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Journal of Cystic Fibrosis 5 (2006) 205 – 213

www.elsevier.com/locate/jcf

Review

Inhalation solutions – which one are allowed to be mixed?


Physico-chemical compatibility of drug solutions in nebulizers
Wolfgang Kamin a,*, Astrid Schwabe b,1, Irene Krämer b,2
a
Kinderklinik und Kinderpoliklinik der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, D-55101 Mainz, Germany
b
Apotheke der Unikliniken Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany

Received 20 October 2005; received in revised form 21 December 2005; accepted 16 March 2006
Available online 5 May 2006

Abstract

Therapy of chronic respiratory diseases often involves inhalation therapy with nebulizers. Patients often attempt to shorten the time
consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. This article considers the issue of
physico-chemical compatibility of admixtures of drug solutions/suspensions in nebulizers.
A search of databases, prescribing information and primary literature was conducted to locate literature concerning the physico-chemical
compatibility of inhalation solutions/suspensions. This was supplemented by telephone interviews.
Admixtures of albuterol with ipratropium and/or cromolyn, of albuterol and budesonide, or tobramycin, or colistin are physico-
chemically compatible. Physico-chemical compatibility has been demonstrated for admixtures of cromolyn with albuterol and/or
ipratropium and for admixtures of cromolyn and budesonide. Admixtures of budesonide with ipratropium and/or fenoterol, and
admixtures of budesonide and albuterol, or cromolyn are physico-chemically compatible. Both cromolyn and colistin are
incompatible with benzalkonium chloride. Admixtures should be prepared from inhalation solutions/suspensions formulated without
preservatives.
Besides studies of the physico-chemical compatibility, the aerodynamic behaviour of physico-chemical mixtures needs to be studied
before a final recommendation of simultaneous nebulization of compatible admixtures can be made.
D 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Keywords: Compatibility; Inhalation solutions; Nebulizer; Review

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2. Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3.1. Albuterol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3.2. Cromolyn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3.3. Budesonide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
3.4. Ipratropium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
3.5. Acetylcysteine and colistin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

* Corresponding author. Tel.: +49 6131 17 2602; fax: +49 6131 17 5597.
E-mail addresses: kamin@kinder.klinik.uni-mainz.de (W. Kamin), schwabe@apotheke.klinik.uni-mainz.de (A. Schwabe),
kraemer@apotheke.klinik.uni-mainz.de (I. Krämer).
1
Tel.: +49 6131 17 4224; fax: +49 6131 17 5564.
2
Tel.: +49 6131 17 7209; fax: +49 6131 17 5525.

1569-1993/$ - see front matter D 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jcf.2006.03.007
206 W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213

3.6. Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210


3.7. Dornase alfa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

1. Introduction nebulizable medications, which are known to be incompat-


ible. Knowledge of the physico-chemical compatibility of
For patients suffering from chronic airways disease, e.g. admixtures of nebulization products is an important issue.
cystic fibrosis (CF) or asthma, inhalation of aerosolized This review aims to provide a literature overview and
medications is the mainstay of therapy. Although inhalation recommendations for mixing nebulizable medications.
therapy with hand-held inhalers is more common, nebulizers
are also widely used. In nebulizers ultrasound or a jet stream
of compressed air is used to convert the drug solution/ 2. Material and methods
suspension into an aerosol. Aerosolized droplets or particles
should be 1 to 5 Am diameter in size. Larger particles will In order to get information about the compatibility/
deposit in the upper airways; smaller particles may be stability of combinations of nebulizer solutions in inhalation
exhaled [1]. therapy the pharmaceutical and medical literature databases
Drug substances commonly used for inhalation ther- ‘‘International Pharmaceutical Abstracts’’ [2], ‘‘Embase’’ and
apy comprise albuterol, ipratropium, cromolyn, budeso- ‘‘Medline’’ were searched for combinations of the terms
nide, tobramycin, colistin and the rhDNAse dornase alfa ‘‘nebulizer solution’’, ‘‘inhalation’’, ‘‘compatibility’’, ‘‘stabil-
(Table 1). Inhalation therapy takes 10 to 15 min and ity’’, ‘‘combination’’, ‘‘HPLC’’, ‘‘aerodynamic behaviour’’
afterwards the nebulizer must be cleaned, dried and and the drug substance names albuterol, ipratropium,
reassembled. Inhalation of several nebulizable medications cromolyn, budesonide, tobramycin, colistin and dornase alfa.
may take up to 45 min or longer. It is quite evident that ‘‘HPLC’’(high-performance liquid chromatography) was
patients need strict discipline to adhere to this time- searched for, because it is a common analytical method to
consuming daily procedure. Mixing nebulizable medications determine compatibility or stability of admixtures. Besides
for simultaneous inhalation is an obvious way to reduce the the databases, in pharmacy departments commonly used
duration of nebulization and is a commonly used procedure. reference books like the ‘‘AHFS Drug Information’’ [4], and
Interviews conducted at the CF centre of our university the ‘‘Handbook on Injectable Drugs’’ [5] and the database
hospital identified 40 patients, who took more than one ‘‘Drugdex’’ [3] were searched for information concerning
nebulizable medication daily. Eight of them routinely mixed acetylcysteine and the drugs given above.

Table 1
Overview of inhalation solutions/suspensions
Drug substance Examples for brands Possibly relevant excipients
Albuterol Sultanol FertiginhalatR (unit dose) (Germany) No known relevant excipients
SultanolR (Germany) BAC
ProventilR 0.5% (US) BAC
Ipratropium AtroventR LS (Germany) BAC, EDTA
AtroventR Inhalation solution (unit dose) No known relevant excipients
Cromolyn IntalR No known relevant excipients
Budesonide PulmicortR EDTA
Tobramycin TobiR No known relevant excipients
GernebcinR (Germany) Sodium disulfit
Dornase alfa PulmozymeR No known relevant excipients
Colistin COLISTINR zur Inhalation (Germany) No known relevant excipients
PromixinR Powder (UK) No known relevant excipients
Orciprenaline AlupentR Inhalation Solution (no longer available) Sodium disulfit , EDTA
Terbutaline BricanylR 1% Solution (Germany) Chlorbutanol, EDTA
Ipratropium plus Berodual LS (Germany) BAC, EDTA
Fenoterol DuoventR (unit dose) (UK) No known relevant excipients
Acetylcysteine FluimucilR (Germany) EDTA
MucomystR (US) Not known
Ambroxole MucosolvanR Inhalation Solution 15 mg/2 mL (Germany) BAC
BAC = benzalkonium chloride, EDTA= ethylenediaminetetraacetic acid.
W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213 207

For each inhalation solution/suspension that is licensed in benzalkonium chloride (BAC) as preservative. The ipra-
Germany, the prescribing information for health care tropium inhalation solution also contained ethylenediami-
professionals (‘‘Fachinformation’’) was consulted for details netetraacetic acid (EDTA). Under various storage
concerning compatibility in nebulizers. Additionally, man- conditions, the admixture was found to be physically and
ufacturers of approved nebulizable medications of the drug chemically stable over 5 days.
substances albuterol, ipratropium, cromolyn, budesonide, Gooch [6] demonstrated that an admixture of albuterol
tobramycin, colistin, dornase alfa, acetylcysteine and inhalation solution and tobramycin infusion solution
ambroxole were contacted and asked for information about concentrate remained physically and chemically stable
the compatibility of their drug with other inhalation over seven days when stored under refrigeration. Hood
solutions/suspensions in nebulizers. and White [9] documented physical and chemical stability
of an albuterol and tobramycin admixture over 24 h;
addition of ipratropium inhalation solution did not impair
3. Results stability.
According to Roberts et al. [10], cloudiness developed in
The results are shown for each of the different drugs. an admixture of colistin inhalation solution and albuterol
The prescribing information and information obtained inhalation solution. The albuterol inhalation solution used
from the manufacturers is correct for the brands that are was a multidose product containing BAC. The cloudiness
licensed in Germany. persisted for at least 10 h but by 24 h the admixture had
regained complete clarity. The cloudiness was attributed to
3.1. Albuterol an interaction of BAC with colistin. Cloudiness was more
pronounced and lasted longer with increasing concentra-
The prescribing information for brands of albuterol tions of BAC and when the admixtures were stored at lower
contains no information about compatibility with other temperatures. The effect of cloudiness on the aerodynamic
nebulizable medications. The prescribing information for behaviour of the admixture is unknown. Mixing colistin and
MucosolvanR inhalation solution 15 mg/2 mL (brand of preservative-free unit-dose albuterol inhalation solution
ambroxole) contains the information that it can be mixed with avoids this problem and the admixture is chemically stable
adrenergic bronchodilators. The manufacturer of SultanolR over 1 h.
(brand of albuterol) told us that the inhalation solution is
compatible with solutions of ipratropium (AtroventR), 3.2. Cromolyn
cromolyn (IntalR), ambroxole (MucosolvanR) and acetyl-
cysteine (FluimucilR) [personal communication, Glaxo The authors are aware that cromolyn is not a standard
SmithKline, Bad Oldesloe, Germany]. therapy in cystic fibrosis. But in the interview conducted at
According to the albuterol monograph in AHFS Drug our CF centre, 7% of the patients inhaling more than one
Information [4], physical and chemical compatibility of nebulizable drug reported to inhale cromolyn.
albuterol admixtures has not been established. On the Prescribing information for brands of cromolyn contains
other hand, the ipratropium monograph states that admix- no advice for mixing with other inhalation solutions. The
tures of albuterol and ipratropium are chemically and prescribing information for AtroventR (brand of ipra-
physically stable for 1 h. Moreover, in the US, a tropium) states that the drug should not be mixed with
combination of albuterol 2.5 mg and ipratropium bromide cromolyn inhalation solution as precipitation can occur. The
0.5 mg in 3 mL unit-dose polyethylene vials (DuoNebR) manufacturer of IntalR (brand of cromolyn) informed us,
is commercially available. that incompatibilities with other inhalation solutions are not
Drugdex [3] mentions that an admixture of albuterol and known [personal communication Fisons/Rhône-Poulenc
tobramycin is physically and chemically stable [6]. Rorer, Cologne, Germany].
The primary literature on the physical and chemical According to the cromolyn monograph in AHFS Drug
stability of admixtures containing albuterol is summarized Information [4], the physical and chemical stability of
in Table 2. cromolyn admixtures is unknown. On the other hand, the
In several studies, compatibility and stability of admix- ipratropium monograph states that admixtures of cromolyn
tures of albuterol and ipratropium are shown. Nagtegaal et and ipratropium inhalation solutions are chemically and
al. [7] manufactured two different combination inhalation physically stable over 1 h.
solutions in glass ampoules free of preservatives. The Drugdex [3] cites the study of Lesko and Miller [11] and
combination of albuterol and ipratropium was more stable reports that admixtures of cromolyn and various adrenergic
than the combination of albuterol, ipratropium and cromo- bronchodilators as well as acetylcysteine inhalation solu-
lyn, with ipratropium as the stability limiting drug sub- tions are physically and chemically stable.
stance. Jacobson and Peterson [8] investigated the The primary literature on the physical and chemical
compatibility of commercially available albuterol and stability of admixtures containing cromolyn inhalation
ipratropium inhalation solutions. Both brands contained solutions is summarized in Table 3.
208 W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213

Table 2
Compatibility of admixtures of albuterol inhalation solutions with other drugs for inhalation
Admixed inhalation solution/suspension Study conditions Result Reference
Ipratropium bromide (62.5 Ag/mL) Storage: at RT or 45 -C/65 -C/85 -C Compatible storage life (loss of [7]
Determination: days 1 to 5, weekly for 6 ipratropium 10%) 18 months at 20 -C,
months, every 3 months for 1 year (for RT) 3.8 years at 3 – 8 -C
Method: HPLC
Ipratropium bromide (62.5 Ag/mL) + Storage: at RT or 45 -C/65 -C/85 -C Compatible storage life (loss of [7]
Cromolyn (5 mg/mL) Determination: days 1 to 5, weekly for 6 ipratropium 10%) 10 months at 20 -C,
months, every 3 months for 1 year (for RT) 1.9 years at 3 – 8 -C
Method: HPLC
Ipratropium bromide (AtroventR Storage: 5 days Compatible (loss 10%) [8]
250 Ag/mL), mixed volume ratio 1 : 1 Protected from light: 4 T 0.5 -C/22 T 0.25 -C
Fluorescent light: 22 T 0.25 -C
Determination: days 0/1/2/5
Method: HPLC
Ipratropium (AtroventR 250 Ag/mL) + Storage: RT Compatible (loss 10%) [12]
Cromolyn (IntalR 20 mg/2 mL); mixed Determination: 0/about every 12 min for 1 h
volume ratio 1 : 1 : 1 Method: HPLC Opacity for 48 h (IntalR + AtroventR)
Cromolyn (IntalR 1%); admixture: 0.5 mL Storage: RT Compatible (loss 2%) [14]
VentolinR + 2 mL IntalR + 1 mL NaCl Determination: 0/30/60/90 min
0.9% Method: HPLC
Tobramycin (NebcinR, 40 mg/mL); Storage: 4 -C, glass container Compatible (at 2 – 8 -C) (loss 10%) [6]
admixture: 0.5 mL VentolinR + 1 mL Determination: days 0/1/2/7
NebcinR + 2 mL NaCl 0.9% Methods: HPLC (albuterol), fluorescent
immunoassay (tobramycin)
Tobramycin (no information given about Storage: not known Compatible [9]
studied concentrations) Determination: over 24 h
Methods: not known
Tobramycin + Ipratropium (no information Storage: not known Compatible [9]
given about studied concentrations) Determination: over 24 h
Method: not known
Colistin (Coly-Mycin M ParenteralR Storage: RT Compatible for 1 h for solution without [10]
4.5 million units vials, 1 million units or Determination: 1 h, 24 h (albuterol only) preservatives, cloudiness due to BAC;
33.3 mg/mL); admixture: 1 mL Methods: HPLC (albuterol), bioassay loss: albuterol 7% (1 h), 14% (24 h),
albuterol + 1 mL Coly-Mycin M (+1 mL (colistin) colistin 2% (1 h)
NaCl 0.9% for colistin determination)
Budesonide (PulmicortR 0.25 mg/2 mL or Storage: RT Compatible (loss 10%) [16]
0.5 mg/2 mL); admixture: 0.5 mL Determination: 0/5/15/30 min
ProventilR + 2 mL PulmicortR or 3 mL Method: HPLC
XopenexR + 2 mL PulmicortR
Budenoside (PulmicortR 0.25 mg/2 mL or Storage: RT Compatible (loss 10%) [15]
0.5 mg/2 mL); admixture: 0.5 mL Determination: 0/5/15/30 min
albuterol + 2 mL PulmicortR Method: HPLC
Used brands of albuterol inhalation solutions: [7]: albuterol sulfate 1.5 mg/mL, [6,8,14]: VentolinR 0.5%, [12]: RespolinR Respirator Solution 5 mg/mL, [16]:
ProventilR 5 mg/mL or XopenexR 0.63 mg/3 mL or 1.25 mg/3 mL, [15]: albuterol 5 mg/mL, [10]: salbutamol 5 mg/mL respirator solution.
RT = room temperature.

The compatibility of cromolyn, albuterol and ipratropium According to its own studies, the manufacturer of IntalR
inhalation solutions has already been described above [7]. attributed cloudiness of IntalR and AtroventR admixtures to
Iacono et al. [12] studied admixtures of cromolyn and BAC [13]. BAC formed an oily, non-crystalline complex
ipratropium inhalation solutions with and without addition with cromolyn, depending on the BAC concentration. They
of albuterol inhalation solutions. Cloudiness developed suggested that Iacono et al. [12] might have used
instantly on mixing cromolyn and ipratropium inhalation supersaturated solutions, resulting in delayed crystallization.
solutions (IntalR and AtroventR). The mixture cleared within Studies conducted by the manufacturer reconfirmed com-
48 h and no precipitate was detected. The authors then mixed patibility of admixtures of IntalR with AtroventRas well as
aqueous solutions of BAC or EDTA (0.01% –2%) with with VentolinR or RespolinR (albuterol), AlupentR (orci-
IntalR or an aqueous solution of cromolyn (20 mg/2 mL) as prenaline), BerotecR (fenoterol), and BricanylR (terbuta-
well as AtroventR with an aqueous solution of cromolyn. No line), each in the recommended dosage for up to 15 h [13].
cloudiness was observed. The authors concluded that Emm et al. [14] studied the compatibility of admixtures of
cloudiness was not related to pH or preservatives contained cromolyn and albuterol or orciprenaline inhalation solutions
in AtroventR solution (BAC, EDTA). They attributed the in various concentrations. In two of three admixtures of
cloudiness to an unknown excipient in IntalR. cromolyn and orciprenaline 0.6% (IntalR and AlupentR) the
W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213 209

Table 3
Compatibility of admixtures of cromolyn inhalation solutions with other drugs for inhalation
Admixed inhalation solution/suspension Study conditions Result Reference
Ipratropium bromide (62.5 Ag/mL) + Albuterol Storage: at RT or 45 -C/65 -C/85 -C Compatible storage life (loss of [7]
sulfate (1.5 mg/mL) Determination: days 1 to 5, weekly for ipratropium 10%) 10 months at
6 months, every 3 months for 1 year (for RT) 20 -C, 1.9 years at 3 – 8 -C
Method: HPLC
Ipratropium bromide (AtroventR 250 Ag/mL); Storage: RT Compatible (loss 10%) opacity for [12]
mixed volume ratio 1 : 1 Determination: 0/about every 12 min for 1 h 48 h (IntalR + AtroventR)
Method: HPLC
Ipratropium bromide (AtroventR Storage: RT Compatible (loss 10%) cloudiness [12]
250 Ag/mL) + Albuterol sulfate (RespolinR Determination: 0/about every 12 min for 1 h for 48 h (IntalR + AtroventR)
Respirator Solution 5 mg/mL); mixed Method: HPLC
volume ratio 1 : 1 : 1
Albuterol sulfate (VentolinR 0.5%); admixture: Storage: RT Compatible (loss 2%) [14]
2 mL IntalR + 0.5 mL VentolinR + 1 mL Determination: 0/30/60/90 min
NaCl 0.9% Method: HPLC
Orciprenaline sulfate (AlupentR 5%, Storage: RT Compatible (loss 2%) [14]
multidose, no metabisulfite or AlupentR Determination: 0/30/60/90 min
0.6% inhalation solution); admixture: 2 mL Method: HPLC
IntalR + 0.3 mL AlupentR 5% + 2.5 mL
NaCl 0.9% or 2 mL IntalR + 2.5 mL
AlupentR 0.6%
Orciprenaline sulfate (AlupentR 5%); Storage: RT Compatible (loss 10%) [11]
admixture: 2 mL IntalR + 0.3 mL Determination: 0/15/30/45/60 min
AlupentR 5% + 2.5 mL NaCl 0.9% Method: HPLC
Terbutaline sulfate (BrethineR 0.1%); Storage: RT Compatible (loss 10%) [11]
admixture: 2 mL IntalR + 0.5 mL Determination: 0/15/30/45/60 min
BrethineR 0.1% Method: HPLC
Acetylcysteine (MucomystR 20%); admixture: Storage: RT Compatible (loss 10%) [11]
2 mL IntalR + 2 mL MucomystR 20% Determination: 0/15/30/45/60 min
Method: HPLC
Budesonide (PulmicortR 0.25 mg/2 mL or Storage: RT Compatible (loss 10%) [15,16]
0.5 mg/2 mL); admixture: 2 mL Determination: 0/5/15/30 min
IntalR + 2 mL PulmicortR Method: HPLC
Used brands of cromolyn inhalation solutions: [7]: cromolyn 5 mg/mL, [11,12,14,15,16]: IntalR 20 mg/2 mL.
RT = room temperature.

content of the active substances declined by more than 2% with cromolyn (IntalR) or ambroxole (MucosolvanR).
after 90 min (cromolyn 8.4%, orciprenaline 10%). The This information is not included in the prescribing
authors attributed these results to analytical error rather than information and is not corroborated by the studies cited
degradation as one of the three samples of this admixture below [15,16].
demonstrated no change in drug concentration. AHFS Drug Information [4] includes no monograph
In the 1980s, Lesko and Miller [11] investigated the on budesonide inhalation solution. Drugdex [3] contained
compatibility of cromolyn and various adrenergic broncho- no information about compatibility of admixtures of
dilators or acetylcysteine inhalation solutions. In some budesonide inhalation suspension with other inhalation
admixtures containing cromolyn and an adrenergic bron- solutions.
chodilator, the authors observed discoloration and precipi- The primary literature on the physical and chemical
tation after 24 h storage at room temperature without light stability of admixtures containing budesonide inhalation
protection. They attributed these changes to oxidation of the suspension is summarized in Table 4.
adrenergic bronchodilators. Smaldone et al. [15] and McKenzie et al. [16] demon-
strated chemical and physical compatibility of admixtures of
3.3. Budesonide budesonide with albuterol, cromolyn or ipratropium inhala-
tion solutions. Gronberg et al. [17] studied admixtures of
The prescribing information for PulmicortR inhalation budesonide with ipratropium and/or fenoterol or acetylcys-
suspensions (brand of budesonide) states that the inhalation teine inhalation solutions. All of them were compatible.
suspension can be mixed with other inhalation solutions
(e.g. terbutaline, albuterol, cromolyn, ipratropium). In a 3.4. Ipratropium
telephone interview representatives of the manufacturer
(Astra-Zeneca GmbH, Wedel, Germany) informed us The prescribing information for AtroventR (brand of
that cloudiness occurred in admixtures of PulmicortR ipratropium) states that mixing and simultaneous inhala-
210 W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213

Table 4
Compatibility of admixtures of budesonide inhalation suspension with other inhalative drugs
Admixed inhalation solution Study conditions Result Reference
Albuterol (ProventilR 5 mg/mL or XopenexR 0.63 mg/3 mL or 1.25 mg/3 Storage: RT Compatible [16]
mL); admixture: 2 mL PulmicortR + 0.5 mL ProventilR or 2 mL Determination: 0/5/15/30 min (loss 10%)
PulmicortR + 3 mL XopenexR Method: HPLC
Albuterol (5 mg/mL); admixture: 2 mL PulmicortR + 0.5 mL albuterol Storage: RT Compatible [15]
Determination: 0/5/15/30 min (loss 10%)
Method: HPLC
Cromolyn (IntalR 20 mg/mL); admixture: 2 mL PulmicortR + 2 mL IntalR Storage: RT Compatible [15,16]
Determination: 0/5/15/30 min (loss 10%)
Method: HPLC
Ipratropium bromide (AtroventR 0.2 mg/mL); admixture: Storage: RT Compatible [15]
2 mL PulmicortR + 2.5 mL AtroventR Determination: 0/5/15/30 min (loss 10%)
Method: HPLC
Ipratropium bromide (AtroventR 0.25 mg/mL); mixed volume ratio 2 : 1 Storage: 22 – 25 -C, protected from light Compatible [17]
(PulmicortR : AtroventR) Determination: 0/18 h
Method: HPLC
Fenoterol hydrobromide (BerotecR 5 mg/mL); mixed volume ratio 8 : 1 Storage: 22 – 25 -C, protected from light Compatible [17]
(PulmicortR : BerotecR) Determination: 0/18 h
Method: HPLC
Ipratropium bromide (DuoventR 0.125 mg/mL) + Fenoterol hydrobromide Storage: 22 – 25 -C, protected from light Compatible [17]
(DuoventR 0.31 mg/mL); mixed volume ratio 1 : 1 (PulmicortR : DuoventR) Determination: 0/18 h
Method: HPLC
Acetylcysteine (LysomucilR 100 mg/mL); mixed volume ratio 2 : 3 Storage: 22 – 25 -C, protected from light Compatible [17]
(PulmicortR : LysomucilR) Determination: 0/18 h
Method: HPLC
Used brands of budesonide inhalation suspension: [15,16]: PulmicortR 0.25 mg/2 mL or 0.5 mg/2 mL, [17]: PulmicortR 0.5 mg/mL.
RT = room temperature.

tion of ipratropium and ambroxole (e.g. MucosolvanR) According to the AHFS Drug Information [4] monograph
and fenoterol (BerotecR LS 0.1%, no longer available on on acetylcysteine and the prescribing information for
the German market) is feasible. Mixing AtroventR with FluimucilR (brand of acetylcysteine), admixtures with some
cromolyn is not recommended, because of known nebulizable antibiotic drugs are physically and/or chemical-
incompatibility (see above). The prescribing information ly unstable. Drugdex [3] states that MucomystR 10% is
for BerodualR inhalation solution (brand of ipratropium compatible with colistin 37.5 mg/mL, based on the
and fenoterol) is consistent with respect to the compat- Mucomyst product information. Immediate use after mixing
ibility with MucosolvanR (brand of ambroxole). The is recommended. The prescribing information for Colistin
monograph on ‘‘ipratropium bromide’’ in Drugdex [3] zur InhalationR (brand of colistin) states that precipitation in
supplies no information about the stability of admixtures admixtures with other nebulizable antibiotic drugs may
of ipratropium inhalation solution. However, there are occur.
monographs on nebulizable combination products of
ipratropium and albuterol or fenoterol. The AHFS Drug 3.6. Tobramycin
Information [4] monograph on ipratropium reports com-
patibility of an admixture with orciprenaline sulfate over According to the prescribing information of GernebcinR
1 h. and TOBIR (brands of tobramycin) and the AHFS Drug
Tzung-Yiet et al. found an admixture of AceteinR (brand Information [4] monograph on tobramycin sulfate, tobra-
of N-acetylcysteine sodium 352.4 mg/2 mL) with mycin inhalation solution should not be diluted or mixed
AtroventR (brand of ipratropium bromide 500 Ag/2 mL) with other drugs. Drugdex [3] includes a warning against
to be compatible for 1 h; admixture with BerotecR (brand of mixing tobramycin and dornase alfa (PulmozymeR) in
fenoterol hydrobromide 1.25 mg/2 mL) was stable for at addition to the above mentioned compatibility of tobramy-
least 7 h [18]. cin and albuterol admixture [6].

3.5. Acetylcysteine and colistin 3.7. Dornase alfa

Compatibility over 1 h has been reported for admixtures The prescribing information for PulmozymeR (brand of
of MucomystR (brand of acetylcysteine 1 g/5 mL) and dornase alfa), Drugdex [3] and AHFS Drug Information [4]
NetromicineR (brand of netilmicin 100 mg/1 mL) or all consistently state that dornase alfa inhalation solution
CelesteneR (brand of betamethasone 4 mg/1 mL), when should not be diluted or mixed with other drug solutions in
test solutions were stored at room temperature [19]. nebulizers.
W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213 211

Aerodynammic behaviour of admixtures of nebulizer and volumes tested. In addition, transferring results of
solutions has hardly been studied. According to our experimental studies from one drug product to another is
literature research, only in one study [29] an admixture of difficult as preservatives and other excipients can vary and
budesonide (PulmicortR 0.25 or 0.50 mg/2 mL) and cause incompatibilities. For example the preservative BAC
albuterol (0.5 mL ProventilR solution for inhalation 0.5% causes cloudiness in admixtures containing cromolyn
in 2.5 mL sterile saline or 3 mL albuterol sulfate, USP [12,13,21] or colistin [10]. The cloudiness is due to an
inhalation solution, 0.083%) was nebulized. The authors oily, non-crystalline complex [12,13,21] and increases with
describe an increase of budesonide delivery and nebuliza- increasing concentrations of BAC [13,21]. The influence of
tion time with increasing volume of nebulizer charge. complex formation on the aerodynamic behaviour of the
admixtures has not been studied [21].
Furthermore, it is questionable whether the quantitative
4. Discussion analysis of drug substances in samples taken from the
admixture containers is adequate, or whether the drug
Our own experience, together with inquiries among content needs to be determined in the aerosols. Owsley et
colleagues and patients, revealed considerable demand for al. [24] questioned the reported compatibility of admix-
information about the compatibility of drug solutions and tures containing cromolyn [11,14]. Using a filtration
suspensions for oral inhalation (which we have described as method (USP method for analyzing particulates in large
‘‘inhalation solutions’’). However, the available data are volume parenterals [25]), 22 admixtures of various
limited and inconsistent. inhalation solutions were analyzed in samples taken 0, 5,
The well-known handbook on drug compatibility, 10, 20 min and 24 h after mixing. With a maximum
‘‘Handbook of Injectable Drugs [5]’’, considers injectable allowed particle load of 50 particles  10 Am diameter or 5
drugs only. No information is given about the compatibility particles  25 Am diameter per mL admixture, 19 of 22
of inhalation solution admixtures. In prescribing informa- admixtures were classified as incompatible, including all
tion for licensed inhalation solutions, there is no consistent admixtures containing cromolyn. The authors [24] postu-
standard regarding information about compatibility of lated that the mobile phase used in HPLC experiments
admixtures. Moreover, few studies on the physical and may solve invisible precipitates, leading to erroneous
chemical stability of inhalation solution admixtures have results of unchanged drug content and an incorrect
been published and the quality of studies and reviews conclusion about compatibility. However, for inhalation
[20,21] varies. In some cases, the compatibility of inhalation solutions, the chosen limits of particle diameters of  10
solutions is stated without any supporting experimental data Am and  25 Am may not be adequate. The portion of
[22,23]. In summary, the problem of compatibility of particles with a diameter > 5 Am might have been even
inhalation solution admixtures receives little attention at more relevant.
present and has not been comprehensively researched at all. In the European and the US pharmacopoeia [25,26]
Strictly speaking, compatibility demonstrated in experi- analytical methods to determine the proportion of droplets
mental studies can only be accepted for the concentrations and particles < 5 Am in diameter are described. The US

Table 5
Admixture advices for commonly used drug solutions/suspensions in nebulizers

Albuterol Ipratropium Cromolyn Budesonide Tobramycin Colistin Dornase alfa


Not
Albuterol Possible Possible Possible Possible Possible recommended
Not
Ipratropium Possible Possible Possible Possible No information recommended
Not Not
Cromolyn Possible Possible Possible recommended No information recommended
Not Not
Budesonide Possible Possible Possible recommended No information recommended
Not Not Not
Tobramycin Possible Possible recommended recommended Not reasonable recommended
Not
Colistin Possible No information No information No information Not reasonable recommended
Not Not Not Not Not Not
Dornase alfa recommended recommended recommended recommended recommended recommended

Possible Mixtures are compatible, if preservative-free solutions (no benzalkonium choride) are used.
Not applicable.
212 W. Kamin et al. / Journal of Cystic Fibrosis 5 (2006) 205 – 213

pharmacopoeia [25] requires that the particle size of the incompatible with the preservative BAC, the admixtures
medication delivered must be carefully controlled, and the must be prepared with brands of inhalation solutions
average diameter of the particles should be less than 5 Am. containing no preservatives.
The European pharmacopoeia [27] only states that the size For those admixtures of inhalation solutions where no
of aerosol particles to be inhaled is controlled so that a information about compatibility is available or admixtures
significant fraction is deposited in the lung. are not recommended by the manufacturer, the authors
Even if the admixtures are physically and chemically decided to perform compatibility studies. Results will be
compatible in the nebulizer cup, the aerodynamic behaviour published in the near future. In addition to the compat-
may be influenced by mixing inhalation solutions. Ques- ibility studies the aerodynamic behaviour of compatible
tions such as droplet and particle size distribution in the admixtures will be studied to ensure that simultaneous
aerosols and incompatibilities arising during nebulization of nebulization of admixtures is recommendable.
the admixtures remain to be addressed.
Clay et al. [28] report that the temperature of the
inhalation solutions in the nebulizer cup decreases to Acknowledgments
different extents during nebulization depending on the type
of jet nebulizer used. When nebulizing 2 mL solution with The authors wish to thank Dr. Frank Erdnüß for his help
compressed air at a flow of 4 L/min the temperature of the in preparing this manuscript.
solution dropped up to 12 -C during the first 5 min and
remained constant afterwards. It is not known whether this
drop in temperature causes any changes in the compatibility References
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