RESUMEN

Magnesium stearate (MgSt) and lactose fines are often used as ternary components in carrier-based dry powder inhalers (DPIs) to improve fine particle fraction (FPF), but whether they act synergistically to improve aerosolization performance of DPI formulations is currently less studied. In addition, the applicability of utilizing powder rheological parameters to predict the FPF needs to be further verified. Thus, in this study, using fluticasone propionate (FP) as a model drug, effect of lactose fines addition in 0.5% MgSt containing DPI formulations on their powder and aerodynamic properties was explored. Influence of MgSt and fines mixing order on the DPIs performance was also investigated. The results showed that addition of lactose fines (1-10%) in 0.5% MgSt containing formulations could further improve flowability and enhance adhesion of the mixtures, and they could act synergistically to improve FPF. Moreover, the presence of 0.5% MgSt can greatly reduce the amount of lactose fines required to achieve the comparable FPF. The mixing order can affect distribution of MgSt on the carrier surface, with higher FPF noted when MgSt was mixed with carrier first, followed by lactose fines. A good linear relationship between powder rheological parameters such as basic flowability energy (BFE), Permeability and FPF was disclosed. In conclusion, in FP based DPIs, MgSt and lactose fines act synergistically to enhance FPF by tuning powder characteristics. Good flowability (27.39%) and strong adhesion (72.61%) contributed to the enhanced drug deposition in the lung.

Asunto(s)

Aerosoles , Inhaladores de Polvo Seco , Fluticasona , Lactosa , Tamaño de la Partícula , Polvos , Ácidos Esteáricos , Lactosa/química , Fluticasona/química , Fluticasona/administración & dosificación , Polvos/química , Ácidos Esteáricos/química , Excipientes/química , Reología , Composición de Medicamentos/métodos , Administración por Inhalación , Química Farmacéutica/métodos , Broncodilatadores/administración & dosificación , Broncodilatadores/química

RESUMEN

A new theory for the dispersibility enhancing effect of excipient fines for adhesive mixtures for inhalation is presented in this paper, while at the same time the shortcomings of current hypotheses are discussed. The proposed mechanism, denoted the 'viscoelastic damping effect', states that the presence of fines particles acts to dampen the collisions between carrier particles during mixing. As a consequence, fewer fine particles are 'irreversibly' pressed into the carriers, which in turn entails a higher fine particle fraction. The mechanism was demonstrated experimentally at different levels of added lactose fines by studying the influence of processing on fine particle fraction. This approach furthermore enabled quantification of the effect. All fine particles present in the blend (APIs and excipient fines) act together to exert the damping effect. The proposed mechanism is able to explain the main body of published data, including the effect of added excipient fines, the effect of an increased drug load, and the effect of removal of carrier fines. The viscoelastic damping mechanism is general in nature and conveys a broader and more general understanding of the behavior of adhesive mixtures for inhalation.

Asunto(s)

Adhesivos , Excipientes , Lactosa , Tamaño de la Partícula , Lactosa/química , Excipientes/química , Administración por Inhalación , Adhesivos/química , Química Farmacéutica/métodos , Portadores de Fármacos/química

RESUMEN

Background: Development of an inhalable nanoformulation of dacomitinib (DMB) encapsulated in poly-(lactic-co-glycolic acid) nanoparticles (NPs) to improve solubility, facilitate direct lung delivery and overcome the systemic adverse effects.Methods: DMB-loaded poly-(lactic-co-glycolic acid) NPs were prepared using solvent evaporation and characterized for particle size, polydispersity index and zeta-potential. The NPs were evaluated for in vitro drug release, aerosolization performance and in vitro efficacy studies.Results: The NPs showed excellent particle characteristics and displayed a cumulative release of ∼40% in 5 days. The NPs demonstrated a mass median aerodynamic diameter of ∼3 µm and fine particle fraction of ∼80%. Further, in vitro cell culture studies showed improved cytotoxic potential of DMB-loaded NPs compared with free drug.Conclusion: The study underscores the potential of DMB-loaded NPs as a viable approach for non-small cell lung cancer treatment.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Portadores de Fármacos , Liberación de Fármacos , Neoplasias Pulmonares , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quinazolinonas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Administración por Inhalación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Portadores de Fármacos/química , Quinazolinonas/química , Quinazolinonas/administración & dosificación , Quinazolinonas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Administración Oral , Línea Celular Tumoral , Ácido Poliglicólico/química , Ácido Láctico/química

RESUMEN

The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 µm) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 µm) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.

Asunto(s)

Aerosoles , Budesonida , Liberación de Fármacos , Inhaladores de Polvo Seco , Tamaño de la Partícula , Dióxido de Silicio , Dióxido de Silicio/química , Dióxido de Silicio/administración & dosificación , Budesonida/química , Budesonida/administración & dosificación , Budesonida/farmacocinética , Porosidad , Inhaladores de Polvo Seco/métodos , Administración por Inhalación , Sistemas de Liberación de Medicamentos/métodos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Broncodilatadores/administración & dosificación , Broncodilatadores/química , Broncodilatadores/farmacocinética , Portadores de Fármacos/química

RESUMEN

The aim of this study was to investigate how the propensity for aerosolisation in binary adhesive mixtures was affected by the drug load, and to determine whether these findings could be linked to different blend states. Binary blends of two different lactose carriers, each with varying size and morphology, were prepared together with budesonide. In vitro aerosolisation studies were conducted at four different pressure drops, ranging from 0.5 to 4 kPa, utilising a Next Generation Impactor. Several dispersion parameters were derived from the relationship between the quantity of dispersed API and the pressure drop. The evolution of the parameters with drug load was complex, especially at low drug loads. While similar responses were observed for both carriers, the range of drug load that could be used varied significantly. The choice of carrier not only influenced the capacity for drug loading but also affected the spatial distribution of the API within the mixture, which, in turn, affected its aerosolisation propensity. Thus, the drug dispersion process could be linked to different configurations of the lactose carrier and budesonide in the blends, i.e. blend states. In conclusion, the study suggests that the concept of blend states can provide an explanation for the complex dispersion process observed in adhesive blends.

Asunto(s)

Adhesivos , Aerosoles , Budesonida , Portadores de Fármacos , Lactosa , Budesonida/química , Budesonida/administración & dosificación , Lactosa/química , Administración por Inhalación , Adhesivos/química , Portadores de Fármacos/química , Tamaño de la Partícula , Química Farmacéutica/métodos

RESUMEN

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called 'rake' approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters. Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations. The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest Cmax value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, Cmax and AUC72h. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC72h of Glyco, Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.

Asunto(s)

Inhaladores de Polvo Seco , Nebulizadores y Vaporizadores , Humanos , Administración por Inhalación

RESUMEN

This study investigates the effect of different mixers and the applicability of the mixing energy (ME) concept to dry powder formulations for inhalation. With the aim to step-wise build and expand this concept, adhesive mixtures of 2 % budesonide and lactose carrier were investigated, both with 1 % magnesium stearate (MgSt) added in a 'coating' step, and without, the latter referred to as 'naked' formulations. For high shear mixed formulations, the fine particle fraction (FPF) was found to increase with increasing ME up to 60 % and thereafter decreased, using the Novolizer device. The data could be well fitted to the modeling equation, thus confirming the validity of the ME concept. The naked formulations displayed a linear decrease in FPF with increasing ME, again showing the validity of the ME concept. For Turbula mixed formulations, FPF increased with increased mixing time (and mixing energy) for all batches. The naked (binary) composition reached to higher FPF values than for high shear mixing and the formulation with MgSt reached to FPF values around 60 %, demonstrating that it is possible to achieve the same high drug dispersibility with the Turbula mixer as for high shear mixer. An equation for calculation of mixing energy in Turbula mixing was set up in an analogous way to the equation for high shear mixing, which enabled direct comparison between the two mixers.

Asunto(s)

Adhesivos , Química Farmacéutica , Portadores de Fármacos , Administración por Inhalación , Budesonida , Polvos , Tamaño de la Partícula , Lactosa , Inhaladores de Polvo Seco

RESUMEN

The device or the formulation? Which one governs drug dispersibility from the inhaler? To address this question, three budesonide-containing reservoir DPIs: Novopulmon Novolizer®, Giona Easyhaler® and DuoResp Spiromax®, were analyzed using the Next Generation Impactor, NGI. Thereafter, the devices were carefully opened, emptied, and formulations were switched between devices. Finally, three 'prototype' formulations with carriers of different particle size were produced and tested in the Novolizer and Easyhaler devices. Among the DPI products, the two devices which have a flow path with a cyclone-type geometry, i.e., the Novolizer and the Spiromax, yielded a fine particle fraction, FPF, above 40%. The Easyhaler, which has a straight mouthpiece outlet, produced an FPF of 18%. When the Novopulmon and the DuoResp formulations were assayed in the Easyhaler device, poor fine particle fractions were obtained. To the contrary, the Giona formulation produced a high FPF when tested in the Novolizer device. The results clearly show that the device is the dominating factor to dispersibility for the investigated products. Along the same lines, all three 'prototype' formulations produced high fine particle fractions in the Novolizer device, with the formulation with the largest carrier giving the best performance. Tested in the Easyhaler device, the prototype formulations produced low fine particle fractions, but interestingly, the formulation with the smallest carrier particle size yielded the highest FPF. It can be concluded that there is a link between inhaler design and the effect of carrier particle size, where larger carriers provide better dispersion in cyclone-type devices while smaller carriers seem to be more beneficial for inhalers which has a straight flow path for the powder formulation.

Asunto(s)

Adhesivos , Nebulizadores y Vaporizadores , Polvos , Administración por Inhalación , Budesonida , Tamaño de la Partícula , Inhaladores de Polvo Seco , Aerosoles

RESUMEN

In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for orally inhaled formulations, as there is no commonly accepted test for assessing their dissolution pattern. Up until a few years ago, there was no consensus that assessing the dissolution of orally inhaled drugs is a key factor in the assessment of orally inhaled products. With the advancement of research in the field of dissolution methods for orally inhaled products and a focus on systemic delivery of new, poorly water-soluble drugs at higher therapeutic doses, an evaluation of dissolution kinetics is proving crucial. Dissolution and permeability testing can determine the differences between the developed formulations and the innovator's formulations and serve as a useful tool in correlating in vitro and in vivo studies. The current review highlights recent advances in the dissolution and permeability testing of inhalation products and their limitations, including recent cell-based technology. Although a few new dissolution and permeability testing methods have been established that have varying degrees of complexity, none have emerged as the standard method of choice. The review discusses the challenges of establishing methods that can closely simulate the in vivo absorption of drugs. It provides practical insights into method development for various dissolution testing scenarios and challenges with dose collection and particle deposition from inhalation devices for dissolution tests. Furthermore, dissolution kinetic models and statistical tests to compare the dissolution profiles of test and reference products are discussed.

RESUMEN

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.

RESUMEN

This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and TGA. Using a Twin-Stage Impinger (TSI), the in vitro aerosolization of the formulations with and without carrier lactose was studied at a flow rate of 60± 5 L/min and the IBF was determined using a validated HPLC method. The flow properties were determined by the Carr's Index (CI), Hausner Ratio (HR) and Angle of Repose (AR) of the milled IBF with 4-6.25% leucine and leucine containing formulations showed higher flow property than those of formulations without leucine. The fine particle fraction (FPF) of IBF from the prepared formulations was significantly (p = 0.000278) higher (37.1 ± 3.8%) compared to the original drug (FPF 3.7 ± 0.9%) owing to the presence of leucine, which enhanced the aerosolization of the milled IBF particles. Using quantitative phase analysis, the XPRD data revealed the crystallinity and accurate weight percentages of the milled IBF in the formulations. FTIR revealed no changes of the structural integrity of the milled IBF in presence of leucine or MgSt. The presence of 2.5% MgSt in the selected formulations produced the highest solubility (252.8 ± 0.6 µg/mL) of IBF compared to that of unmilled IBF (147.4 ± 1.6 µg/mL). The drug dissolution from all formulations containing 4-6.25% leucine showed 12.2-18.6% drug release in 2.5 min; however, 100% IBF dissolution occurred in 2 h whereas around 50% original and dry milled IBF dissolved in 2 h. The results indicated the successful preparation of inhalable IBF microparticles by the wet milling method and the developed DPI formulations with enhanced aerosolization and solubility due to the presence of leucine may be considered as future IBF formulations for inhalation.

RESUMEN

Surface roughness of carrier particles can impact dry powder inhaler (DPI) performance. There are opposing views on the effect of roughness on DPI performance. Hence, a systematic approach is needed to modify carrier surfaces and evaluate the impact on drug delivery. Carrier particle surfaces were modified by fluid bed coating with saturated lactose containing micronized lactose of different sizes (2, 5 and 8 µm) and coated to different levels (20, 40, 60 and 80%). Their drug delivery performance was assessed by the fine particle fraction (FPF). Roughness parameters, mean arithmetic roughness (Ra) and arithmetic mean height (Sa), of the carrier particles, were also evaluated using optical profilometry and scanning laser microscopy. Generally, particles of higher Ra had higher FPF. Higher Sa resulted in higher FPF only for particles with 60 and 80% coat levels. Reduced contact surface area between the drug particle and rougher carrier particle resulted in easier drug detachment during aerosolization. The 5 µm micronized lactose produced optimal carrier particles with respect to FPF and surface roughness. The study highlighted that with the ideal particles for surface roughening and coating level, surface roughening could be efficiently achieved by fluid bed coating for superior DPI performance.

Asunto(s)

Portadores de Fármacos , Inhaladores de Polvo Seco , Lactosa , Administración por Inhalación , Aerosoles , Albuterol , Sistemas de Liberación de Medicamentos/métodos , Inhaladores de Polvo Seco/métodos , Excipientes , Tamaño de la Partícula , Polvos , Propiedades de Superficie

RESUMEN

Based on the drug repositioning strategy, niclosamide (NCL) has shown potential applications for treating COVID-19. However, the development of new formulations for effective NCL delivery is still challenging. Herein, NCL-embedded dry powder for inhalation (NeDPI) was fabricated by a novel spray freeze drying technology. The addition of Tween-80 together with 1,2-Distearoyl-sn-glycero-3-phosphocholine showed the synergistic effects on improving both the dispersibility of primary NCL nanocrystals suspended in the feed liquid and the spherical structure integrity of the spray freeze dried (SFD) microparticle. The SFD microparticle size, morphology, crystal properties, flowability and aerosol performance were systematically investigated by regulating the feed liquid composition and freezing temperature. The addition of leucine as the aerosol enhancer promoted the microparticle sphericity with greatly improved flowability. The optimal sample (SF- 80D-N20L2D2T1) showed the highest fine particle fraction of ∼47.83%, equivalently over 3.8 mg NCL that could reach the deep lung when inhaling 10 mg dry powders.

RESUMEN

We have performed Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) simulations of air and particles in a commercial ELLIPTA® inhaler. We simulated the fluidization, deagglomeration and transport of carrier and API particles, with two realistic inhalation profiles that are representative of moderate asthma and very severe COPD patients, and three different mouthpiece designs. In each of the ten cases simulated, we determined the fine particle fraction (FPF) in the stream leaving the mouthpiece, the temporal evolution of the spatial distribution of the particles, the mean air (slip) velocity seen by the carrier particles, and the average numbers and normal impact velocities of carrier-carrier and carrier-wall collisions inside the inhaler. In the cases examined, the air-carrier and carrier-carrier interactions affected the FPF, while the carrier-wall interactions were too infrequent to have a substantial effect. The simulations revealed the benefit of loading both blisters even when only a single medication needs to be delivered.

RESUMEN

Active pharmaceutical ingredient (API)-embedded dry powder for inhalation (AeDPI) is highly desirable for pulmonary delivery of high-dose drug. Herein, a series of spray freeze-dried (SFD) ciprofloxacin hydrochloride (CH)-embedded dry powders were fabricated via a self-designed micro-fluidic spray freeze tower (MFSFT) capable of tuning freezing temperature of cooling air as the refrigerant medium. The effects of total solid content (TSC), mass ratio of CH to L-leucine (Leu) as the aerosol dispersion enhancer, and the freezing temperature on particle morphology, size, density, moisture content, crystal properties, flowability, and aerodynamic performance were investigated. It was found that the Leu content and freezing temperature had considerable influence on the fine particle fraction (FPF) of the SFD microparticles. The optimal formulation (CH/Leu = 7:3, TSC = 2%w/w) prepared at - 40°C exhibited remarkable effective drug deposition (~ 33.38%), good aerodynamic performance (~ 47.69% FPF), and excellent storage stability with ultralow hygroscopicity (~ 1.93%). This work demonstrated the promising feasibility of using the MFSFT instead of conventional liquid nitrogen assisted method in the research and development of high-dose AeDPI.

Asunto(s)

Ciprofloxacina , Inhaladores de Polvo Seco , Administración por Inhalación , Aerosoles/química , Química Farmacéutica/métodos , Ciprofloxacina/química , Inhaladores de Polvo Seco/métodos , Liofilización/métodos , Leucina , Tamaño de la Partícula , Polvos/química

RESUMEN

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

RESUMEN

BACKGROUND: Inhalable nanocomposite particles using O/W emulsions were studied. The effect of the composition of the dispersed phase on the nanoparticles in the nanocomposite particles was reported, however, the effect on the inhalation characteristics of nanocomposite particles has not been investigated. OBJECTIVE: The aim of this study was to study the effects of lower alcohols in the dispersed phase of O/W emulsions on inhalable nanocomposite particles. METHODS: Nanocomposite particles were prepared using a spray dryer from O/W emulsion. A mixed solution of dichloromethane and lower alcohols in which rifampicin (RFP) and poly(L-lactide-co-glycolide) were dissolved was used as a dispersed phase, and an aqueous solution in which arginine and leucine were dissolved was used as a continuous phase. RESULTS: We succeeded in preparing non-spherical nanocomposite particles with an average diameter of 9.01-10.91 µm. The results of the fine particle fraction (FPF) measurement showed that the higher the hydrophobicity of the lower alcohol mixed in the dispersed phase, the higher the FPF value. The FPF value of the nanocomposite particles was significantly increased by using ethanol and 1-propanol. CONCLUSIONS: The results were revealed that mixing 1-propanol with the dispersed phase increased the amount of RFP delivered to the lungs.

Asunto(s)

Alcoholes , Nanocompuestos , 1-Propanol , Emulsiones , Tamaño de la Partícula , Rifampin

RESUMEN

The transport and aerosolization of particles are studied in several different dry powder inhaler geometries via Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) simulations. These simulations combine Large Eddy Simulation of gas with Discrete Element Model simulation of all the carrier particles and a representative subset of the active pharmaceutical ingredient (API) particles. The purpose of the study is to probe the dominant mechanism leading to the release of the API particles and to demonstrate the value of the CFD-DEM simulations where one tracks the motion of all the carrier and API particles. Simulations are performed at different inhalation rates and initial dose loading conditions for the screen-haler geometry, a simple cylindrical tube inhaler, and five different geometry modifications that took the form of bumpy walls and baffles. These geometry modifications alter the residence time of the powder sample in the inhaler, pressure drop across the inhaler, the severity of gas-carrier interactions, and the number of collisions experienced by the carrier particles, all of which are quantified. The quality of aerosolization is found to correlate with the average air-carrier slip velocity, while collisions played only a secondary role. Some geometry modifications improved aerosolization quality with very little increase in the pressure drop across the device.

Asunto(s)

Inhaladores de Polvo Seco , Administración por Inhalación , Aerosoles , Diseño de Equipo , Tamaño de la Partícula , Polvos

RESUMEN

This study aimed to design dry powder inhaler formulations using a hydrophilic polymeric polysaccharide, phytoglycogen (PyG), as a multi-functional additive that increases the phagocytic activity of macrophage-like cells and enhances pulmonary delivery of drugs. The safety and usefulness of PyG were determined using in vitro cell-based studies. Dry powder inhaler formulations of an antitubercular drug, rifampicin, were fabricated by spray drying with PyG. The cytotoxicity, effects on phagocytosis, particle size, and morphology were evaluated. The aerosolization properties of the powder formulations were evaluated using an Andersen cascade impactor (ACI). Scanning electron microscope images of the particles on each ACI stage were captured to observe the deposition behavior. PyG showed no toxicity in A549, Calu-3, or RAW264.7 cell lines. At concentrations of 0.5 and 1 g/L, PyG facilitated the cellular uptake of latex beads and the expression of pro-inflammatory cytokine genes in RAW264.7 cells. Formulations with outstanding inhalation potential were produced. The fine particle fraction (aerodynamic size 2-7 µm) of the porous particle batch reached nearly 60%, whereas in the formulation containing wrinkled carrier particles, the extra-fine particle fraction (aerodynamic particle size < 2 µm) was 25.0% ± 1.7%. The deposition of porous and wrinkled particles on individual ACI stages was distinct. The inclusion of PyG dramatically improved the inhalation performance of porous and wrinkled powder formulations. These easily inhaled immunostimulatory carrier particles may advance the state of research by enhancing the therapeutic effect and alveolar delivery of antitubercular drugs.

Asunto(s)

Antituberculosos/administración & dosificación , Sistemas de Liberación de Medicamentos , Glucógeno/química , Rifampin/administración & dosificación , Células A549 , Administración por Inhalación , Aerosoles , Animales , Antituberculosos/química , Antituberculosos/toxicidad , Línea Celular Tumoral , Química Farmacéutica/métodos , Inhaladores de Polvo Seco , Excipientes/química , Humanos , Ratones , Tamaño de la Partícula , Porosidad , Células RAW 264.7 , Rifampin/química , Rifampin/toxicidad , Distribución Tisular

RESUMEN

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to in vivo lung deposition from scintigraphy data. If the dissolution and absorption processes after deposition are adequately understood, the correlation may be extended to the pharmacokinetics and pharmacodynamics of the delivered drugs. Correlation of impactor data to lung deposition is a relatively new research area that has been gaining recent interest. Although few in number, experiments and meta-analyses have been conducted to examine such correlations. An artificial neural network approach has also been employed to analyse the complex relationships between multiple factors and responses. However, much research is needed to generate more data to obtain robust correlations. These predictive models will be useful in improving the efficiency in product development by reducing the need of expensive and lengthy clinical trials.

Asunto(s)

Aerosoles/administración & dosificación , Pulmón/metabolismo , Modelos Biológicos , Preparaciones Farmacéuticas/administración & dosificación , Administración por Inhalación , Animales , Humanos , Aprendizaje Automático