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Inhalation solutions — Which ones may be mixed? Physico-chemical compatibility of drug solutions in nebulizers — Update 2013

Open ArchivePublished:October 30, 2013DOI:https://doi.org/10.1016/j.jcf.2013.09.006

      Abstract

      Many patients suffering from chronic respiratory diseases rely on inhalation therapy with nebulizers. About 25% of patients who need to inhale several different drugs per day save time by mixing them for simultaneous inhalation. This review presents a comprehensive overview of the available data concerning physico-chemical compatibility of commonly mixed nebulizer solutions and suspensions. Information is based on our in vitro studies and a thorough literature search.
      Results indicate that many nebulizer solutions/suspensions are mixable without provoking incompatibilities. However, certain excipients contained in some of the tested drug products could be identified as a reason for incompatibilities, e.g. impaired activity of dornase alfa. Studies assessing the aerosol characteristics of compatible mixtures nebulized with commonly used nebulizers are limited and should be encouraged. The clinical efficacy of simultaneous inhalation of duplicate, tripartite or quadripartite mixtures must be evaluated in clinical studies before final recommendations for the inhalation regimens can be made.

      Keywords

      1. Introduction

      Patients suffering from cystic fibrosis (CF) or other chronic airway diseases widely rely on inhalation therapy. Besides dry powder inhalers (DPI) and metered dose inhalers (MDI) nebulizers are used, although nebulization is much more time consuming than inhaling with a DPI or MDI. In contrast to DPI's and MDI's, nebulizers deliver the drugs continuously and larger doses can be administered. For children nebulization is advantageous because the coordination requirements are less strict [
      • Virchow J.C.
      What plays a role in the choice of inhaler device for asthma therapy?.
      ]. They often cannot handle a MDI since the coordination of medication release (i.e. actuation of the device) and simultaneous inhalation is too difficult. Concerning DPI's, children aren't able to generate the peak inspiratory flow (PIF) necessary to release the drug [
      • Dolovich M.B.
      • Ahrens R.C.
      • Hess D.R.
      • Anderson P.
      • Dhand R.
      • Rau J.L.
      • et al.
      Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.
      ].
      Studies indicate that different nebulizer systems from different manufacturers, i.e. ultrasonic, jet, or vibrating membrane nebulizers with ventilator, humidifier or Y-piece, generate different aerosol mass distribution profiles and thus, drug deposition in the airways varies [
      • Scherer T.
      • Geller D.E.
      • Owyang L.
      • Tservistas M.
      • Keller M.
      • Boden N.
      • et al.
      A technical feasibility study of dornase alfa delivery with eFlow® vibrating membrane nebulizers: aerosol characteristics and physicochemical stability.
      ,
      • Pitance L.
      • Reychler G.
      • Leal T.
      • Reychler H.
      • Liistro G.
      • Montharu J.
      • et al.
      Aerosol delivery to the lung is more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer.
      ,
      • Arzhavitina A.
      • Steckel H.
      Surface active drugs significantly alter the drug output rate from medical nebulizers.
      ,
      • Coates A.L.
      • MacNeish C.F.
      • Meisner D.
      • Kelemen S.
      • Thibert R.
      • MacDonald J.
      • et al.
      The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols.
      ,
      • Sidler-Moix A.L.
      • Dolci U.
      • Berger-Gryllaki M.
      • Pannatier A.
      • Cotting J.
      • Di Paolo E.R.
      Albuterol delivery in an in vitro pediatric ventilator lung model: comparison of jet, ultrasonic, and mesh nebulizers.
      ,
      • Berlinski A.
      • Willis J.R.
      Albuterol delivery by 4 different nebulizers placed in 4 different positions in a pediatric ventilator in-vitro model.
      ]. Adequate drug delivery can be achieved if a specific medicinal product approved for nebulization is prescribed together with a specific nebulizer which was evaluated to be an effectively functioning drug-device combination [
      • Arzhavitina A.
      • Steckel H.
      Surface active drugs significantly alter the drug output rate from medical nebulizers.
      ]. But apart from that, daily practice is even worse, especially if patients have to inhale several drugs per dose interval. Instead of cleaning, reassembling and refilling the nebulizer to perform consecutive nebulization at least 25% of patients save time by mixing the inhalation solutions/suspensions [
      • Rosenfeld M.
      • Emerson J.
      • Astley S.
      • Joy P.
      • Williams-Warren J.
      • Standaert T.A.
      • et al.
      Home nebulizer use among patients with cystic fibrosis.
      ,
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ]. Nebulization of medication mixtures increases the aerosol output of the nebulizer while its dead volume remains the same. If nebulization is continued until the nebulizer runs dry, total mass output and inhaled mass of the nebulized drug will rise [
      • Akapo S.
      • Gupta J.
      • Martinez E.
      • McCrea C.
      • Ye L.
      • Roach M.
      Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions.
      ,
      • Clay M.M.
      • Pavia D.
      • Newman S.P.
      • Lennard-Jones T.
      • Clarke S.W.
      Assessment of jet nebulisers for lung aerosol therapy.
      ,
      • McKenzie J.
      • Gronberg S.
      • Cruz Rivera M.
      • et al.
      Budesonide inhalation suspension can be nebulized with solutions containing albuterol sulphate.
      ,
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      Effect of nebulizer volume on drug delivery: budesonide inhalation suspension.
      ]. However, incompatibility and/or instability of the medication mixtures can lead to impaired drug safety and/or reduced efficacy up to treatment failure.
      Further, simultaneous nebulization of inhalation solutions can affect drug delivery by altering the aerosol particle size distribution. Particle size should be 1 to 5 μm in diameter, because larger particles will deposit in the upper airways and smaller particles may be exhaled [
      • Boe J.
      • Dennis J.H.
      • O'Driscoll B.R.
      • Bauer T.T.
      • Carone M.
      • Dautzenberg B.
      • et al.
      European Respiratory Society Guidelines on the use of nebulizers.
      ]. Hence, even if physico-chemical compatibility of mixtures is proven final recommendations for simultaneous inhalation cannot be made. Aerodynamic characteristics of mixtures need to be studied. In addition, the clinical relevance of inhaling different drugs simultaneously and the differences in therapeutic outcome compared to consecutive inhalation should be investigated.
      Drug substances commonly prescribed for nebulization therapy in Europe comprise the bronchodilators albuterol (salbutamol) and ipratropium bromide, the corticosteroids budesonide and fluticasone-17-propionate, the antibiotics tobramycin and colistimethate, and dornase alfa. In addition, formoterol, acetylcysteine, sodium chloride solutions (0.9% to 7%), and the mast cell stabilizer cromolyn are used.
      In 2006 we published our first results concerning physico-chemical compatibility and stability of several nebulizable drug solutions/suspensions predominantly used in Europe [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ]. Since then various mixtures have been experimentally tested by us and other groups, also in regard to the resulting aerosol characteristics. Results were published in several articles of the primary literature and Burchett et al. developed a preliminary compatibility guide for aerosolized medications used in the US [
      • Burchett D.K.
      • Darko W.
      • Zahra J.
      • Noviasky J.
      • Probst L.
      • Smith A.
      Mixing and compatibility guide for commonly used aerosolized medications.
      ]. In this issue we present a comprehensive overview of the available data based on our own studies and the search of relevant literature as well as the up-to-date version of the compatibility data in table format.

      2. Methods

      2.1 Physico-chemical compatibility of nebulizable drug mixtures

      In the following paragraphs we present an overview of the methods used to determine the physico-chemical compatibility of duplicate, tripartite and quadripartite drug solutions/suspensions inhaled via nebulizers. According to the conventional definition of compatibility, mixtures of inhalation medications can be designated as physico-chemical compatible, when chemical stability (≤10% degradation) of each active substance and unchanged pH values, osmolality and physical appearance are given over a test period of ≤24 h. In general, potencies or concentrations of the active substances of the mixtures were determined under specified conditions.

      2.1.1 Preparation of admixtures

      Test solutions/suspensions were prepared by mixing commonly used doses of medication approved and marketed in Europe. Mixtures were stored at room temperature or under refrigeration and exposed to light for several hours. Analyses were performed immediately after preparation and after defined intervals [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
      ,
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ].

      2.1.2 Physical compatibility

      Physical compatibility of the inhalation mixtures was determined by visual inspection for any changes up to 24 h after mixing as well as by measuring pH and osmolality [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
      ,
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ,
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
      ]. Mixtures were designated as physically incompatible when color or odor changed, and haze or precipitation occurred. The lack of physical incompatibility does not rule out chemical decomposition.

      2.1.3 Chemical compatibility (Table 1)

      Potencies of antibiotics in inhalation mixtures were determined by fluorescence immunoassay (tobramycin) [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
      ,
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
      ] or by using the ‘Microbiological assay of antibiotics’ (agar diffusion assay) of the European Pharmacopoeia (Ph. Eur.) in comparison to a reference standard (colistimethate, tobramycin) [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ,
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
      ].
      Table 1Analytical methods (own data only) used to determine chemical compatibility of mixed nebulizer solutions/suspensions.
      DrugMethod
      Dornase alfaKinetic colorimetric DNase activity assay
      Size-exclusion high performance liquid chromatography (SE-HPLC)
      Ultraviolet spectroscopy
      Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)
      Tentacle strong cation-exchange chromatography
      TobramycinFluorescence immunoassay, microbiological assay of antibiotics Ph. Eur.
      ColistimethateMicrobiological assay of antibiotics (agar diffusion assay) Ph. Eur.
      BudesonideRP-HPLC: stability-indicating high performance liquid chromatography with ultraviolet detection
      Fluticasone-17-propionateRP-HPLC
      Ipratropium bromideRP-HPLC
      AlbuterolRP-HPLC
      Dornase alfa activity was determined by a kinetic colorimetric DNase activity assay [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ]. Stability of dornase alfa was determined by size-exclusion high performance liquid chromatography (SE-HPLC), ultraviolet spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and tentacle strong cation-exchange chromatography [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
      ].
      Concentrations of the corticosteroids (budesonide and fluticasone-17-propionate) and the bronchodilators (ipratropium bromide and albuterol) were measured by stability-indicating high performance liquid chromatography assays with ultraviolet detection (RP-HPLC) [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ,
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ,
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ,
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
      ,
      • Blewett A.J.
      • Varma D.
      • Gilles T.
      • Butcher R.
      • Jacob J.
      • Amazan J.
      • et al.
      Development and validation of a stability-indicating high-performance liquid chromatography method for the simultaneous determination of albuterol, budesonide, and ipratropium bromide in compounded nebulizer solutions.
      ].

      2.2 Aerosol characteristics

      A subset of mixtures was analyzed in regard to their aerosol characteristics after nebulization with the PARI eFlow® rapid. Particle size distribution, Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD) and Fine Particle Fraction (FPF; particles <5 μm) were determined via cascade impaction with the Next Generation Pharmaceutical Impactor (NGI) in comparison to aerodynamic parameters of unmixed solutions under specified conditions (Fig. 1). RP-HPLC and SE-HPLC were used to assess drug concentrations deposited on each impactor stage, in the induction port and in the nebulizer. We tested duplicate mixtures of dornase alfa and tobramycin, i.e. Pulmozyme® with Bramitob® and Pulmozyme® with TOBI® (Table 3) as well as the tripartite mixture of ipratropium bromide, albuterol and fluticasone-17-propionate, i.e. Atrovent®, Sultanol® forte and Flutide® forte.
      Figure thumbnail gr1
      Fig. 1Schematic test set-up of the impaction experiments.
      Table 2Results of the HPLC assays of quadripartite mixtures containing Colistin CF, Atrovent, Sultanol forte and Flutide forte
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      .
      n = 9Ipratropium bromideSalbutamol sulfateFluticasone-17-propionate
      Nominal concentration [μg/ml]55.5526.6622.22
      Arithmetic mean ± relative SD [μg/ml]58.4 ± 0.5527.68 ± 0.3523.82 ± 0.32
      Percentage rate of nominal concentration105.13103.80107.20
      Table 3Nebulizer and aerosol characteristics of Pulmozyme® mixed with 0.9% NaCl solution, Bramitob® or Tobi®. Results expressed as mean ± SD of triplicate assays of 4 test solutions
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
      .
      Pulmozyme® mixture with
      n = 120.9% NaCl solutionBramitob®TOBI®
      Nebulization time [min] ± SD5.85 ± 0.105.46 ± 0.225.66 ± 0.33
      Delivered dose [%] ± SD73.91 ± 2.7874.41 ± 3.9776.56 ± 2.62
      MMAD [μm] ± SD4.75 ± 0.134.73 ± 0.174.70 ± 0.08
      GSD ± SD1.65 ± 0.061.60 ± 0.001.63 ± 0.05
      FPF < 5 μm [%] ± SD54.36 ± 2.555.14 ± 2.554.70 ± 1.72

      2.3 Literature search

      In order to get additional information about the compatibility/stability of mixed nebulizer solutions/suspensions for inhalation therapy we searched the literature databases “Medline” and “International Pharmaceutical Abstracts” for combinations of the terms “nebulizer solution”, “inhalation”, “aerosol”, “compatibility”, “stability”, “combination”, “HPLC”, and “aerodynamic behavior”.

      3. Results and discussion

      Both, the results of our own experimental studies and of the literature search are presented together for the respective nebulizable drug mixtures. (In)compatibility results for the eight most commonly used drugs in inhalation therapy are finally summarized in table format (Table 4). Further we introduce particular tripartite and quadripartite mixtures analyzed for physico-chemical compatibility and discuss the impact of certain excipients commonly used to formulate nebulizer solutions, i.e. preservatives and stabilizers. Finally, we present results from our aerodynamic studies performed with cascade impaction.
      Table 4Physico-chemical compatibility of inhalation solutions/suspensions. No sufficient information available for yellow marked combinations. *Mixtures not recommendable from a clinical viewpoint. **Compatibility applies only to preservative-free dosage forms. #Unchanged aerosol characteristics and drug output have been proved.
      Table thumbnail t1

      3.1 Dornase alfa

      Dornase alfa (Pulmozyme®) is a mucolytic drug substance that decreases viscoelasticity and adherence of sputum, improves lung function and reduces respiratory exacerbations in cystic fibrosis (CF) patients. Administration is usually carried out via jet nebulizers, but a recent study indicates that perforated vibrating membrane devices deliver the drug more efficiently [
      • Scherer T.
      • Geller D.E.
      • Owyang L.
      • Tservistas M.
      • Keller M.
      • Boden N.
      • et al.
      A technical feasibility study of dornase alfa delivery with eFlow® vibrating membrane nebulizers: aerosol characteristics and physicochemical stability.
      ].
      CF patients often mix dornase alfa with bronchodilatators like ipratropium bromide (Atrovent® and Atrovent® Fertiginhalat) and albuterol (Sultanol® and Sultanol® forte Fertiginhalat). Our studies revealed that dornase alfa activity is affected by benzalkonium chloride, used as excipient in Atrovent® and Sultanol®, and disodium edetate used as an excipient in Atrovent®. But in the mixtures of Pulmozyme® with the preservative-free single dosage forms of Atrovent® 500 mg/2 mL Fertiginhalat or Sultanol® forte 2.5 mg/2.5 mL Fertiginhalat a decrease of dornase alfa activity was hardly measurable. Thus, these mixtures are most probably compatible [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ]. To ensure this designation a more precise assay for determination of dornase alfa activity has to be applied and the nebulization properties of the proposed inhalation mixture have to be studied. Correspondent experimental studies were later on performed for mixtures of dornase alfa and tobramycin (see following paragraph). Ipratropium bromide and albuterol concentrations were not affected by mixing the drug products [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ].
      Concomitant inhalation of dornase alfa and antibiotics seems to be advantageous for antipseudomonal treatment [
      • Yang Y.
      • Tsifansky M.D.
      • Wu C.J.
      • Yang H.I.
      • Schmidt G.
      • Yeo Y.
      Inhalable antibiotic delivery using a dry powder co-delivering recombinant deoxyribonuclease and ciprofloxacin for treatment of cystic fibrosis.
      ] and thus, in daily practice many CF patients mix the drug with antibiotics, mainly tobramycin, which is available on the market in different formulations manufactured by different pharmaceutical companies. We analyzed activity and stability of dornase alfa after it was mixed with Tobi®, Bramitob® or Gernebcin®. We found no physical incompatibilities or decomposition in mixtures with Tobi® and Bramitob® [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
      ], whereas the mixture with Gernebcin® is designated as incompatible. Results indicated that dornase alfa activity was especially affected by sodium metabisulfite used as an excipient in Gernebcin® (not in Tobi® and Bramitob®), since the activity loss was most pronounced when Pulmozyme® was mixed with pure solutions of sodium metabisulfite [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
      ]. Tobramycin concentrations were not affected in any of the mixtures.
      Mixed inhalation solutions of dornase alfa and the corticosteroid fluticasone-17-propionate (Flutide® forte Fertiginhalat) are considered as incompatible. Enzymatic activity of dornase alfa measured at room temperature declined from initially 93% of nominal activity to 72% after 24 h, probably due to the phosphate buffer used in Flutide® forte. Dornase alfa activity was hardly impaired in mixtures with the corticosteroid budesonide (Pulmicort®). Enzymatic activities measured up to a 31 hour interval after mixing resulted in at least 86% of the nominal activity and the mixtures were designated as compatible [
      • Krämer I.
      • Schwabe A.
      • Kamin W.
      Physikalisch-chemische Kompatibilität von Mischinhalationslösungen und -suspensionen zur simultanen Feuchtinhalationstherapie bei Mukoviszidosepatienten.
      ].

      3.2 Antibiotics

      3.2.1 Tobramycin

      We investigated the compatibility of tobramycin and colistimethate nebulizable drug admixtures although we are aware that at present simultaneous inhalation is not an accepted standard in cystic fibrosis patients. However, mixing both antibiotics is practiced by patients, especially for treatment of mucoid Pseudomonas aeruginosa infections [
      • Berlana D.
      • Llop J.M.
      • Manresa F.
      • Jodar R.
      Outpatient treatment of Pseudomonas aeruginosa bronchial colonization with long-term inhaled colistin, tobramycin, or both in adults without cystic fibrosis.
      ]. If antibiotic combination therapy via inhalation becomes clinically relevant, the physico-chemical compatibility of tobramycin and colistimethate is one of the prerequisites for simultaneous inhalation. Our study revealed that neither colistimethate nor tobramycin showed any losses of antibiotic potency after mixing. Values of pH and osmolality remained unchanged [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing colistimethate and tobramycin.
      ].
      Physico-chemical compatibility of tobramycin (Nebcin®, 40 mg/mL) and albuterol (Ventolin®) has been proven earlier [
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      ]. Our compatibility studies concerning mixtures of tobramycin (Tobi® and Gernebcin®) with the corticosteroids fluticasone-17-propionate (Flutide® forte Fertiginhalat) or budesonide (Pulmicort®) revealed that eight hours after mixing tobramycin concentrations remained unchanged, i.e. at a minimum of 96% of the nominal concentration [
      • Krämer I.
      • Schwabe A.
      • Kamin W.
      Physikalisch-chemische Kompatibilität von Mischinhalationslösungen und -suspensionen zur simultanen Feuchtinhalationstherapie bei Mukoviszidosepatienten.
      ].

      3.2.2 Colistimethate

      Pulmonary infections with Gram-negative bacteria resistant to tobramycin or other antibiotics in CF patients may require the inhalation of colistimethate in addition to standard inhalation therapy. Thus, we tested the physico-chemical compatibility of a quadripartite mixture containing colistimethate (Colistin CF) and the anticholinergic ipratropium bromide (preservative-free dosage form of Atrovent®), the β2-agonist albuterol (preservative-free dosage form of Sultanol® forte), and the corticosteroid fluticasone-17-propionate (preservative-free Flutide® forte). Based on the results (see Section 3.9) we assume that incompatibilities in duplicate and triplicate mixtures containing colistimethate and one or two of the tested substances are unlikely. But results apply only to the preservative-free single dose formulations of these drugs [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ].
      Compatibility of colistimethate (Colistin® CF) and the glucocorticoid budesonide (Pulmicort®) was also tested. The duplicate mixture showed no loss in drug concentration of budesonide and no change in antibiotic activity of colistimethate over a period of 24 h after mixing. During the first six hours after mixing an increase of the pH (5.5 to 7.3) was measured [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
      ] and according to the definition of compatibility the mixture is to be categorized as incompatible. But because no other parameters, i.e. osmolality and physical appearance, were altered and chemical stability of the active substances was given over a period of 24 h, we judged mixtures of Colistin® CF and Pulmicort® to be physico-chemically compatible [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
      ].
      We also studied compatibility of admixtures containing colistimethate and 5.85% sodium chloride solution, since nebulized hypertonic saline solution has been established as an effective adjunctive therapy for respiratory symptoms in CF patients [
      • Wark P.A.
      • McDonald V.
      • Jones A.P.
      Nebulised hypertonic saline for cystic fibrosis.
      ,
      • Elkins M.R.
      • Robinson M.
      • Rose B.R.
      • Harbour C.
      • Moriarty C.P.
      • Marks G.B.
      • et al.
      A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis.
      ]. We found the mixture to be physico-chemically compatible and stable over a period of 48 h stored under refrigeration [
      • Krämer I.
      • Walz-Jung H.
      • Stanko C.
      • Kamin W.
      Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
      ].

      3.3 Ipratropium bromide

      We evaluated the physico-chemical compatibility of the anticholinergic ipratropium bromide (Atrovent® LS), the β2-agonist albuterol (Sultanol®) and the corticosteroid fluticasone-17-propionate (Flutide® forte) by experimental studies of the tripartite mixture with validated analytical assays (see Section 3.9). We found compatibility over a period of five hours, i.e. almost no changes in drug concentrations, pH and osmolality could be detected and no visible changes occurred [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ]. Thus, we consider the duplicate mixtures of these drug products to be compatible.
      Compatibility of different formulations of ipratropium bromide (Atrovent®, Duovent®, i.e. fenoterol plus ipratropium) and budesonide (Pulmicort®) were tested by different working groups. No evidence of any physico-chemical incompatibility was found [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort) with other nebulization products (Abstract). Personal communication. 2001.

      ].
      When ipratropium bromide and cromolyn (Intal®) containing inhalation solutions were mixed compatibility was given only with the preservative-free formulation of Atrovent® [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ,
      • Kramer I.
      • Klemmer A.
      Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
      ,
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      ].
      Finally, a study from China raised concerns about the packaging material of ipratropium bromide containing aerosol products. Yue et al. [
      • Yue Z.H.
      • Shen D.D.
      • Hu C.Q.
      The compatibility between packing material and ipratropium bromide aerosol.
      ] reported that the active substance is absorbed and leachable additives from the primary package may be present in the drug solution.

      3.4 Albuterol and levalbuterol

      In Europe the most common β2-agonist prescribed is albuterol, but its stereoisomer levalbuterol is widely used in the US. Both substances have similar pharmacokinetic and pharmacodynamic properties. We concentrated on albuterol whereas in one recently published study the compatibility of different duplicate mixtures containing levalbuterol was evaluated.

      3.4.1 Albuterol

      In several studies the compatibility and stability of mixtures of albuterol and ipratropium bromide was proven [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ,
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      ,
      • Jacobson G.A.
      • Peterson G.M.
      Stability of ipratropium bromide and salbutamol nebuliser admixtures.
      ]. Moreover, there are combination products for nebulization available which contain both albuterol and ipratropium bromide, e.g. Berodual® LS in Germany and DuoNeb® in the US. For these products stability is proven.
      Several studies proved the compatibility of albuterol (Proventil® or Xopenex®) and budesonide (Pulmicort®) [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ]. Recently Melani [
      • Melani A.S.
      Effects on aerosol performance of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide.
      ] tested the aerosol characteristics of this particular drug mixture (see Section 3.11.).
      The mixture of albuterol (Ventolin®) and cromolyn (Intal®) was also found to be compatible [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical-chemical compatibility of cromolyn sodium nebulizer solution: bronchodilator inhalant solution admixtures.
      ].

      3.4.2 Levalbuterol

      Bonasia et al. [
      • Bonasia P.J.
      • McVicar W.K.
      • Bill W.
      • Ong S.
      Chemical and physical compatibility of levalbuterol inhalation solution concentrate mixed with budesonide, ipratropium bromide, cromolyn sodium, or acetylcysteine sodium.
      ] investigated several two-drug admixtures of levalbuterol by visual inspection, pH measurement and high performance liquid chromatography (HPLC assays). For duplicate nebulizable drug admixtures containing levalbuterol and budenoside, ipratropium bromide, cromolyn (DNCG), or acetylcysteine sodium no evidence of physical incompatibility and/or chemical decomposition were registered over a period of at least 30 minute storage at room temperature.
      Yamreudeewong et al. evaluated the stability of a mixture containing levalbuterol and ipratropium over a period of 28 days at room temperature. They found no significant decrease in concentrations of the active drugs, i.e. decrease in concentration of each drug was below 10% of the initial concentration [
      • Yamreudeewong W.
      • Teixeira M.
      • Mayer G.
      Stability of levalbuterol in a mixture of levalbuterol and ipratropium nebulizer solution.
      ].

      3.5 Budesonide

      Compatibility of budesonide and cromolyn is known [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz-Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      ]. When budesonide nebulizable suspension (Pulmicort®) was mixed with 5.85% sodium chloride solution no loss in drug concentration of budesonide was detected over a test period of 24 h. Osmolality and pH remained unchanged and visual inspection revealed no abnormality [
      • Klemmer A.
      • Krämer I.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
      ].

      3.6 Cromolyn

      Although cromolyn is not a standard therapy in cystic fibrosis we decided to report compatibility with other nebulizable drug products. As stated before [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ], 7% of patients at our CF center reported inhaling cromolyn mixed with other drugs and prescribing information about miscibility with cromolyn is not consistent. Information about compatibility is reported in the above 3.3, 3.4.1, 3.5.

      3.7 Hypertonic sodium chloride solution

      We determined the physico-chemical compatibility of 5.85% sodium chloride (NaCl) solution with either colistimethate (see Section 3.2.2) or budesonide (see Section 3.5). Fox et al. [
      • Fox L.M.
      • Foushee J.A.
      • Jackson D.J.
      • Watson H.
      Visual compatibility of common nebulizer medications with 7% sodium chloride solution.
      ] assessed the physical compatibility of eleven nebulizable drug products with 7% sodium chloride solution. The duplicate mixtures of 7% NaCl solution and acetylcysteine, albuterol, atropine, cromolyn sodium, dexamethasone, glycopyrrolate, ipratropium, metaproterenol, sodium bicarbonate, terbutaline, or tobramycin were analyzed by serial turbidimetric testing and visual inspection. The authors stated compatibility for all different mixtures, except for cromolyn sodium, which was found to be visually incompatible with 7% NaCl solution.

      3.8 Miscellaneous

      Formoterol and arformoterol were analyzed by Akapo et al. [
      • Akapo S.
      • Gupta J.
      • Martinez E.
      • McCrea C.
      • Ye L.
      • Roach M.
      Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions.
      ] with regard to physico-chemical compatibility and aerodynamic characteristics (see Section 3.11) of different duplicate mixtures. They found compatibility for formoterolfumarate 20 mg/2 ml when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 ml, ipratropium bromide 0.5 mg/2.5 ml, cromolyn sodium 20 mg/2 ml, or 10% acetylcysteine solution (100 mg/ml). However, mixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization and the authors emphasize that clinical implications of the in vitro data have not been determined.
      The chemical and physical compatibility of duplicate mixtures of arformoterol (15 mg/2 ml) with ipratropium bromide (0.5 mg/2.5 ml), acetylcysteine (800 mg/4 ml), or budesonide (0.25 mg/2 ml and 0.5 mg/2 ml) was tested. Visual inspection, pH measurement, and HPLC assays of each active component revealed no signs of incompatibility in any of these mixtures [
      • Bonasia P.
      • Cook C.
      • Cheng Y.
      • Ong S.
      Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs.
      ].

      3.9 Tripartite and quadripartite mixtures

      We analyzed several tripartite mixtures containing the anticholinergic ipratropium bromide (Atrovent® LS) and the β2-agonist albuterol (Sultanol®). Physico-chemical compatibility was proven with fluticasone-17-propionate (Flutide® forte) [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ]. Mixtures of albuterol, tobramycin and ipratropium bromide (no information available about studied brands) were found to be compatible, too [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ].
      In mixtures with cromolyn (Intal®) compatibility is given for mixtures prepared with the preservative-free single use dosage forms Atrovent® Fertiginhalat and Sultanol® forte Fertiginhalat [
      • Kramer I.
      • Klemmer A.
      Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
      ]. Compatibility seemed to be affected by certain excipients like benzalkonium chloride. In order to minimize the risk of physical incompatibility, only preservative-free formulations of albuterol or ipratropium bromide inhalation solutions should be mixed with Intal® [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Kramer I.
      • Klemmer A.
      Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
      ].
      Comparable results were obtained after mixing ipratropium bromide and albuterol with dornase alfa (Pulmozyme®). Dornase alfa activity was more compromised in mixtures containing the excipients benzalkonium chloride and disodium edetate. Thus, the preservative-free single use dosage forms Atrovent® Fertiginhalat and Sultanol® forte Fertiginhalat are designated as mixable with Pulmozyme® without reducing the efficacy of dornase alfa [
      • Kramer I.
      • Schwabe A.
      • Lichtinghagen R.
      • Kamin W.
      Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
      ].
      The compatibility of Berodual® and Pulmicort® was tested in an experimental setting. The tripartite mixture, i.e. Berodual® which contains ipratropium bromide and fenoterol, turned out to be physico-chemically compatible [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
      ,
      • Kramer I.
      • Klemmer A.
      Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
      ].
      We analyzed the physico-chemical compatibility of colistimethate (Colistin CF), fluticasone-17-propionate (Flutide® forte), ipratropium bromide and albuterol. This quadripartite mixture was found to be compatible, but only when preservative-free single-dose formulations of the drug products (Atrovent® Fertiginhalat, Sultanol® forte Fertiginhalat) were used (Table 2).

      3.10 Excipients

      Many multiple dosage forms of inhalative drugs contain not only the active agent but also excipients as preservatives and stabilizers, e.g. benzalkonium chloride, disodium edetate, and sodium metabisulfite. Our studies revealed that most probably these additives are responsible for detected incompatibilities, e.g. limited activity of dornase alfa (Pulmozyme®) and colistimethate (Colistin® CF). Hence, patients should be informed about possible incompatibilities caused by excipients and should be educated to check the excipients declared on the package and package insert of each medicinal product.

      3.11 Aerosol characteristics

      Aerosol output of the nebulizer and particle size distribution of the aerosol produced are the most important issues for successful inhalation therapy, since particle size influences the deposition pattern and bioavailability of drugs delivered to the respiratory system [
      • Pilcer G.
      • Amighi K.
      Formulation strategy and use of excipients in pulmonary drug delivery.
      ]. Special conditions are required for an effective inhalation therapy of infants and young children [
      • Amirav I.
      • Newhouse M.T.
      • Minocchieri S.
      • Castro-Rodriguez J.A.
      • Schuepp K.G.
      Factors that affect the efficacy of inhaled corticosteroids for infants and young children.
      ]. To figure out if mixing of dornase alfa (Pulmozyme®) and tobramycin (Tobi® and Bramitob®) causes changes in particle size distribution, the physico-chemical compatible admixtures (see Section 3.1) were nebulized with the PARI eFlow® rapid. Aerosol characteristics, i.e. MMAD, GSD and FPF, of dornase alfa were assessed via cascade impaction with the NGI. SE-HPLC was used to assess the dornase alfa concentrations deposited on the impactor stages. The aerosol patterns of admixtures of dornase alfa and tobramycin were compared to those of dornase alfa diluted with 0.9% sodium chloride solution in order to achieve the same volume. There was no difference in particle size distribution, MMAD, GSD and FPF (Table 3).
      Melani [
      • Melani A.S.
      Effects on aerosol performance of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide.
      ] evaluated the aerosol output, drug output, and aerosol particle size characteristics of two corticosteroids (budesonide, beclomethasone dipropionate) and two bronchodilators (albuterol, ipratropium bromide) when nebulized alone or in tripartite mixtures (budesonide or beclomethasone and albuterol and ipratropium).
      Using the SideStream and VentStream-Pro nebulizers, run with the AirClinic compressor, the author found that mixing reduced drug output and increased mass median aerodynamic diameter (MMAD) with the SideStream, but not always with the VentStream-Pro. However, drug output and MMAD never reached critical values, i.e. outside the respirable range. When nebulized alone, the respirable mass of bronchodilators ranged from 18% to 40% of the nominal dose compared to 13% to 37% when mixed. The respirable mass of corticosteroids nebulized alone ranged from 10% to 24% of the nominal dose, in mixtures it ranged from 10% to 17%. Hence, both nebulizers can be recommended in terms of aerosol performance for inhalation therapy with these particular drug mixtures.
      Akapo et al. [
      • Akapo S.
      • Gupta J.
      • Martinez E.
      • McCrea C.
      • Ye L.
      • Roach M.
      Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions.
      ] assessed the aerodynamic characteristics of formoterol fumarate (20 mg/2 ml) when mixed or sequentially nebulized with budesonide inhalation suspension (0.5 mg/2 ml), ipratropium bromide (0.5 mg/2.5 ml), cromolyn sodium (20 mg/2 ml), or acetylcysteine 10% (100 mg/ml). Aerosols were generated with a Pari LC Plus® nebulizer and characterized by using an 8-stage cascade impactor. They found a significantly increased respirable fraction/delivered dose (p < 0.05) for the mixed or sequentially nebulized drugs and assume that this was due to an increased drug volume or reconcentration in the nebulizer cup by sequential nebulization. Both facts decreased the amount of drugs retained in the dead volume. In contrast, the FPF, MMAD, and GSD generally remained unchanged for all admixtures, except for the FPF of the formoterol/budesonide combination. This may be caused by polysorbate 80 used as surfactant in the budesonide formulation. The authors conclude that mixing or sequential nebulization significantly increases the amount of drug delivered compared with single drug nebulization.
      Itazawa et al. [
      • Itazawa T.
      • Adachi Y.
      • Ito Y.
      • Higuchi O.
      • Mochizuki H.
      • Shimojo N.
      • et al.
      Aerosol characteristics of admixture of budesonide inhalation suspension with a beta2-agonist procaterol.
      ] analyzed the aerosol characteristics of a duplicate mixture containing budesonide (Pulmicort®) and the β2-agonist procaterol (Meptin®). They found no relevant differences in drug output and particle size distribution with regard to budesonide when nebulized alone or in the admixture. In contrast, they detected a significantly higher amount of delivered procaterol and a higher rate of smaller particle sizes containing procaterol in the admixture compared to the unmixed solution.
      The physico-chemical compatible tripartite mixture containing fluticasone-17-propionate (Flutide® forte), albuterol (Sultanol® forte Fertiginhalat) and ipratropium bromide (Atrovent® Fertiginhalat) [
      • Kamin W.
      • Schwabe A.
      • Kramer I.
      Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
      ] was nebulized by Stanko and the aerosol characteristics were analyzed. Particle size distribution, MMAD, GSD, and FPF were assessed via cascade impaction and results revealed no relevant changes [
      • Kramer I.
      • Klemmer A.
      Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
      ].

      4. Conclusion

      Our in vitro studies and search of relevant literature indicate that most of the tested nebulizer suspensions are mixable without provoking any measurable incompatibilities. A major exception is dornase alfa. Its activity was affected by certain excipients contained in some of the drug products. The same excipients caused incompatibility when albuterol and/or ipratropium bromide was mixed with cromolyn or colistimethate.
      Mixtures should always be prepared directly before inhalation and surplus quantities should be discarded.
      Only a limited number of mixtures have been tested yet with regard to aerosol characteristics. More studies assessing particle size distribution of common mixtures administered with popular nebulizers are needed.
      Finally, the clinical efficacy of inhalation therapy with duplicate, tripartite or even quadripartite mixtures must be evaluated in comparison to consecutive inhalation of the same drugs, before final recommendations for patients can be made.

      Acknowledgments

      The authors gratefully acknowledge the efforts in data collection of Anja Klemmer, Astrid Schwabe, Christine Stanko and Hannah Walz-Jung.

      References

        • Virchow J.C.
        What plays a role in the choice of inhaler device for asthma therapy?.
        Curr Med Res Opin. 2005; 21: S19-S25
        • Dolovich M.B.
        • Ahrens R.C.
        • Hess D.R.
        • Anderson P.
        • Dhand R.
        • Rau J.L.
        • et al.
        Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.
        Chest. 2005; 127: 335-371
        • Scherer T.
        • Geller D.E.
        • Owyang L.
        • Tservistas M.
        • Keller M.
        • Boden N.
        • et al.
        A technical feasibility study of dornase alfa delivery with eFlow® vibrating membrane nebulizers: aerosol characteristics and physicochemical stability.
        J Pharm Sci. 2011; 100: 98-109
        • Pitance L.
        • Reychler G.
        • Leal T.
        • Reychler H.
        • Liistro G.
        • Montharu J.
        • et al.
        Aerosol delivery to the lung is more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer.
        J Aerosol Med Pulm Drug Deliv. 2013; 26: 208-214
        • Arzhavitina A.
        • Steckel H.
        Surface active drugs significantly alter the drug output rate from medical nebulizers.
        Int J Pharm. 2010; 384: 128-136
        • Coates A.L.
        • MacNeish C.F.
        • Meisner D.
        • Kelemen S.
        • Thibert R.
        • MacDonald J.
        • et al.
        The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols.
        Chest. 1997; 111: 1206-1212
        • Sidler-Moix A.L.
        • Dolci U.
        • Berger-Gryllaki M.
        • Pannatier A.
        • Cotting J.
        • Di Paolo E.R.
        Albuterol delivery in an in vitro pediatric ventilator lung model: comparison of jet, ultrasonic, and mesh nebulizers.
        Pediatr Crit Care Med. 2013; 14: e98
        • Berlinski A.
        • Willis J.R.
        Albuterol delivery by 4 different nebulizers placed in 4 different positions in a pediatric ventilator in-vitro model.
        Respir Care. 2013; 58: 1124-1133
        • Rosenfeld M.
        • Emerson J.
        • Astley S.
        • Joy P.
        • Williams-Warren J.
        • Standaert T.A.
        • et al.
        Home nebulizer use among patients with cystic fibrosis.
        J Pediatr. 1998; 132: 125-131
        • Kamin W.
        • Schwabe A.
        • Kramer I.
        Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers.
        J Cyst Fibros. 2006; 5: 205-213
        • Akapo S.
        • Gupta J.
        • Martinez E.
        • McCrea C.
        • Ye L.
        • Roach M.
        Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions.
        Ann Pharmacother. 2008; 42: 1416-1424
        • Clay M.M.
        • Pavia D.
        • Newman S.P.
        • Lennard-Jones T.
        • Clarke S.W.
        Assessment of jet nebulisers for lung aerosol therapy.
        Lancet. 1983; 2: 592-594
        • McKenzie J.
        • Gronberg S.
        • Cruz Rivera M.
        • et al.
        Budesonide inhalation suspension can be nebulized with solutions containing albuterol sulphate.
        Chest [Poster]. 2002; 122 ([poster]) ([Suppl.])
        • Smaldone G.C.
        • McKenzie J.
        • Cruz Rivera M.
        Effect of nebulizer volume on drug delivery: budesonide inhalation suspension.
        Am J Respir Crit Care Med. 2000; 161
        • Boe J.
        • Dennis J.H.
        • O'Driscoll B.R.
        • Bauer T.T.
        • Carone M.
        • Dautzenberg B.
        • et al.
        European Respiratory Society Guidelines on the use of nebulizers.
        Eur Respir J. 2001; 18: 228-242
        • Burchett D.K.
        • Darko W.
        • Zahra J.
        • Noviasky J.
        • Probst L.
        • Smith A.
        Mixing and compatibility guide for commonly used aerosolized medications.
        Am J Health Syst Pharm. 2010; 67: 227-230
        • Krämer I.
        • Walz-Jung H.
        • Stanko C.
        • Kamin W.
        Physicochemical compatibility of nebuliser solution admixtures containing colistimethate and hypertonic saline or colistimethate, fluticasone-17- propionate, ipratropium bromide and salbutamol sulphate.
        Eur J Hosp Pharm Sci Pract. 2012; 19: 1-6
        • Kramer I.
        • Schwabe A.
        • Lichtinghagen R.
        • Kamin W.
        Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.
        Pediatr Pulmonol. 2009; 44: 134-141
        • Kamin W.
        • Schwabe A.
        • Kramer I.
        Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.
        Int J Chron Obstruct Pulmon Dis. 2007; 2: 599-607
        • Kramer I.
        • Schwabe A.
        • Lichtinghagen R.
        • Kamin W.
        Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.
        Pharmazie. 2007; 62: 760-766
        • Klemmer A.
        • Krämer I.
        • Kamin W.
        Physicochemical compatibility and stability of nebulizable drug admixtures containing dornase alfa and tobramycin.
        Pulm Pharmacol Ther. 2013; ([Submitted and currently under review])
        • Klemmer A.
        • Krämer I.
        • Kamin W.
        Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline.
        Int J Pharm Compd. 2013; ([accepted for publication])
        • Blewett A.J.
        • Varma D.
        • Gilles T.
        • Butcher R.
        • Jacob J.
        • Amazan J.
        • et al.
        Development and validation of a stability-indicating high-performance liquid chromatography method for the simultaneous determination of albuterol, budesonide, and ipratropium bromide in compounded nebulizer solutions.
        J AOAC Int. 2011; 94: 110-117
        • Yang Y.
        • Tsifansky M.D.
        • Wu C.J.
        • Yang H.I.
        • Schmidt G.
        • Yeo Y.
        Inhalable antibiotic delivery using a dry powder co-delivering recombinant deoxyribonuclease and ciprofloxacin for treatment of cystic fibrosis.
        Pharm Res. 2010; 27: 151-160
        • Krämer I.
        • Schwabe A.
        • Kamin W.
        Physikalisch-chemische Kompatibilität von Mischinhalationslösungen und -suspensionen zur simultanen Feuchtinhalationstherapie bei Mukoviszidosepatienten.
        Krankenhauspharmazie. 2007; 28: 170-178
        • Berlana D.
        • Llop J.M.
        • Manresa F.
        • Jodar R.
        Outpatient treatment of Pseudomonas aeruginosa bronchial colonization with long-term inhaled colistin, tobramycin, or both in adults without cystic fibrosis.
        Pharmacotherapy. 2011; 31: 146-157
        • Klemmer A.
        • Krämer I.
        • Kamin W.
        Physicochemical compatibility of nebulizable drug admixtures containing colistimethate and tobramycin.
        Pharmazie. 2013; ([accepted for publication])
        • Gooch M.D.
        Stability of albuterol and tobramycin when mixed for aerosol administration.
        Respir Care. 1991; 36: 1387-1390
        • Wark P.A.
        • McDonald V.
        • Jones A.P.
        Nebulised hypertonic saline for cystic fibrosis.
        Cochrane Database Syst Rev. 2005; : CD001506
        • Elkins M.R.
        • Robinson M.
        • Rose B.R.
        • Harbour C.
        • Moriarty C.P.
        • Marks G.B.
        • et al.
        A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis.
        N Engl J Med. 2006; 354: 229-240
        • Smaldone G.C.
        • McKenzie J.
        • Cruz Rivera M.
        • Hoag J.
        Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
        Chest. 2000; 118
      1. Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort) with other nebulization products (Abstract). Personal communication. 2001.

        • Iacono M.
        • Johnson G.J.
        • Bury R.W.
        An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
        Aust J Hosp Pharm. 1987; 17: 158-161
        • Kramer I.
        • Klemmer A.
        Physico-chemical compatibility: beta-sympathomimetics and other drugs for aerosol inhalation treatment.
        Pharm Unserer Zeit. 2011; 40: 403-409
        • Nagtegaal J.E.
        • De Jong A.
        • De Waard W.J.
        • Van der Meer Y.G.
        Formulation and shelf life of two solutions for inhalation.
        Ziekenhuisfarmacie. 1997; 13: 23-29
        • Yue Z.H.
        • Shen D.D.
        • Hu C.Q.
        The compatibility between packing material and ipratropium bromide aerosol.
        Yao Xue Xue Bao. 2010; 45: 1035-1038
        • Jacobson G.A.
        • Peterson G.M.
        Stability of ipratropium bromide and salbutamol nebuliser admixtures.
        Int J Pharm Pract. 1995; 3: 169-173
        • Melani A.S.
        Effects on aerosol performance of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide.
        Respir Care. 2011; 56: 319-326
        • Emm T.
        • Metcalf J.E.
        • Lesko L.J.
        • Chai M.F.
        Update on the physical-chemical compatibility of cromolyn sodium nebulizer solution: bronchodilator inhalant solution admixtures.
        Ann Allergy. 1991; 66: 185-189
        • Bonasia P.J.
        • McVicar W.K.
        • Bill W.
        • Ong S.
        Chemical and physical compatibility of levalbuterol inhalation solution concentrate mixed with budesonide, ipratropium bromide, cromolyn sodium, or acetylcysteine sodium.
        Respir Care. 2008; 53: 1716-1722
        • Yamreudeewong W.
        • Teixeira M.
        • Mayer G.
        Stability of levalbuterol in a mixture of levalbuterol and ipratropium nebulizer solution.
        Hosp Pharm. 2008; 43: 303-306
        • McKenzie J.E.
        • Cruz-Rivera M.
        Compatibility of budesonide inhalation suspension with four nebulizing solutions.
        Ann Pharmacother. 2004; 38: 967-972
        • Fox L.M.
        • Foushee J.A.
        • Jackson D.J.
        • Watson H.
        Visual compatibility of common nebulizer medications with 7% sodium chloride solution.
        Am J Health Syst Pharm. 2011; 68: 1032-1035
        • Bonasia P.
        • Cook C.
        • Cheng Y.
        • Ong S.
        Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs.
        Curr Med Res Opin. 2007; 23: 2477-2483
        • Pilcer G.
        • Amighi K.
        Formulation strategy and use of excipients in pulmonary drug delivery.
        Int J Pharm. 2010; 392: 1-19
        • Amirav I.
        • Newhouse M.T.
        • Minocchieri S.
        • Castro-Rodriguez J.A.
        • Schuepp K.G.
        Factors that affect the efficacy of inhaled corticosteroids for infants and young children.
        J Allergy Clin Immunol. 2010; 125: 1206-1211
        • Itazawa T.
        • Adachi Y.
        • Ito Y.
        • Higuchi O.
        • Mochizuki H.
        • Shimojo N.
        • et al.
        Aerosol characteristics of admixture of budesonide inhalation suspension with a beta2-agonist procaterol.
        Allergol Int. 2013; 62: 131-135