapsulation efficiency were selected as quality target profile. Plackett-Burman design (PBD) was used as the first design to evaluate 7 high-risk variables that have significant effect on the characteristics of PLHNCs. Among the 7 high-risk variables, 3 variables (i.e., concentration of polymer, lipid to polymer ratio and drug input) had a significant effect on encapsulation efficiency of PLHNCs. Box-Behnken design (BBD) was employed as the second statistical design to fully elucidate the formulation development parameters. It was found that the optimized range for the parameters showed promising results to achieve a quality target profile. Further, the optimized PLHNCs formulation was subjected to lyophilization using various cryoprotectants to increase drug retention and dry powder inhaler was developed using different grades of modified lactose to achieve better aerodymic properties. The PLHNCs developed using PBD and BBD showed significant increase in Docetaxel encapsulation along with high shRNA pDNA complexation. The developed product had an higher fine particle fraction (68.3 ± 2.5%) along with high drug retention (98.3 ± 3.1%) which showed how efficiently the developed dry powder of PLHNCs would be able to target the respiratory zone of the lungs.

A Systematic Review on Technical Aspects in the Development of Dry Powder Inhalers (DPI)

A Systematic Review on Technical Aspects in the Development of Dry Powder Inhalers (DPI)

Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist

Chalcone derivatives are shown to possess excellent anti-inflammatory and anti-oxidant properties which are of great interest in treating respiratory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). This study successfully designed and developed dry powder inhaler (DPI) formulations of TMC (2-trifluoromethyl-2′-methoxychalone), a new synthetic trifluorinated chalcone and Nrf2 agonist, for targeted pulmonary inhalation aerosol drug delivery. An advanced co-spray drying particle engineering technique was used to design and produce microparticulate/nanoparticulate formulations of TMC with a suitable excipient (mannitol) as inhalable particles with tailored particle properties for inhalation. Raw TMC and co-spray dried TMC formulations were comprehensively characterized for the first time using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) spectroscopy, thermal analysis, X-ray powder diffraction (XRPD), and molecular fingerprinting as dry powders by ATR-FTIR spectroscopy and Raman spectroscopy. Further, biocompatibility and suitability of formulations were tested with in vitro cellular transepithelial electrical resistance (TEER) in air-interface culture (AIC) using a human pulmonary airway cell line. The ability of these TMC formulations to perform as aerosolized dry powders was systematically evaluated by design of experiments (DOEs) using three different FDA-approved human inhaler devices followed by interaction parameter analyses. Multiple spray drying pump rates (25%, 75%, and 100%) successfully produced co-spray dried TMC:mannitol powders. Raw TMC exhibited a first-order phase transition temperature at 58.15 ± 0.38 °C. Furthermore, the results demonstrate that these innovative TMC dry powder particles are suitable for targeted delivery to the airways by inhalation.

Development of an adaptive bypass element for passive entrainment flow control in dry powder inhalers

The release of drug from dry powder inhalers is strongly dependent on the patient's inhalation profile. To maximise the effect of the treatment, it is necessary to optimise dry powder inhalers to achieve drug delivery that (A) is independent of the inhalation manoeuvre and (B) is targeted to the correct site in the lung. The purpose of this study is to develop a dry powder inhaler with an adaptive bypass element that achieves desired drug delivery behaviour. Computational and experimental methods are used. First, the effect of a generic variable bypass element on entrainment behaviour is modelled. This is done by modelling a dry powder inhaler as a network of flow. Second, the behaviour of a potential variable bypass element, a flap valve, is studied both computationally and experimentally. Third, the flow resistances are optimised to achieve consistent and desired entrainment behaviour for patients with very different inhalation manoeuvres. A simulated dry powder inhaler device design was found that achieves an approximately constant entrainment flow rate of 12 L/min when total flow rates larger than 20 L/min are applied. The developed dry powder inhaler is predicted to accurately deliver drug for patients with highly different inhalation manoeuvres.

Delivery of Dry Powders to the Lungs: Influence of Particle Attributes from a Biological and Technological Point of View.

Dry powder inhalers are medical devices used to deliver powder formulations of active pharmaceutical ingredients via oral inhalation to the lungs. Drug particles, from a biological perspective, should reach the targeted site, dissolve and permeate through the epithelial cell layer in order to deliver a therapeutic effect. However, drug particle attributes that lead to a biological activity are not always consistent with the technical requirements necessary for formulation design. For example, small cohesive drug particles may interact with neighbouring particles, resulting in large aggregates or even agglomerates that show poor flowability, solubility and permeability. To circumvent these hurdles, most dry powder inhalers currently on the market are carrier-based formulations. These formulations comprise drug particles, which are blended with larger carrier particles that need to detach again from the carrier during inhalation. Apart from blending process parameters, inhaler type used and patient's inspiratory force, drug detachment strongly depends on the drug and carrier particle characteristics such as size, shape, solid-state and morphology as well as their interdependency. This review discusses critical particle characteristics. We consider size of the drug (1-5 µm in order to reach the lung), solid-state (crystalline to guarantee stability versus amorphous to improve dissolution), shape (spherical drug particles to avoid macrophage clearance) and surface morphology of the carrier (regular shaped smooth or nano-rough carrier surfaces for improved drug detachment.) that need to be considered in dry powder inhaler development taking into account the lung as biological barrier.

Assessment of Dry Powder Inhaler Carrier Targeted Design: A Comparative Case Study of Diverse Anomeric Compositions and Physical Properties of Lactose.

The pulmonary administration landscape has rapidly advanced in recent years. Targeted design of particles by spray-drying for dry powder inhaler development offers an invaluable tool for engineering of new carriers. In this work, different formulation and process aspects of spray-drying were exploited to produce new lactose carriers. Using an integrated approach, lactose was spray-dried in the presence of polyethylene glycol 200 (PEG 200), and the in vitro performance of the resulting particles was compared with other grades of lactose with varying anomeric compositions and/or physical properties. The anomeric composition of lactose in lactose-PEG 200 feed solutions of variable compositions was analyzed via polarimetry at different temperatures. These results were correlated with the solid-state and anomeric composition of the resulting spray-dried particles using modulated differential scanning calorimetry and wide-angle X-ray scattering. The distinct selected grades of lactose were characterized in terms of their micromeritic properties using laser diffraction, helium pycnometry, and gas adsorption, and their particle surface morphologies were evaluated via scanning electron microscopy. Adhesive mixtures of the different lactose carriers with inhalable-sized salbutamol sulfate, as a model drug, were prepared in low doses and evaluated for their blend homogeneity and aerodynamic performance using a Next Generation Impactor. Characterization of the spray-dried particles revealed that predominantly crystalline (in an anomeric ratio 0.8:1 of α to β) spherical particles with a mean size of 50.9 ± 0.4 μm could be produced. Finally, it was apparent that micromeritic, in particular, the shape, and surface properties (inherent to solid-state and anomeric composition) of carrier particles dominantly control DPI delivery. This provided an insight into the relatively inferior performance of the adhesive blends containing the spherical spray-dried lactose-PEG 200 composites.

How does secondary processing affect the physicochemical properties of inhalable salbutamol sulphate particles? A temporal investigation

As pulmonary drug delivery is extended from low doses to high doses, physicochemical characteristics of the active pharmaceutical ingredient gain importance in the development of dry powder inhalers. Therefore, the present work aims to understand the impact of distinct engineering techniques on the process induced physicochemical characteristics of salbutamol sulphate particles over time. The particle engineering techniques chosen were jet-milling and spray-drying, two well used processes in the production of predominately crystalline and amorphous inhalable particles, respectively. Fourier transform infrared spectroscopy, modulated differential scanning calorimetry, particle size distribution and tensiometry experiments were used to characterise the engineered powders immediately, 7, 14 and 21 days after production. The rugged spherical amorphous particles (3.75±0.08μm) obtained via spray-drying showed that they were capable of forming strong agglomerates (5.01±0.22μm) through “amorphous bridging”. On the other hand, jet-milling produced smaller (2.06±0.08μm), crystalline, irregular shaped particles with a very large surface area (11.04±0.10m2/g) that, over time, formed looser particle aggregates of decreasing size (3.76±0.10μm). Temporal evolution of the properties of spray-dried and jet milled particles showed a notable influence on the efficiency of blending with a model carrier at 0, 7 and 21 days (e.g. relative standard deviation of drug content of 11.3, 7.0 and 21.6%, respectively).

Development of dry powder inhaler containing tadalafil-loaded PLGA nanoparticles.

Inhalable dry powders containing poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were developed for the delivery of tadalafil (TAD) for treatment of life-treating pulmonary arterial hypertension. Taguchi design was employed to evaluate the effects of different formulation variables on the physicochemical characteristics of PLGA-NPs prepared using emulsion solvent evaporation method. Inhalable PLGA-NPs of TAD were successfully prepared by co-spray drying the PLGA-NPs with inert carriers. Physicochemical characteristics and in vitro deposition of the aerosolized drug were also evaluated. The optimized formulation was prepared using 7.5 mg of PLGA, 2.5 mg of TAD, sonication time of 6 min and 2% polyvinyl alcohol (PVA) as the stabilizer. The optimized aqueous/oil phase ratio for PLGA-NPs preparation was 10:1. Polymer/drug ratio was the most effective parameter on the release efficiency. Encapsulation efficiency, zeta potential and particle size of PLGA-NPs were more affected by aqueous/organic phase ratio. The spray dried powders containing PLGA-NPs had a mass median aerodynamic diameter (MMAD) in the range of 1.4–2.8 μm that was suitable for TAD delivery to the deep region of lung. The presence of L- leucine in mannitol containing formulations decreased the interparticulate forces between particles and increased significantly the process yield and fine particle fraction (FPF). The results indicated that prepared dry powders containing TAD-loaded PLGA-NPs were suitable for inhalation and has the potential for the treatment of pulmonary arterial hypertension.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Formulation considerations for dry powder inhalers.

The market for inhalable dry powder medication has consistently grown over past years. Targeting the lungs has been recognized to offer several advantages compared with oral application of drugs. The successive development of inhalation products has led to advances in local treatment of different respiratory diseases, but has also demonstrated the possibility to utilize the lungs for systemic drug delivery. Since a dry powder inhalation product is always a combination of drug formulation and inhalation device, the requirements for the development of such a system may be particularly complex. Therefore, this review aims to give an overview of the necessary considerations for a successful dry powder inhaler development.

Rapid characterisation of the inherent dispersibility of respirable powders using dry dispersion laser diffraction

Understanding and controlling powder de-agglomeration is of great importance in the development of dry powder inhaler (DPI) products. Dry dispersion laser diffraction measures particle size readily under controlled dispersing conditions, but has not been exploited fully to characterise inherent powder dispersibility. The aim of the study was to utilise particle size-dispersing pressure titration curves to characterise powder cohesivity and ease of de-agglomeration. Seven inhaled drug/excipient powders (beclometasone dipropionate, budesonide, fluticasone propionate, lactohale 300, salbutamol base, salmeterol xinafoate and tofimilast) were subjected to a range of dispersing pressures (0.2-4.5 Bar) in the Sympatec HELOS/RODOS laser diffractometer and particle size measurements were recorded. Particle size-primary pressure data were used to determine the pressures required for complete de-agglomeration. The latter were employed as an index of the cohesive strength of the powder (critical primary pressure; CPP), and the curves were modelled empirically to derive the pressure required for 50% de-agglomeration (DA₅₀). The powders presented a range of CPP (1.0-3.5 Bar) and DA₅₀ (0.23-1.45 Bar) which appeared to be characteristic for different mechanisms of powder de-agglomeration. This approach has utility as a rapid pre-formulation tool to measure inherent powder dispersibility, in order to direct the development strategy of DPI products.

Arising of electrostatic charge in the mixing process and its influencing factors

The aim of this work is to improve the understanding of how triboelectric charge arises on pharmaceutical powders and of how it can be influenced and controlled especially with respect to dry powder inhaler development. In the present work the triboelectric properties of mannitol are examined because very few literature treating this new alternative carrier material for dry powder inhalers is available. To study the very complex triboelectric charging process in a simple and controlled way mixing studies are carried out. The powder samples are blended in polypropylene and stainless steel mixing containers for defined durations using a tumble blender (T2F Turbula®, Willy A. Bachofen AG — Maschinenfabrik, Switzerland) and then poured into a Faraday cup where charge measurement is performed. Several influencing factors like mixing time, particle size, mixing container size and the addition of a fines fraction to the powder are studied. In contrast to other published literature the present work focuses on the new alternative carrier material mannitol and uses statistical tools like design of experiments (DOE) to check the significance of the influence of factors and also the interactions between the influencing factors. The study reveals a direct relationship between the arising charge and the container size as well as the fines fraction and an indirect relationship between the arising charge and the particle size. Further also three different charge dissipation scenarios are investigated. It is shown that charge dissipation to the atmosphere is negligible within an hour. Keeping the powder inside the mixing container allowing charge dissipation via the container walls is more effective. Additional grounding of the mixing container does not result in a significant enhancement of the dissipation process. This is because charge transport from the powder bulk to the mixing container walls is limited.

A uHPLC-MS mathematical modeling approach to dry powder inhaler single agglomerate analysis

Demonstration of content uniformity (CU) is critical toward the successful development of dry powder inhalers (DPIs). Methods for unit dose CU determination for DPI products are well-established within the field of respiratory science. Recent advances in the area include a uHPLC-MS method for high-throughput uniformity analysis, which allows for a greater understanding of blending operations as the industry transitions to a quality-by-design approach to development. Further enhancements to this uHPLC-MS method now enable it to determine CU and sample weight at the single agglomerate level, which is roughly 50× smaller than a unit dose. When coupled with optical microscopy-based agglomerate sizing, the enhanced uHPLC-MS method can also predict the density and porosity of individual agglomerates. Expanding analytical capabilities to the single agglomerate level provides greater insights and confidence in the DPI manufacturing process.

Effect of carrier morphology and surface characteristics on the development of respirable PLGA microcapsules for sustained-release pulmonary delivery of insulin

The effect of morphology and surface characteristics of carriers were investigated for development of dry powder inhaler (DPI) formulation of insulin-loaded poly (D,L-lactic-co-glycolic acid) microcapsules for sustained-release pulmonary delivery of insulin. Microcapsule/carrier powder mixtures were prepared consisting of insulin-loaded PLGA microcapsules and sorbitol or mannitol as the carriers with various particle surface morphologies prepared by spray-drying and freeze-drying techniques. Powders were assessed by particle size analyzer, scanning electron microscopy, surface area analyzer, atomic force microscopy, helium pycnometer, X-ray diffraction, differential scanning calorimetery, bulk and tapped densitometers. Aerosol dispersion of microcapsules was examined by a twin impinger using Spinhaler device. The flowability results showed that the lowest (27.51+/-2.24%) and the highest (48.53+/-3.36%) Carr's indices were obtained for the samples containing sieved mannitol and spray-dried mannitol, respectively. The in vitro inhalation properties of the powder mixture prepared using various carrier shape and surface morphology were different, suggesting that the separation of microcapsules from carrier was a determining step to improve inhalation properties of DPIs. The results showed that the highest fine particle fraction (18.3+/-1.65%) and fine particle dose (62.22+/-3.74 microg) were obtained for the microcapsules formulated with sieved mannitol and these values were the lowest when the sieved mannitol was replaced by sieved sorbitol (10.5+/-0.86% and 35.70+/-2.51 microg). It was concluded that optimization of surface roughness is a critical parameter in development of DPIs. It also suggested that the elongation of carrier particles may play an important role in determining the aerosolization properties of the microcapsules. It seems that decrease in crystalline content of carriers may contribute to a decreased in fine particle fraction delivered.

Development of Dry Powder Inhalers

Development of dry powder inhalers involves powder recrystallization, formulation, dispersion, delivery, and deposition of the therapeutic agent in different regions of the airways in prophylaxis/ treatment/ diagnosis of pulmonary and systemic disorders. Conventional powder production by crystallization and milling has many limitations resulting into development of alternative techniques to overcome the problems. In the last decade many patents have been filed claiming improvement in aerosol performance of dry powder inhalers through the use of (i) incorporation of fines of carrier particles to occupy active sites on the surface and use of hydrophobic carriers to facilitate deaggregation through reduced surface energy and particle interaction (ii) reducing aerodynamic diameters through particle engineering and incorporating drug into porous or low particle density, and/or (iii) preparing less cohesive and adhesive particles through corrugated surfaces, low bulk density, reduced surface energy and particle interaction and hydrophobic additives. Moisture within dry powder inhaler (DPI) products has also been shown to influence aerosol performance via capillary force and electrostatic interaction. Better understanding of particle forces and surface energy has been achieved by the use of sophisticated analytical techniques. Understanding the intricacies of particle shape and surface properties influencing specific lung deposition has been further facilitated by the availability of newer and advanced softwares. A critical review of recent patents claiming different approaches to improve lung deposition of dry powder inhalers will help in deciding the focus of the research in the area of technological gaps.

Efficacy, tolerability, and effect on asthma-related quality of life of formoterol bid via multidose dry powder inhaler and albuterol QID via metered dose inhaler in patients with persistent asthma: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study

Background: Inhaled beta 2-agonists are widely used in asthma treatment. The design limitations of pressurizedmetered dose inhalers (pMDIs) have prompted the development of dry powder inhalers (DPIs) for the delivery of asthma medications. Objective: The goal of this study was to evaluate the efficacy, tolerability, and effect on asthma-related quality of life (QOL) of a long-acting beta 2-adrenoreceptor agonist, formoterol, delivered via multidose DPI, compared with albuterol delivered via pMDI or placebo in adolescents and adults with persistent asthma. Methods: This multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-groupstudy was conducted in outpatient clinics at 18 US centers. Adolescents and adults with persistent asthma received formoterol 10 pg BID via multidose DPI, albuterol 180 μg QID via pMDI, or placebo for 12 weeks. The primary efficacy variable was the 12-hour AUC of forced expiratory volume in 1 second (FEV 1) after 12 weeks treatment. Secondary efficacy variables included asthma-related QOL, asthma symptom scores, rescue medication use, and other pulmonary function measures. Results: A total of 239 patients (147 females, 92 males; age range, 13–85 years) with persistent asthma were enrolled (formoterol, n = 80; albuterol, n = 79; placebo, n = 80). Formoterol delivered via the multidose DPI resulted in clinically relevant and statistically significant increases in 12-hour AUC of FEV 1 after 12 weeks of treatment compared with albuterol pMDI and placebo ( P < 0.019 and P < 0.001, respectively). Asthma-related QOL (total score) was significantly improved with formoterol treatment compared with placebo ( P < 0.015). Nocturnal asthma symptom scores significantly improved with formoterol compared with albuterol and placebo ( P < 0.001 and P < 0.003, respectively) and rescue medication use was significantly less with formoterol compared with albuterol and placebo ( P < 0.004 and P < 0.002, respectively). Treatment with formoterol was well tolerated. Conclusions: In this study of adolescents and adults with persistent asthma, 12 weeks of treatment with formoterol 10 μg BID delivered via a multidose DPI provided significantly greater 24-hour bronchodilation compared with albuterol and placebo and resulted in significant improvements in asthma-related QOL compared with placebo. Formoterol was well tolerated in these patients.