The clinical relevance of dry powder inhaler performance for drug delivery (original) (raw)
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International Journal of Research -GRANTHAALAYAH, 2020
Most of the inhalation products in the market use metered dose inhaler (MDI) technology or dry powder inhaler (DPI) technology. MDIs use propellant to deliver desired dose of liquid formulation in aerosol form. DPI contains active in fine particulate form embedded onto an inert carrier. In both cases, amount of drug dispensed from the device reaching the lungs is dependent upon drug product characteristics as well as formulation-device relationship. Hence, in addition to particle size, aerodynamic distribution of the drug upon delivery by the device plays an important role in determining amount of drug reaching the lungs. Therefore particle size characterization is an important tool in determining the extent of drug delivery from the metered dose inhaler. Aerodynamic particle size distribution is frequently determined by use of cascade impactors and data so generated is accepted by regulatory agencies as a tool for predicting efficacy of MDIs and DPIs. This review discusses principl...
Dry powder inhaler device influence on carrier particle performance
Journal of …, 2012
Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 :m were dispersed from both an Aerolizer R and Handihaler R through a cascade impactor at 60 L min −1 . For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 :m), medium (108 :m), and large (275 :m) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer R , reflecting the improved performance observed in vitro. Collisions within the Handihaler R , in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.
Effect of carrier particle shape on dry powder inhaler performance
International journal of pharmaceutics, 2011
The aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer ® inhaler device. Solid-state and morphological characterization showed that CM product was in pure -form having particles with smaller ER (CM: ER = 1.62 ± 0.04) whereas ACM and ECM mannitol particles were in pure ␣ form with higher ER (ACM: ER = 4.83 ± 0.18, ECM: ER = 5.89 ± 0.19). CCM product crystallised as mixtures of -form and ␦-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (D b ), smaller tap density (D t ), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a "limit" as increasing carrier ER from 4.83 ± 0.18 (ACM) to 5.89 ± 0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r 2 = 0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.
Formulation and Evaluation of Dry Powder Inhaler
International Journal for Research in Applied Science & Engineering Technology (IJRASET), 2022
This review focuses on the dry powder inhaler (DPI) formulation and development process. Most DPI formulations consist of micronized drug blended with larger carrier particles, which enhance flow, reduce aggregation, and aid in dispersion. A combination of intrinsic physicochemical properties, particle size, shape, surface area, and morphology affects the forces of interaction and aerodynamic properties, which in turn determine fluidization, dispersion, delivery to the lungs, and deposition in the peripheral airways. When a DPI is actuated, the formulation is fluidized and enters the patient's airways. Under the influence of inspiratory airflow, the drug particles separate from the carrier particles and are carried deep into the lungs, while the larger carrier particles impact on the oropharyngeal surfaces and are cleared. If the cohesive forces acting on the powder are too strong, the shear of the airflow may not be sufficient to separate the drug from the carrier particles, which results in low deposition efficiency. This review thus demonstrates that the successful delivery of dry powder aerosols to the lung requires careful consideration of the powder production process, formulation and inhaler device. The developments and improvements towards high dose powder pulmonary drug delivery are summarized and discussed here. It also throws light on the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. I. INTRODUCTION OF DRY POWDER INHALER Inhalation drug delivery has been used for many years for the delivery of pharmacologically active agents to treat respiratory disease .Traditional asthma therapy with bronchodilators, steroids, mast cell stabilizers, and anticholinergic drugs has primarily used the pressurized metered-dose inhaler (MDI). However, this delivery system is now under increasing threat because of the environmental concerns regarding chlorofluorocarbon (CFC) propellants. A range of alternative devices, such as dry powder inhalers, which do not contain propellants, are being evaluated and developed. [1] Dry powder inhalers contain the drug in a powder formulation, where drug particles (< 5 μm) are blended with a suitable large carrier (e.g. lactose) to improve flow properties and dose uniformity and drug powders are delivered into the deep lung via a device known as dry powder inhaler (DPI). Powder de-agglomeration and aeroionisation from these formulations are achieved by the patient's inspiratory airflow. In a DPI, the aerosol needs to be generated from the powder formulation by patient 'sown effort'. For achieving this, a high turbulence is needed to break the large agglomerates of the drug into smaller, finer and inhalable particles. Turbulence is generated by creating resistance to air flow in the DPI device and the effort required to generate adequate flow rates is dependent on the extent of resistance. Whereas the flow rates required to be generated vary among various available DPIs, a flow rate of 60-90 L/min is generally required. Pulmonary drug delivery by Dry Powder Inhalers (DPIs), by virtue of its propellant free nature, high patient compliance, high dose carrying capacity, drug stability and patent protection, has encouraged rapid development in recent past to realize full potential of lungs for local and systemic treatment of diseases. But DPIs are complex in nature and their performance relies on many aspects including the design of inhaler, the powder formulation and the airflow generated by the patient. In last decade, performance of DPIs has improved significantly through the use of engineered drug particles and modified excipient systems. Exploration of inhalation aerosols for drug delivery has contributed vastly in treating pulmonary diseases for decades.Interestingly, inhalation of powders has been used for many centuries dating back to ancient times by the ancient Egyptians and Greeks. In the 19th century, Newton and Nelson each patented a DPI, after which the inhalation aerosol therapy took a detour away from DPI until 1948, when Abbott introduced Aerohalor for penicillin. Although drug delivery through inhalation was achieved many years ago, dose control was poor. When the pharmaceutical industry succeeded in delivering controlled doses of drug, there was no looking back. Treatment of pulmonary diseases, especially asthma, was revolutionized. Today, drug delivery has come a long way in successfully delivering drug to the lungs not only for local action but also for systemic application. Yet, inhalation aerosol drug delivery faces challenge in achieving consistent dose delivery and toxicity related to higher dosages delivered to the lungs. The four major classes of inhalation aerosol delivery systems are nebulizers, pMDIs and DPIs. Each has its own advantages, disadvantages and limitations in regard to the type of formulation that can be used, the types of drugs that can be used, and the amount of respirable dose that can be generated from these devices. In the past two decades, respiratory drug delivery has focused on two main aspects of drug delivery: replacing chlorofluorocarbon propellants and methodology to increase drug bioavailability.
Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler
Pharmaceutics
This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses () with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet number) leads to the formation of higher density particles with high packing densities. This enables ultrahigh (>100 mg of drug) to be achieved from a single receptacle. The emptying of powder from capsules is directly proportional to the m...
Clinically Relevant In Vitro Performance Tests for Powder Inhalers
2016
Predicting drug dose in the lung and its relevant aerosol characteristics for dry powder inhalers (DPIs) is possible by conducting realistic in vitro tests using human mouth-throat (MT) models and inhalation profiles (IPs) that mimic inhaler use in the clinic. Improved in vitro–in vivo correlations (IVIVCs) of lung deposition can help drug developers better estimate a DPI's performance under realistic clinical conditions and identify possible product-or human-related factors that may influence inhaler quality. Budelin® Novolizer® is used to illustrate how realistic in vitro tests can be used to estimate clinical performance of a DPI. Two studies were designed to characterize the (a) total lung dose in vitro (TLD in vitro) and (b) aerodynamic particle size distribution of TLD in vitro (APSD TLDin vitro). When the medium (and extremes) MT and IP were incorporated in inhaler testing, variations of TLD in vivo (ranging from 9.4% to 41.0%) could be predicted from in vitro (TLD in vitro ranging from 9.3% to 44.5%). Results for APSD TLDin vitro also indicated that the inhaler's clinical performance could be sensitive to subject's IPs. While the selection of MTs and IPs are yet to be standardized, product development scientists wishing to perform realistic in vitro tests may need to study possible variations in MT model and IP to fully explore the extent of variability in clinical lung deposition and the associated particle size distributions for their chosen DPI.
Predicting extrathoracic deposition from dry powder inhalers
Journal of Aerosol Science, 2004
The deposition of monodisperse aerosols entering an idealized oral cavity geometry through a variety of inlets was experimentally measured. Aerosol particles with diameters of 2.5, 3.8 and 5:0 m were investigated at ow rates ranging from 15 to 90 L=min. The tested inlets ranged in diameter from 3 to 17 mm and included contraction nozzles, straight tubes, a turbulence generator and six commercially available dry powder inhalers (DPIs). A model for predicting the oral cavity deposition was derived from the data based on the particle Stokes number near the primary impaction location modiÿed to incorporate the turbulent kinetic energy at the inlet. The model predicted similar (but slightly underestimated) deposition for monodisperse aerosols entering through DPIs, with increasing deposition for decreasing inlet diameter. The model was then extended to predict extrathoracic deposition for polydisperse aerosol formulations in vivo. Improved agreement was found between the in vitro predictions and the in vivo measurements compared to previous attempts. ?
Goals of Inhalation Therapy Dry Powder Inhalers DPI Use During Mechanical Ventilation
2015
Pressurized metered-dose inhalers (pMDIs) are commonly employed for administering bronchodilator aerosols to mechanically ventilated patients. Although it is feasible to employ dry powder inhalers in ventilator circuits, the presence of humidity in the ventilator circuit could reduce their efficiency. A complex array of factors influence drug delivery from pMDIs during mechanical ventilation, and subtle differences in the method of administration can markedly alter aerosol deposition in the lower respiratory tract. However, when the technique of administration is optimized, the efficiency of drug delivery from pMDIs in mechanically ventilated patients is comparable to that in ambulatory patients. Significant bronchodilator effects are observed with as few as 4 puffs from a pMDI and cylindrical spacer. In mechanically ventilated patients, pMDIs are a cost-effective, convenient, and safe method for delivering bronchodilator aerosols.
Dry Powder Inhalers -An Overview
The drug product encompasses the pharmacologic activity with the pharmaceutical properties. The ideal characteristics are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organs and availability at the site of action. A Dry powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. For the DPI, these goals can be met with a suitable powder formulation, an efficient metering system and a perfectly selected device. This review focuses on the dry powder inhaler formulation, evaluation, material methods and development processes. Most of the dry powder inhaler formulation encompasses micronized drug particles blended with larger carrier particles that promote the flow properties, reduce aggregation and help in dispersion. A combination of the physicochemical properties, particle size, shape, surface area and morphology affects the forces of interaction and aerodynamic properties, which in turn determine the fluidization, dispersion, delivery to the lungs and deposition in the peripheral airways. However the properties of free micronized powders often interfere with the drug handling and with drug delivery, reducing the dose consistency. Dry powder inhalers are evaluated by the drug product characterization studies such as the in vitro dose proportionality, effect of patient dose, priming etc. The development of the new designs of the DPI is governed by the driving forces such as the regulatory and pharmacopoeial requirements, delivery systems for the NCE, clinical factors and commercial factors.
The influence of dose on the performance of dry powder inhalation systems
International Journal of Pharmaceutics, 2005
The relationship between drug/lactose ratio and aerosolisation performance of conventional carrier based formulations was investigated using the twin stage impinger. A dose range of ∼10-450 g of drug in a 50 mg lactose carrier formulation was studied. Statistical differences in both the fine particle dose and fine particle fraction were observed across the dosage range (ANOVA, p < 0.05). In general, no statistically significant difference (Fishers Pairwise, p < 0.05) in fine particle dose was observed between drug levels of approximately 10 g and 135 g, whereas a linear decrease in fine particle fraction was observed across the same drug level range (R 2 = 0.977). Increasing the dose from ∼135 g to 450 g resulted in a statistically significant increase in both fine particle dose and fraction (ANOVA p < 0.05). Such observations may be attributed to the occupation of 'active' carrier sites by drug particles at low drug concentration, since the quantity of drug particles liberated from the carrier during aerosolisation remains constant at the lower dosing regimes. (P.M. Young).