In contrast to the compounds described above, there is only a very limited number of studies investigating particle production and administration of different macrolides to the lung via aerosol, even though such type of therapy would be of benefit due to is anti-inflammatory, immunomodulatory, and antimicrobial effects (Tables 1 and 2), although there are differences between various macrolides regarding their properties (Brodt et al. 2013; Altenburg et al. 2011a; Culic et al. 2001). In vitro studies investigating physicochemical properties of aerosols demonstrated that macrolide aerosol particles may serve for inhalation and will achieve sufficient lung deposition. Animal studies demonstrated feasibility of pulmonary macrolide administration and showed that higher concentrations in alveolar macrophages (AM) and epithelial lining fluid (ELF) than in plasma were achieved after aerosol than after oral administration. The results of relevant studies are described below in more detail.

Hickey et al. (2006) investigated characteristics of azithromycin aerosols delivered from three different nebulizers (Acorn II, Updraft RCI, and Pari LC Plus) operated at 8 l/min with concentrations of 10 mg/ml, 50 mg/ml, and 100 mg/ml and filling volumes of 5 ml, 12 ml, and 5 ml, respectively. Particle size analysis was performed by means of inertial impaction and laser diffraction and emitted doses were determined. In the Acorn II nebulizer there was an effect of the azithromycin concentration on the mass median aerodynamic diameter (MMAD) resulting in an increase from 1.4 ± 0.1 μm to 1.8 ± 0.1 μm, and 1.9 ± 0.2 μm at concentrations of 10 mg/ml, 50 mg/ml, and 100 mg/ml, respectively. Fine particle fraction (FPF) <2.1 μm was highest at 10 mg/ml with values of 70.0 ± 2.0 %, 52.0 ± 1.0 %, and 53.7 ± 3.8 %, whereas there was no difference in FPF <4.7 μm with values of 86.7 ± 2.1 %, 86.0 ± 1.0 %, and 85.3 ± 1.5 %, respectively. Correspondingly, fine particle doses (FPD) and dose rates strongly increased with azithromycin concentration. The experiments with azithromycin concentration of 100 mg/ml demonstrated highest MMAD for the Updraft nebulizer (2.8 ± 0.1 μm), followed by LC Plus and Acorn nebulizers (2.2 ± 0.1 μm and 1.9 ± 0.2 μm, respectively). FPF <2.1 μm was highest in the Acorn nebulizer (53.7 ± 3.8 %), followed by LC Plus and Updraft nebulizers (41.7 ± 1.5 % and 35.0 ± 2.0 %, respectively). However, FPF <4.7 μm was highest in Acorn and LC Plus nebulizers (85.3 ± 1.5 % and 85.3 ± 0.6 %, respectively) and lowest in the Updraft nebulizer (75.3 ± 2.5 %). FPD <2.1 μm, FPD <4.7 μm, and emitted dose rates were highest for the LC Plus nebulizer (23.0 ± 0.4 mg/min, 47.0 ± 0.3 mg/min, and 55.1 ± 1.5 mg/min, respectively) and lowest for the Updraft nebulizer (5.6 ± 0.3 mg/min, 12.1 ± 0.4 mg/min, and 16.1 ± 1.1 mg/min, respectively). In summary, it was shown that of the nebulizers and experimental conditions investigated the best results for pulmonary aerosol deposition were found for the LC Plus nebulizer and the azithromycin concentration of 100 mg/ml.

In another study Pilcer et al. (2013) investigated co-spray dried porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Co-administration of both antibiotics would result in an improved penetration and efficiency of tobramycin due to enhanced clarithromycin-induced biofilm destruction and reductions of required daily doses, costs of treatment, and improved patient compliance and clinical outcomes (Tre-Hardy et al. 2010). However, both compounds differ strongly regarding their physicochemical properties; tobramycin is highly soluble in water as opposed to clarithromycin. That raises potential problems in cases of co-administration, due to differences in particle desagglomeration within the inhalation process and in the release of the compounds after pulmonary deposition which may cause lung irritation and excessive non-absorptive clearance of solid particles by macrophage phagocytosis or mucociliary clearance followed by a rapid dose reduction in the lung. Pilcer et al. (2013) characterized particles consisting of tobramycin-clarithromycin in a ratio of 10:1 and surfactant (2 % Na glycocholate) by a number of methods including laser diffraction, scanning electron microscopy (SEM), X-ray powder diffraction, thermo gravimetric analysis, aerodynamic particle size analysis by means of a next-generation impactor (NGI), considering the requirements of the European Pharmacopoeia (Eur. Ph. 7) and U.S. Pharmacopeia (USP35) for testing of aerodynamic behavior, and dissolution tests followed by high performance liquid chromatography (HPLC). In brief, the authors observed that local drug deposition profiles were similar for tobramycin and clarithromycin, which allows both antibiotics to reach the target simultaneously, and both drugs might dissolve without any difficulties in the lung. The fine particle fractions (FPF) of a spray-dried formulation were 63 ± 2 % and 62 ± 2 % for tobramycin and clarithromycin compared with 35 ± 4 % and 31 ± 4 % for the physical blend measured with an NGI at 100 l/min with a withdrawal of air of 4 l. Even reductions of the flow (40 l/min, withdrawal 4 l; and 60 l/min, withdrawal 2 l) were followed by only a minor reduction of FPF of the spray-dried formulation (52 ± 2 % and 51 ± 2 % vs. 10 ± 3 % and 6 ± 3 %; and 53 ± 2 % and 50 ± 2 % vs. 19 ± 2 % and 15 ± 2 %, respectively) indicating that infected lung areas can be targeted even in patients with severe lung damage and reduced lung capacity.

A bitter taste of macrolides was addressed by Sollohub et al. (2011) in a study investigating the taste masking of roxithromycin. The taste is not only a problem in oral treatment with macrolides, but might also be of relevance in aerosol therapy as a relevant proportion might be deposited in the oral cavity and in the upper respiratory tract. The use of sweeteners, e.g., aspartame and saccharin and flavor mixes for the purpose of taste masking is restricted due to poor effects and risk of toxic or allergic reactions. Sollohub et al. (2011) used a spray-drying technique for roxithromycin microencapsulation and Eudragit L30D-55 (methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 %) to form the taste masking coat. Particles were visualized by scanning electron microscopy and analyzed by electronic tongue sensor arrays. Eudragit L30D-55 was shown to create a continuous, thick, and stable coating of roxithromycin, which showed a significantly different cluster in analysis by means of electronic tongue sensor assays when compared to pure roxithomycin. A sufficient stability of microcapsules dispersed in phosphate buffer pH 6.8 was observed and the taste masking effect disappeared after 10–20 min. However, it should be noted that the diameter of pure and masked particles was beyond 10 μm and therefore not suitable for inhalation.

Togami et al. (2010) investigated the delivery of telithromycin aerosol in rats. In detail, doses of 0.2 mg/kg telithromycin in phosphate buffered saline solution (pH 7.4) were administered through the nasal cavity by means of a Liquid MicroSprayer and administration of an oral dose of 50 mg/kg served for reference. Time courses of telithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages (AM), and plasma were determined up to 24 h after both administrations by means of HPLC. Telithromycin concentrations in ELF and AM more rapidly increased and were largely higher after aerosol administration than after oral dosage. On the other hand, largely higher plasma concentrations were found after oral dosage when compared with aerosol administration (area under the curve – AUC; aerosol administration: 106, 3,097, and 0.0223 μg · h/ml for ELF, AM, and plasma, respectively; oral administration: 31.5, 836, and 10.1 μg · h/ml for ELF, AM, and plasma, respectively), indicating both a high effectiveness and therapeutic availability especially in AM and a low risk of systemic side effects after aerosol administration. The investigators also provided data based on AUC and minimal inhibitory concentration (MIC) demonstrating a sufficient antibacterial effect of aerosolized telithromycin. Furthermore, they reported a sufficient stability of the compound in ELF and AM, and no relevant toxicity of telithromycin on lung tissues, i.e., no release of lactate dehydrogenase (LDH) after aerosol administration (Table 3).