Inhalation Drug Delivery System Research Articles

Evaluation of Appropriateness of Inhaled Drug Delivery Systems in COPD Patients

Evaluation of Appropriateness of Inhaled Drug Delivery Systems in COPD Patients

Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B–cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.

Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs

Event Abstract Back to Event Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs Elżbieta Pamuła1, Katarzyna Reczyńska1 and Wojciech Chrzanowski2 1 AGH University of Science and Technology, Department of Biomaterials, Faculrty of Materials Science and Ceramics, Poland 2 The University of Sydney, Faculty of Pharmacy, Australia Introduction: Currently the treatment of lung cancer lacks non-invasively targetable and controlled release topical inhalation therapy. Passive targeting using iron-oxide nanoparticles and magnetic field and their ability to induce localised hyperthermia under oscillating magnetic field could potentially enable both goals in one system. This study developed temperature sensitive lipid-based drug carriers containing superparamagnetic iron-oxide nanoparticles (SPIONs) that are: inhalable, targetable and temperature-sensitive. This system exploits combined effects of pharmaceutics and hyperthermia to enhance synergistically efficacy of the cancer therapy. Materials and Methods: Fatty acids (lauric, palmitic and stearic as well as their mixtures) with melting temperature of 40 - 45oC (hyperthermia conditions) were chosen. Paclitaxel (PAX) and SPIONs were dissolved/dispersed in a melted lipid phase at different SPION/lipid ratios and solid lipid particles were produced using oil in water emulsification. The particle size, thermal properties, chemical composition were assessed using Raman spectroscopy, SEM,EDX, AFM, DSC and drug release tests. Results and Discussion: Developed particles were spherical shape, with an average diameter of 2-6 μm. Thermal and chemical analyses confirmed the presence of PAX and SPIONs inside the lipid matrix. Thermal properties of lipid microparticles, thus their ability to release the drug at specific temperature, were tuned by the formation of eutectic composition obtained by mixing different types of fatty acids. The lipid formulations were shown to have slow release profile at body temperature, but fast release at hyperthermic conditions (45°C), suggesting a potentially powerful controlled release therapy of lung cancer. Conclusion: (i) PAX and SPIONs loaded lipid microparticles of desired size and physical-chemical characteristics were fabricated using oil in water emulsification technique; (ii) the lipid system was thermo-sensitive, allowing controlled release of PAX; (iii) the system holds a promise as an effective drug vehicle in targeted and controlled inhalation therapy. This study was supported by Polish National Science Center (No 2014/14/M/ST5/00649). Keywords: Drug delivery, stimuli-response, targeting delivery, Nano/micro particle Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Biomaterials for therapeutic delivery Citation: Pamuła E, Reczyńska K and Chrzanowski W (2016). Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02822 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Scholar Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski PubMed Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Inhalable self-assembled albumin nanoparticles for treating drug-resistant lung cancer

Direct pulmonary delivery of anti-cancer agents is viewed as an effective way of treating lung cancer. Here, we fabricated inhalable nanoparticles made of human serum albumin (HSA) conjugated with doxorubicin and octyl aldehyde and adsorbed with apoptotic TRAIL protein (TRAIL/Dox HSA-NP). The octyl aldehyde and doxorubicin endowed HSA with significant hydrophobicity that facilitated self-assembly. TRAIL/Dox HSA-NP was found to have excellent particle size (~340nm), morphology, dispersability, and aerosolization properties. TRAIL/Dox HSA-NP displayed synergistic cytotoxicity and apoptotic activity in H226 lung cancer cells vs. HSA-NP containing TRAIL or Dox alone. TRAIL/Dox HSA-NP was well deposited in the mouse lungs using an aerosolizer, and TRAIL and Dox-HSA were found to be gradually released over 3days. The anti-tumor efficacy of pulmonary administered TRAIL/Dox HSA-NP was evaluated in BALB/c nu/nu mice bearing H226 cell-induced metastatic tumors. It was found that the tumors of H226-implanted mice treated with TRAIL/Dox HSA-NP were remarkably smaller and lighter than those of mice treated with TRAIL or Dox HSA-NP alone (337.5±7.5; 678.2±51.5; and 598.9±24.8mg, respectively). Importantly, this improved anti-tumor efficacy was found to be due to the synergistic apoptotic effects of Dox and TRAIL. In the authors' opinion, TRAIL/Dox HSA-NP offers a potential inhalable anti-lung cancer drug delivery system. Furthermore, the synergism displayed by combined use of Dox and TRAIL could be used to markedly reduce doxorubicin doses and minimize its side effects.

Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy

Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10–13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30–50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity.

Magnetised Thermo Responsive Lipid Vehicles for Targeted and Controlled Lung Drug Delivery

Conditions such as lung cancer currently lack non-invasively targetable and controlled release topical inhalational therapies. Superparamagnetic iron-oxide nanoparticles (SPIONs) have shown promising results as a targetable therapy. We aimed to fabricate and test the in-vitro performance of particles with SPION and drug within a lipid matrix as a potentially targetable and thermo-sensitive inhalable drug-delivery system. Budesonide and SPIONs were incorporated into lipid particles using oil-in-water emulsification. Particles size, chemical composition, responsiveness to magnetic field, thermosensitiveness and inhalation performance in-vitro were investigated. Particles of average diameter 2-4 μm with budesonide and SPIONs inside the lipid matrix responded to a magnetic field with 100% extraction at a distance of 5 mm. Formulations were shown to have accelerated rate of drug release at hyperthermic temperatures (45°C)--controlled release. The produced inhalation dry powder presented promising inhalation performance, with an inhalable fine particle fraction of 30%. The lipid system presented thermo-sensitive characteristics, suitable for controlled delivery, the model drug and SPION loaded lipid system was magnetically active and movable using simple permanent magnets, and the system demonstrates promise as an effective drug vehicle in targeted and controlled inhalation therapy.

다공성 PLGA 마이크로입자 제조법의 최적화 연구

Poly(lactic-co-glycolic acid) (PLGA) microspheres have been a useful tool as a controlled drug delivery system for peptides and proteins. Recently, porous microspheres have gained great attention as inhalation drug delivery system due to their low aerodynamic densities. Here, we report highly porous PLGA microspheres, which were prepared by using a single o/w emulsification/solvent evaporation method. Two types of porogen, i.e., (i) extractable Pluronic F127 and (ii) gas foaming salt of ammonium bicarbonate, were used to induce pores on the surface of PLGA microspheres. The respective preparation conditions on dp/cp ratio and porogen concentration were determined by the previous preliminary experiments, and other preparation factors were further optimized on the basis of PLGA Mw and porogen type. The morphological features examined by scanning electron microscope (SEM) show these porous microspheres have highly porous surface structure with a diameter range of 2030 m. These highly porous PLGA microspheres, which have much lower density, would be a practical aerosol system for pulmonary drug delivery.

Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis

The present study was planned to evaluate the chemotherapeutic potential of nebulized solid lipid particles (SLPs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. The SLPs prepared by the "emulsion solvent diffusion" technique possessed a favourable mass median aerodynamic diameter suitable for bronchoalveolar drug delivery. Following a single nebulization to guinea pigs, therapeutic drug concentrations were maintained in the plasma for 5 days and in the organs (lungs, liver and spleen) for 7 days whereas free drugs were cleared by 1-2 days. The mean residence time and drug bioavailability were improved several-fold in the case of drug-loaded SLPs. A similar pharmacokinetic profile was observed in Mycobacterium tuberculosis-infected guinea pigs. On nebulization of drug-loaded SLPs to infected guinea pigs at every 7th day, no tubercle bacilli could be detected in the lungs/spleen after 7 doses of treatment whereas 46 daily doses of orally administered drugs were required to obtain an equivalent therapeutic benefit. Further, there was no evidence of any biochemical hepatotoxicity. Thus, nebulization of SLP-based antitubercular drugs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.

The Measurement of Nicotine in Human Plasma by High-Performance Liquid Chromatography-Electrospray-Tandem Mass Spectrometry

The authors describe a reverse-phase high-performance liquid chromatography-electrospray-tandem mass spectrometry method for the measurement of nicotine in human plasma. Samples (500 microL) with added deuterium-labeled d3-nicotine as an internal standard (IS) were treated with a 2-step process of ether extraction (6 mL) followed by back-extraction into 0.1% formic acid (50 microL). Chromatography was performed on a phenyl Novapak column with a mobile phase consisting of 50% 10 mM ammonium formate (pH 3.3) and acetonitrile (50:50, vol/vol). A flow rate of 0.2 mL/min resulted in a total analysis time of 5 minutes per sample. Mass spectrometric detection was by selected reactant monitoring (nicotine m/z 163.2 --> 130.2; IS m/z 166.2 --> 87.2). The assay was linear from 0.5 to 100 microg/L (r > 0.993, n = 9). The accuracy and imprecision of the method for quality control samples were 87.5% to 113% and <10.2%, respectively. Interday accuracy and imprecision at the limit of quantification (0.5 microg/L) was 113% and 7.2% (n = 4). The process efficiency for nicotine in plasma was >75%. The method described has good process efficiency, stabilized nicotine, avoided concentration steps, and most importantly minimized potential contamination. Further, we have established that water-based standards and controls are interchangeable with plasma-based samples. This method was used successfully to measure the pharmacokinetic profiles of subjects involved in the development of an aerosol inhalation drug delivery system.

A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs

Introduction: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. Methods: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4×4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 μg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 μl solution. Results: Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h. Discussion: Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic.

Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis.

To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization. Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs. The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit. Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.

Chairman's Summary

Journal of Aerosol MedicineVol. 12, No. s1 International Society for Aerosols in Medicine 12th Biennial Congress Symposium NEW ADVANCES IN PROPELLANT-FREE INHALED DRUG DELIVERY Vienna, Austria, June 15,1999Chairman's SummaryDAVID GANDERTONDAVID GANDERTONSearch for more papers by this authorPublished Online:25 Mar 2010https://doi.org/10.1089/jam.1999.12.Suppl_1.S-41AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Chairman's Summary." , 12(s1), pp. S-41–S-42FiguresReferencesRelatedDetailsCited byA novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogsJournal of Pharmacological and Toxicological Methods, Vol. 50, No. 2 Volume 12Issue s1Sep 1999 To cite this article:DAVID GANDERTON.Chairman's Summary.Journal of Aerosol Medicine.Sep 1999.S-41-S-42.http://doi.org/10.1089/jam.1999.12.Suppl_1.S-41Published in Volume: 12 Issue s1: March 25, 2010PDF download

Single Particle Characterization of Albuterol Metered Dose Inhaler Aerosol in Near Real-Time

ABSTRACT Metered dose inhalers produce a fine spray of aerosol particles that are used as an inhalation drug delivery system for a variety of therapeutic purposes. Common analytical methods employed for characterizing the aerosol dosage are typically off-line analyses for both chemical information and particle size distributions, and focus on the bulk aerosol rather than on single particles. Aerosol time-of-flight mass spectrometry offers the capability to analyze the aerosol dose in near real-time, providing both size and chemical information for single particles. Though aerosol time-of-flight mass spectrometry has been used primarily to characterize environmental samples, this is the first demonstration of its bioanalytical capabilities. This paper discusses the characterization of an albuterol metered dose inhaler using both high and low laser power for the desorption/ionization process in order to control the amount of fragmentation observed in the mass spectral analysis. Using high laser power, signi...