Internal mouthpiece designs as a future perspective for enhanced aerosol deposition. Comparative results for aerosol chemotherapy and aerosol antibiotics

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JP-13624; No. of Pages 7

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Contents lists available at ScienceDirect

International Journal of Pharmaceutics

j o ur nal ho me page: www.elsev ier .com/ locate / i jpharm

ersonalised medicine

nternal mouthpiece designs as a future perspective for enhancederosol deposition. Comparative results for aerosol chemotherapy anderosol antibiotics

aul Zarogoulidisa,b,∗, Dimitris Petridisc, Christos Ritzoulis c, Kaid Darwicheb,oannis Kioumisa, Konstantinos Porpodisa, Dionysios Spyratosa,

olfgang Hohenforst-Schmidtd, Lonny Yarmuse, Haidong Huangf, Qiang Li f,utz Freitagb, Konstantinos Zarogoulidisa

Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, GreeceDepartment of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, GermanyDepartment of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, GreeceII Medical Department, “Coburg” Regional Clinic, University of Wuerzburg, Coburg, GermanyDivision of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, USADepartment of Respiratory Diseases Shanghai Hospital, II Military University Hospital, Shanghai, China

r t i c l e i n f o

rticle history:eceived 17 August 2013eceived in revised form 3 September 2013ccepted 5 September 2013vailable online xxx

hemical compounds studied in this article:ztreonam (PubChem CID: 5742832)entamycin (PubChem CID: 3467)obramycin (PubChem CID: 36294)iprofloxacin (PubChem CID: 2764)isplatin (PubChem CID: 84093)arboplatin (PubChem CID: 10339178)aclitaxel (PubChem CID: 36314)ocetaxel (PubChem CID: 148124)

a b s t r a c t

Background: In an effort to identify factors producing a finest mist from Jet-Nebulizers we designed 2mouthpieces with 4 different internal designs and 1–3 compartments.Materials and methods: Ten different drugs previous used with their “ideal” combination of jet-nebulizer,residual-cup and loading were used. For each drug the mass median aerodynamic diameter size had beenestablished along with their “ideal” combination.Results: For both mouthpiece, drug was the most important factor due the high F-values (Flarge = 251.7,p < 0.001 and Fsmall = 60.1, p < 0.001) produced. The design affected the droplet size but only for largemouthpiece (Flarge = 5.99, p = 0.001, Fsmall = 1.72, p = 0.178). Cross designs create the smallest droplets(2.271) so differing from the other designs whose mean droplets were greater and equal ranging between2.39 and 2.447. The number of compartments in the two devices regarding the 10 drugs was found notstatistically significant (p-values 0.768 and 0.532 respectively). Interaction effects between drugs anddesign were statistically significant for both devices (Flarge = 8.87, p < 0.001, Fsmall = 5.33, p < 0.001).Conclusion: Based on our experiment we conclude that further improvement of the drugs intended for

emcitabine (PubChem CID: 60750)oxorubicin (PubChem CID: 31703)

eywords:erosolouthpieceesigns

aerosol production is needed. In addition, the mouthpiece design and size play an important role infurther enhancing the fine mist production and therefore further experimentation is needed.

© 2013 Elsevier B.V. All rights reserved.

. Introduction

Please cite this article in press as: Zarogoulidis, P., et al., Internal mouthpiComparative results for aerosol chemotherapy and aerosol antibiotics. Int J

Currently the main mode of administration for several thera-ies is the intravenous route. In the previous years an effort was

∗ Corresponding author at: “G. Papanikolaou” General Hospital, Aristotle Univer-ity of Thessaloniki, Thessaloniki, Greece. Tel.: +49 15779211742;ax: +30 2130992433.

E-mail addresses: [email protected], [email protected]. Zarogoulidis).

378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2013.09.004

made to explore alternative routes of administration in order toenhance the efficiency of therapy and to minimize adverse effects.As it has been observed with several drugs, the adverse effects aredirectly related to the concentration administered (Miura et al.,2013). In several diseases the target lesion is located to a sitewhich is difficult to approach directly and administer the optimaltreatment. Therefore intravenous administration is administered

ece designs as a future perspective for enhanced aerosol deposition.Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.09.004

in almost every disease. However; higher concentrations have tobe delivered in older to have the desired result. In addition, the dis-comfort and adverse effects from the intravenous administration isanother factor reducing the quality of life of patients (Baron et al.,

dx.doi.org/10.1016/j.ijpharm.2013.09.004


http://www.sciencedirect.com/science/journal/03785173

http://www.elsevier.com/locate/ijpharm

mailto:[email protected]

mailto:[email protected]


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ARTICLEJP-13624; No. of Pages 7

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013; Wynne et al., 2013). The inhaled insulin was one of the firstxamples where a systematic therapy was redesigned to be admin-stered as aerosol (Zarogoulidis et al., 2011). Inhaled antibioticsollowed for patients with cystic fibrosis and patients admitted inhe intensive care unit (Geller et al., 2007). Currently experimen-ation for lung cancer treatment is ongoing as local treatment inhe form of intratumoral administration (endobronchial lesions)Hohenforst-Schmidt et al., 2013), aerosol chemotherapy admin-stration (Zarogoulidis et al., 2012a; Zarogoulidis et al., 2012b)nd inhaled gene therapy (Zarogouldis et al., 2012; Zarogoulidist al., 2013a; Zarogoulidis et al., 2012c). The safety of these novelreatment modalities is under investigation and currently severalerosol production systems are being developed (Darwiche et al.,013; Zarogoulidis et al., 2013b; Zarogoulidis et al., 2013d). Theain concept is to produce treatment administration modalities

hat are both effective and safe. In our previous work we dividedhe aerosol production methodology in two clusters: (i) the pro-uction system and (ii) the delivery system. We included in theroduction system the following parameters: (a) jet-nebulizer,b) residual-cup design, (c) loading of residual-cup and (d) drug.

e investigated the interaction of these four parameters betweenhem to identify in what degree one affected the other. We iden-ified for five chemotherapy drugs and five antibiotic drugs theideal” combination of these parameters producing the smallestroplets (mass median aerodynamic diameter < 5 �m). In our cur-ent work we investigated the “delivery system” which is theonnection between the residual-cup and upper airways. Therere two “delivery systems” that are used nowadays; (a) face masknd (b) mouthpiece. (Fig. 1.) Each one has its advantages and dis-dvantages which will be analyzed in the discussion section (Lint al., 2007b; Sangwan et al., 2004). In specific eighteen differ-


nt mouthpieces were designed in order to evaluate whether thisart of the aerosol delivery process affects the mist productionnd hence the performance. It has been previous investigated thatactors such as; turbulence, inlet size, air flow, mouthpiece and

ig. 1. (A) ISO-NEB® Filtered Nebulizer System, UP-DRAFT II-HUDSON RCI (TFX Medicalrrow indicates the filter, white arrow indicates the residual cup and oxygen connection,

C) valve inner design, (D) valve outer design, (E) Respiromed precision nebulizer special

ndicates the mouthpiece, yellow arrow indicates the filter, white arrow indicates inspipper right of the same figure), red arrow indicates the connection tip for the residual cu

s the same as the expiratory valve), (F) Respiromed precision nebulizer special medicatied arrow indicates the connection tip of the residual cup and oxygen supply, yellow arrortwork, the reader is referred to the web version of the article.)

PRESSof Pharmaceutics xxx (2013) xxx– xxx

grid affect the production of the aerosol mist (Jiang et al., 2012).Inhaled insulin is an example again where different mouthpiecedesigns were investigated in an effort to enhance the aerosol pro-duction. Indeed the mouthpiece design was observed to be a keyfactor affecting the mist production at least for inhaled insulin(Boyd et al., 2004; Coates et al., 2007). The addition of a spacer haspresented again favorable results when connected to a metereddose inhaler or jet-nebulizer production system (Silkstone et al.,2002). A third system identified to further influence the depositionof aerosol mist consists of the following geometrical factors; geo-metrical; mouth, oropharynx, larynx intra-thoracic airways up tosix generations. The intra-thoracic airways however; is not a stablesystems since the diameter changes due to underlying conditions(e.g. bronchoconstriction, excessive mucus production, viscosity ofmucus) and diseases (e.g. chronic obstructive pulmonary disease,cystic fibrosis, asthma) (Lin et al., 2007a). The breathing patternplays also an important role of aerosol deposition (Foust et al., 1991;Nikander et al., 2000). We will present our results and indicatefuture investigational directions towards the aerosol productionmethodology.

2. Materials and methods

2.1. Nebulizers

Based on our previous experiments we identified that forchemotherapy drugs (Cisplatin, Paclitaxel, Docetaxel, Gemcitabineand Carboplatin) the “ideal” combination producing the smallestdroplets (mass median aerodynamic diameter) was the nebulizerMaxineb® (6 l/min and 35 psi), residual cup D with 8 ml loading(Zarogoulidis et al., 2013d). Regarding the antibiotics the “ideal”


combination was for zobactam the residual cup C and G with 6 mlloading, for solvetan residual cup D with 8 ml loading and for max-ipine, begalin, meronem residual cup C with 6 ml loading. Therewas no difference observed between the nebulisers (a) Sunmist®

Ltd., High Wycombe HP12 3ST U.K.), blue arrow indicates the mouthpiece, yellowred arrow indicates aerosol flow valve; (B) UP-DRAFT II-HUDSON RCI system parts,medication, Manufacturer: Int’Air Medical, F-01002 BOURG EN BRESSE, blue arrowratory breath activated valve (the inner structure of this valve is indicated on thep and the green arrow indicates the expiratory activated valve (the inner structureon, Manufacturer: Int’Air Medical, F-01002 BOURG EN BRESSE parts, (G) facemask,w indicates the face mask holes. (For interpretation of the references to color in the


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Fig. 2. Small inlets designs and compartments; Red arrow indicates the side where

tering was preferred over a cascade impactor, as the latter is, bydesign, limited to the number of discriminated size populationsup to the number of its filters. The light scattering set-up used in



6 l/min and 35 psi), (b) Maxineb® (6 l/min and 35 psi) and (c)nvacare® (6 l/min and 35 psi) (Zarogoulidis et al., 2013c). There-ore in all our experiments we chose to use the nebulizer Maxineb®

6 l/min and 35 psi).

.2. Drugs

The chemotherapy drugs were the following; (i) Paxene®

Paclitaxel) 30 mg/5 ml Pharmachemie B.V., (ii) Gemzar®

000 mg 17.5 mg (<1 mmol) sodium in each 1000 mg vial, (iii)isplatin/Hospira® 100 mg/ml ONCO-TAINTM, (iv) Carboplatin®

0 mg/1 ml VIANEX S.A, (v) Taxotere® (Docetaxel) 80 mg/2 mlnd Diluent for Taxotere 80 mg. We gave to the chemotherapyrugs for simplicity in our statistical analysis the following names:isplatin, carboplatin, paclitaxel, docetaxel and gemcitabine. Therugs cisplatin and carboplatin were used as they were in theirial. The drugs paclitaxel and docetaxel were diluted with 20 ml ofaCl 0.9%. In specific 1 vial of paclitaxel or docetaxel was mixedith 20 ml of NaCl 0.9% and vortexed for 15 min until the solutionas homogenous. We wanted to replicate the same solution

s in our previous experiment. These drugs in specific after theerosol administration smeared the glasses of the Malvern® 2000quipment. In any case a thorough cleaning of the chamber wasecessary after every administration even with this dilution. Theemcitabine powder was also diluted with 20 ml of NaCl 0/9%,he mixture was vortexed again for 15 min and a homogenousolution was finally produced (Zarogoulidis et al., 2013d). Severalepetitions of the experiments were necessary.

The following five antibiotics were used in our previousork: (a) Maxipime® (Cefepime) 2gr. Bristol-Myers Squibb, (b)egalin – P® (Sulbactam 1gr/Ampicillin 2gr), (d) 3gr Meropenem®

Meropenem) 500 mg, 1gr ANFARM, (c) Zobactam® (Piperacilingr/Tazobactam 0,5 mg) 4,5 g VOCATE., (e) Solvetan® (Ceftazidime)gr GSK. The drugs were in dry powder formulation and wereiluted with 20 ml NaCl 0.9% in a 50 ml glass container. Again

thorough cleaning of the chamber was necessary after everydministration even with this dilution (Zarogoulidis et al., 2013c).ased on our previous experiments we identified the “ideal” com-inations in order to produce the finest mist. However; therehere cases where 2 different residual-cups offered the finest mistroduction in the antibiotics group. No difference was observedetween the jet-nebulizers. We used only one combination asollows: (a) Zobactam® residual-cup C (6 ml loading) and jet-ebulizer Maxineb®, (b) Solvetan® residual-cup G (8 ml loading)nd jet-nebulizer Maxineb, (c) Begalin® residual-cup C (6 ml load-ng) and jet-nebulizer Maxineb®, (d) Meronem® residual-cup C6 ml loading) and jet-nebulizer Maxineb®, (e) Maxipine® residual-up C (6 ml loading) and jet-nebulizer Maxineb®. Regarding thehemotherapy agents the best combination for all drugs wasdentified to be residual-cup D (8 ml loading) and jet-nebulizer

axineb®.

.3. Mouthpiece design

Best on previous published designs 18 different mouthpiecesere engineered. There were two major groups; (a) large with

hree compartments (A, B, C) and (b) small with two compart-ents (A, B). We decided to incorporate four different inner grid

esigns which we named X, V, Dash and Cross. These structurescted as a “filter” for aerosol that passed through the mouthpiece.hese designs are used by many commercial aerosol systems, how-


ver; we wanted to elicit the effect of the additional compartmentsnd length of mouthpiece in clinical practice. We investigatedow the geometry, size, inner grid designs and number of gridscompartments) affect the produced mass median aerodynamic

mouth is fitted, Yellow arrow indicates ports for introduction of wires for the innerinlet design. (For interpretation of the references to color in the artwork, the readeris referred to the web version of the article.)

diameter (MMAD) of the produced droplets from the Maxineb®

(6 l/min and 35 psi) jet nebulizer. We used the “ideal” combina-tion (residual cup, loading and jet-nebulizer) for each of the drugused identified from our previous work (described in the previ-ous section) (Zarogoulidis et al., 2013c; Zarogoulidis et al., 2013d).(Figs. 2–4.)

2.4. Method of aerosol droplet determination

The determination of the d3.2 mean droplet diameter usinga laser light scattering apparatus (Malvern Mastersizer 2000,Malvern, Worcestershire, UK) equipped with a Scirocco dry acces-sory module (Malvern, Worcestershire, UK). This set-up wasmodified as for the user to be able to spray directly the produceddroplets at the sample cell (at a level vertical to the laser beam).The refractive index used for the droplets was 1.33. Light scat-


Fig. 3. Large inlets designs and compartments; Red arrow indicates the side wheremouth is fitted, Yellow arrow indicates ports for introduction of wires for the innerinlet design. (For interpretation of the references to color in the artwork, the readeris referred to the web version of the article.)


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Fig. 4. Inner mouthpiece designs (only the first compartment is demonstrated int

tntcomettwwstptS

desirable droplet size (1.501).A uniform ranking pattern exists for the first four drugs in the

Fs

his figure for simplicity reasons). (A) Cross, (B) X, (C) Dash, (D) V.

his work measures the light scattering intensity at a very largeumber of angles, hence a very large number of droplet popula-ions, leading to droplet size distribution plot of a very large pointsount and this is the reason why light scattering was preferredver other methods. In addition, light scattering as a measurementethod is non-invasive to the particles, and being measured. Sev-

ral repetitions were performed by the team in order to evaluatehis technique. (Fig. 5.) We continued using this low concentra-ion of NaCl 0.9% (only 20 ml and without any use of filter) as weanted to simulate a future mode of administration where a patientould have a fast treatment administration. This can only be pur-

ued when the volume of the drug is low ≤ 20 ml, otherwise theime of administration is very extended. The medical staff thaterformed the measurements had a protective mask on during


he aerosolization (TY 0839V FFP 3, EN 149:2001) (Mansour andmaldone, 2013).

ig. 5. Figure from Department of Food Technology, School of Food Technology and Nutrtrates the Mastersizer® 2000 and the three Jet-Nebulizers during aerosol droplet measu


2.5. Statistics

In both devices the droplet size (dependent variable) producedby three different factors acting interactively was investigated:

Drug with 10 levelsInlet Design with 4 levels3 compartments per large device2 compartments per small device

Thus a two factor analysis of variance (ANOVA fixed effects)was employed for each device type, drug and compartment lev-els and furthermore drug and inlet design. The droplet size wastransformed to its reciprocal 1/MMAD in order to conform to thenormality of data for both devices measured. After transformation,derived means were extracted to bring the values to the conven-tional scale. Statistically differences between factor levels werechecked using the Tukey’s pair-wise comparison of means.

3. Results

The number of compartments in the two devices regarding the10 drugs was found not statistically significant (p-values 0.768and 0.532 respectively). Therefore another two factor ANOVA wasconducted included drug and design this time. For both mouth-piece, drug was the most important factor due the high F-values(Flarge = 251.7, p < 0.001 and Fsmall = 60.1, p < 0.001) produced by thetest. Table 1 shows the pattern of drug mean changes. It appearsthat for the large device the pattern is more clear showing a dis-tinct ranked mean difference among PACLITAXEL, GEMCITABINEand CISPLATIN. Next come three drugs with higher and equal meanvalues (ZOBACTAM, DOCETATEL, CARBOPLATIN) two drugs witheven higher but equal mean values (MERONEM, BAGALIN) andfinally two drugs with maximum mean droplet size (SOLVETAN,MAXIPINE). Obviously, PACLITAXEL produces the lowest and most


small device. However, clear mean differences are described onlyby PACLITAXEL, BAGALIN and MAXIPINE, the other drugs showing

ition, Alexander Technological Educational Institute, Thessaloniki, Greece. Demon-rement.


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Table 1Grouping information using Tukey method of drug mean comparisons for large andsmall devices. Means that do not share a letter are significantly different.

Large inlet

DRUG N Mean Grouping

PACLITAXEL 12 1.501 AGEMCITABINE 12 1.709 BCISPLATIN 12 1.908 CZOBACTAM 11 2.211 DDOCETAXEL 12 2.409 DCARBOPLATIN 12 2.431 DMERONEM 12 2.852 EBAGALIN 12 3.202 ESOLVETAN 12 3,987 FMAXIPINE 12 4.181 F

Small inlet

DRUG N Mean Grouping

PACLITAXEL 8 1.572 AGEMCITABINE 8 1.851 BCISPLATIN 8 2.095 B CZOBACTAM 8 2.151 B CSOLVETAN 8 2.317 C DCARBOPLATIN 8 2.413 C DDOCETAXEL 8 2.625 DMERONAM 8 2.713 D

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BAGALIN 8 3.517 EMAXIPINE 8 6.398 F

verlapping mean values. Again the same drug, PACLITAXEL,omes first with mean value a little higher than that for largeevice (1.572 > 1.501) and MAXIPINE produces the highest values6.398 and 4.181) for both devices.

The design affected the droplet size but only for large mouth-iece (Flarge = 5.99, p = 0.001, Fsmall = 1.72, p = 0.178). Cross designsreate the smallest droplets (2.271) so differing from the otheresigns whose mean droplets were greater and equal rangingetween 2.39 and 2.447 (Table 2).

Interaction effects between drugs and design were statisti-ally significant for both devices (Flarge = 8.87, p < 0.001, Fsmall = 5.33,

< 0.001). In both cases the combination PACLITAXELxCrossTable 1 Sup.) was the most beneficial for producing small dropletizes since the mean values were too low: 1.407 (large) and 1.525small). These mean interactive values are smaller than the cor-esponding ones for the drug PACLITAXEL for both devices sotressing the superiority of that combination.

. Discussion

The factors affecting the aerosol production from jet-nebulizersave been previously identified; (i) salts of the chemical compoundDavis and Bubb, 1978), (ii) design of the residual cup (Clay et al.,983; Smith et al., 1995; Zarogoulidis et al., 2013c; Zarogoulidist al., 2013d), (iii) residual cup initial filling (Kendrick et al., 1995),


iv) flow rate (nebulizer capability) (Kendrick et al., 1997), (v) tap-ing of the nebulizer chamber during nebulization (Kendrick et al.,997) and (vi) tension-viscosity and drug concentration (Newmant al., 1985). The higher the flow rate and volume in the residual

able 2rouping information using Tukey method of design mean comparisons for largeevices. Means that do not share a letter are significantly different.

DESIGN N Mean Grouping

Cross 30 2.271 AV 29 2.390 BX 30 2.407 BDash 30 2.447 B

PRESSof Pharmaceutics xxx (2013) xxx– xxx 5

cup, the smaller the mass median aerodynamic diameter (Clayet al., 1983). The factors affecting the deposition are summarizedto: (i) MMAD < 5 �m and (ii) humidity and temperature in theairways, since these factors are known to increase the dropletsize (Labiris and Dolovich, 2003a). The time of nebulisation isanother factor that is not usually included in several experimentaltherapies upon evaluation (Kendrick et al., 1995; Smith et al.,1995). However; this is also a key parameter to for efficiencyand superiority of a new therapy. In the case of inhaled insulinadditional aerosol production systems were designed to deliverthe drug formulation in short time (Zarogoulidis et al., 2011). Ourteam identified the “delivery system” as the intermediate stagebetween production of aerosol and deposition. The face masks andmouthpieces are the two major equipment used, each one withits advantages and disadvantages. The face mask does not needbreath synchronization and it can provide the mist of drug to themouth and nose. It can be used by patients in distress, or in normalstatus. However; the main disadvantage is the leaking aerosol tothe eyes and face skin. The deposition of the drug concentrationhas been found to be approximately the same to that of the lung onthe skin surface (Sangwan et al., 2004). Moreover, depending onthe drug several adverse effects could be observed to the eyes (e.g.corticosteroids) or skin (e.g. rash (Mayercik et al., 2011). The facemask design has been found to influence the produced MMAD. Inspecific the fish mask was observed to have higher inhaled massthan the standard mask or dragon mask at least for albuterol (Linet al., 2007b). The face mask aerosol administration has been foundalso to be responsible for influenza particle dispersion. In specificit was presented that the medical personal has to be at least 0.8 maway from hospitilised patients with influenza or suspicious ofinfectious disease (Hui et al., 2009). Mouthpiece designs have beenpreviously examined to investigate differences between malesand females for inhaled insoulin (Boyd et al., 2004). However; nodifferences were found. There are currently several mouthpiecedesigns with and without valves. Theoretically mouthpieces withvalves (inspiratory and expiratory activated) can control moreefficient the drug inhalation pattern and no aerosol is wasted to theenvironment. There are also several designs were a filter absorbsthe aerosol that is exhaled from the mouth and therefore we canmeasure the concentration that is not inhaled. (Fig. 1.) Previousstudies have presented a model where different breathing patternswere used and a filter which was added between the mouthpieceand breathing simulator was used to measure the administeredaerosol (Berg and Picard, 2009). This study presented an evaluationsystem for jet-nebulizers for home care treatment.

In the study by Nikander et. al. (Nikander et al., 2000) itwas presented that breath synchronization administration usingmouthpieces with valves was more efficient than constant aerosoladministration with mouthpiece without valves or face mask. Inthe study by Silkstone et. al. (Silkstone et al., 2002) it was presentedthat the addition of a spacer to a metered dose inhaler delivers up tofive times more drug concentration to the lungs than conventionaljet-nebulizer administration. Moreover; it has been previouslyobserved that the mouthpiece geometry affects the amount ofthroat deposition by controlling the axial component of the exit airflow velocity (Coates et al., 2007). Regarding the mechanically ven-tilated patients or non-invasive mechanically ventilated the majorfactors affecting the deposition is the inspiratory flow rate, theflow rate (we need high flow rate), tidal volume, respiratory rateand aerosol production generator (Ari et al., 2010; Everard et al.,1992; Harris et al., 2007). A high flow rate was used to produceand deliver efficiently aerosol iloprost in mechanically ventilated


patients (Harris et al., 2007). Computational fluid dynamics displaycan be used to evaluate future mouthpiece designs and depo-sition in the respiratory system (Smits and Desmet, 2013). Thedrift flux model displays the aerosol flow dynamics in the upper


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racheobronchial airways and can be used to simulate the trans-ort and deposition of submicrometer respiratory aerosols (Xi andongest, 2008). The different inner mouthpiece designs affect theMAD of the larger droplets produced. The different grid designs

resent different patterns of droplet impaction upon them. Theajor findings were that the cross design produces the smallest

roplets only for large mouthpiece with one compartment. Thisbservation can be explained by the higher velocity, turbulencend spin that a droplet obtains inside the larger mouthpiece. At thend of the tube the droplet hits the grid structure with high forcend breaks into smaller size droplets. The several compartmentsnumber of grids) > 2 act as “net” after some time of continuouserosol production which was not identified in the current work.n specific drops of the aerosolized drug can be observed on the dif-erent inner grids when > 2 compartments are used. Therefore oneompartment at the point of the mouth-mouthpiece connectionas observed to be more efficient in producing smaller droplets.

n addition, another very important observation was the influencef the solution (drug powder/saline) to the produced aerosol, as itas been previously observed with dry powder (Heng et al., 2013;ark et al., 2013). In our study the antibiotics in specific they weren powder and were diluted in 20 ml of NaCl 0.9%. However; the0 ml were not sufficient for all antibiotics, therefore we had toeproduce our experiments several times until the smallest pos-ible MMAD was obtain for each one. We have to state that weanted to have a small volume of solution with high concentra-

ion simulating a future antibiotic drug, where the nebulisationime would be short and the minimum inhibitory concentrationMIC50) efficient delivered. It is our belief that our results wereffected by the large particles within the solutions of the antibi-tics (a filter was never used to clear these particles). In any caseurther development in drug design is needed since the airwaysave different transporters while descending from the upper to the

ower airways (Bosquillon, 2010). Future development of aerosoleposition enhancement should focus not only in the investiga-ion of novel mouthpiece designs but also in production systemsnd modification of aerosolized particles. Regarding Jet-Nebulizerystems we would like to have as future concept molecules thatre produced with high velocity, however; light enough to changerajectory within their route from the mouthpiece to the alveoli.ry powder inhaler administration could be further enhanced byovel inner designs, however; further experimentation is needed.

dentifying which patient is fit (respiratory capability, condition)or each device should be the first step for future experimentation.

oreover, as previously described the defense mechanisms andnvironment of the airways need novel molecules to be designedn order to bypass them (Labiris and Dolovich, 2003b). Finally,

e should choose to use in the clinical practice face masks orouthpiece designs based on the need of the patient and intended

reatment.

onflict of interest

None to declare.

ppendix A. Supplementary data

Supplementary data associated with this article can beound, in the online version, at http://dx.doi.org/10.1016/j.jpharm.2013.09.004.


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Documents

Internal mouthpiece designs as a future perspective for enhanced aerosol deposition. Comparative results for aerosol chemotherapy and aerosol antibiotics