Academic Editor: Josef Jampílek
Introduction: Aerosolised drugs have been approved for several diseases
such as cystic fibrosis and diabetes. Moreover; there are already drugs for
pulmonary hypertension in aerosol form already on the market. Materials
and methods: Two drugs for pulmonary hypertension (Tadalafil and Macitentan)
were milled and transformed from tablets to powder. Three different
jet-nebulizers with seven different residual cups were combined. Moreover, we
used 3 different ultrasound nebulizers with two different release methods.
Results: The drug and residual cup designs produce alone or jointly
different MMAD diameters. The three large (10 mls) residual cups with the
jet-nebulisers produced the smallest aerosol droplets. Both ultrasound nebulisers
are capable of producing optimal size aerosol droplets
The lung parenchyma consists of airways and finally the alveoli. The alveoli are
constructed from a thin tissue layer covered with microvessels. It has been
observed that particles
The following drugs were purchased: (1) Tadalafil® 20 mg/tab, AZ Pharma, ULM, Germany. Typical dosage 5 mg/day and (2) Opsumit® 10 mg/tab (macitentan) Actelion pharmaceuticals Ltd., Neuss, Germany. Usual dosage 10 mg PO qDay.
Three nebulizers were chosen from our department for the experiment:
Maxineb® (6 liters/minute and 35 psi), Sunmist®
(5–7 liters/minute and 35 psi) and Invacare® (4–8 liters-minute
and 36 psi) (Fig. 1). Seven residual cups were included. Four had a capacity of
Upper row with Jet-nebulizers, (A) Maxineb, (B) Sunmist and (C) Invacare. Lower row with ultrasound nebulisers, (D) Easyneb, (E) GIMA and (F) Omron.
Large residual cups that can contain up to 8 mls of liquid.
Small residual cups that can contain up to 6 mls of liquid.
The following ultrasound nebulizers were available in our department. The first
was Omron® NE-U07, Tokyo, Japan with a 10 mL medication cup. The
second was a portable GIMA, Gessate, Italy (Choice Smart Health Care Company
Limited, Wan Chai, Hong Kong, No. G2061259328002) with the following operating
specifications; Particle size: 3–5
A laser scattering apparatus (Malvern Mastersizer 2000, Malvern, Worcestershire, UK) equipped with a Scirocco dry accessory module (Malvern, Worcestershire, UK) was used for the determination of the mass median diameter of the produced particles. A specific surface area od D 4.3 was used. Light scattering was used instead of a cascade impactor, as (i) A cascade impactor is, by design, limited to the number of size populations it may discriminate, that is the number of filters. (ii) Light scattering is non-invasive to all particles . The above, coupled with the application of the very accurate ‘Mie theory‘ used here for transferring the angle-intensity measurements into size-volume data. Our equipment has been previous used in prior publications [4,19-22].
The Tadalafil and Macitentan tablets were milled in a planetary ball mill
(Frisch, Pulverisette-5) equipped with Agate bowls (500 mL) and 8 balls (20 mm,
20 g) with a rotational speed of approximately 800 rpm which results in an
acceleration of about 7.5 g. We initiated our milling at 20 minutes and we
acquired a mass median diameter (MMD) of 3.2
The main object of the study is to find potential effects of 4 factors on MMAD response keeping in mind that the less mass diameter obtained the better function of the combined treatment.
Concerning the jet-nebulizers, a four-way analysis (fixed effects) on mass median aerodynamic diameter (MMAD) response was employed using three types of nebulizers (INVACARE, MAXINEB, SUNMIST), two types of drugs (Macitentan, Tadalafil), four loading dose (mL) levels (2, 4, 6 ,8) and seven designs of residual cups (alphabet letters).
Regarding the ultrasound nebulizers, a four-way analysis of variance (fixed effects) on MMAD response was also employed using three types of nebulizers (EASY NEB, GIMA. OMRON), same types of drugs, two loading levels (2, 4 mL) and two breathing mouthpiece apparatus (face mask, cylinder).
The statistical procedure first involved a compliance with normal distribution of MMAD variable and secondly an ANOVA performance only on the main effects and hereupon on the interaction terms among the statistically significant factors.
For jet-nebulizers, the MMAD variable was transformed to a log
Size frequency distribution of MMAD and boxplot deployment. Dots indicate outliers and the need for a log transformation of MMAD.
Two factors were found to influence the MMAD when jet-nebulizers were used: drug
and residual cup design plus their interaction effect (Fig. 5). The analysis of
drug mean values indicated that Tadalafil produced lower MMAD diameters (2.43
The analysis of drug mean values indicated that Tadalafil
produced lower MMAD diameters (2.43
For ultra sound nebulizers the MMAD variable was also transformed to log
None main effect was observed to influence the MMAD response as Table 1 clearly indicates.
|Source||Nparm||DF||Sum of squares||F ratio||Prob |
Overall, none of the two groups of nebulizers seems to affect the MMAD response, indeed however, the drug and some residual cup designs produce alone or jointly different MMAD diameters.
Underlying disease is a serious issue that has to be evaluated in every patient.
There has been an extensive research initially for inhaled insulin for patients
with asthma and chronic obstructive pulmonary disease (COPD) . The mucus,
airway clearance mechanisms and local genes/transporters play a crucial role in
the local absorption of an inhaled drug . The viscosity of the mucus does not
let the drug to be released to the airway surface . Patients with COPD and
cystic fibrosis have thick mucus and the clearance mechanisms do not work
properly [24,25]. There are different transporters in different sites of the
airways. In the airways there is also 90% humidity, therefore molecules with
high salt concentration will expand by almost 50% as they reach the alveoli from
the upper respiratory system . Exacerbations of COPD and asthma or another
underlying disease is a contraindication for inhalational drugs . Moreover, a
careful respiratory evaluation has to be performed for every patient not only
with spirometry, but also with diffusing capacity of the lung (D
PZ, DP, CS, CK, KT, DM, HH, CB, WHS, GP, IK, GG, SP and CK wrote the manuscript and performed the experiments. DP and PZ performed the statistics. IK, GP and GG provided useful insights.
This research received no external funding.
The authors declare no conflict of interest.