Tens of thousands of children are sick with multidrugresistant forms of tuberculosis (MDR-TB), but there are limited child-friendly delivery systems for second-line medications. This case study presents the devel opment of a granular dosing spoon pediatric delivery system for para-aminosalicylic acid. This product is the first of its kind for MDR-TB and could serve as a model for the development of other urgently needed pediatric delivery systems for second-line anti-tuberculosis drugs

E Lessem

G Brigden

J Furin

Jennifer Furin

M C Becerra

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INT J TUBERC LUNG DIS e-publication ahead of print 3 July 2013
© 2013 The Union; 1–3
http://dx.doi.org/10.5588/ijtld.13.0196
CASE STUDY
Novel pediatric delivery systems for second-line 
anti-tuberculosis medications: a case study
J. Furin,* G. Brigden,† E. Lessem,‡ M. C. Becerra§
* Tuberculosis Research Unit, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; † Campaign 
for Access to Essential Medicines, Médecins Sans Frontières, Geneva, Switzerland; ‡ Treatment Action Group, 
New York, New York, § Harvard Medical School, Boston, Massachusetts, USA 
Correspondence to: Jennifer Furin, Tuberculosis Research Unit, School of Medicine, Case Western Reserve University, 2120 
Circle Drive, Cleveland, OH 44106, USA. Tel: (+1) 216 374 5938. Fax: (+1) 216 368 1490. e-mail: jenniferfurin@gmail.com
Article submitted 14 March 2013. Final version accepted 3 April 2013.
Tens of thousands of children are sick with multidrug-
resistant forms of tuberculosis (MDR-TB), but there are 
limited child-friendly delivery systems for second-line 
medications. This case study presents the devel opment 
of a granular dosing spoon pediatric delivery system for 
para-aminosalicylic acid. This product is the first of its 
kind for MDR-TB and could serve as a model for the 
development of other urgently needed pediatric delivery 
systems for second-line anti-tuberculosis drugs.
K E Y  W O R D S :  pediatric; MDR-TB; PAS; TB
MULTIDRUG-RESISTANT tuberculosis (MDR-TB) 
is a major public health threat, and it is estimated 
that there are more than half a million individuals 
with MDR-TB in the world today.1 Data on pediatric 
MDR-TB are limited, but it is likely that there are at 
least 45 000–50 000 children who become sick with 
MDR-TB globally every year.2 It is estimated that less 
than 1% of children with MDR-TB actually receive 
treatment for their disease,3 although children have 
excellent outcomes.4 
There are multiple reasons why children are over-
looked in the global response to the MDR-TB pan-
demic. One barrier is diagnosing MDR-TB in the pe-
diatric population.5 Once a diagnosis has been made, 
the major challenge faced by clinicians is initiating 
children with MDR-TB on appropriate treatment. 
Pharmacokinetic data in pediatric populations are 
lacking, making dosing recommendations unclear.6 
Further compounding the problem is the lack of pe-
diatric formulations of or delivery systems for most 
second-line anti-tuberculosis medications.7 
The lack of child-friendly delivery systems is not 
unique to the problem of MDR-TB and has been 
confronted in other diseases, most notably human 
immunodefi ciency virus infection.8 One approach has 
been the development of fi xed-dose combinations 
(FDCs) in dispersable tablet forms. Such delivery sys-
tems for MDR-TB treatment are likely decades away, 
however, and there is an urgent need for child-friendly 
formulations for treating children currently sick with 
MDR-TB. 
This article presents a case study of the develop-
ment of a pediatric delivery system for granular 
para-aminosalicylic acid (PAS) as a possible alterna-
tive approach to developing pediatric formulations 
of second-line anti-tuberculosis medications. This 
is the fi rst such delivery system available for pe-
diatric second-line anti-tuberculosis drugs and can 
be an instructive case for pediatric MDR-TB drug 
development.
CASE STUDY
Para-aminosalicylic acid 
PAS is a second-line medication used in the treatment 
of drug-resistant TB.9 PAS was originally one of the 
fi rst medications used to treat TB and was often given 
with streptomycin before the development of isonia-
zid. The use of PAS was limited by the large pill bur-
den and the large size of the pills. To improve the 
safety profi le and to ease administration, a gastro-
r esistant granular form of PAS (Paser®) was developed 
by Jacobus Pharmaceuticals (Princeton, NJ, USA, 
http://www.onlinedrugtest.info/companies/jacobus-
pharmaceutical-company-pharmaceuticals-company.
html), and this is the formulation most commonly 
used worldwide. Paser comes in sachets of 4 g PAS. 
Dosing PAS for pediatric patients can be diffi cult: as 
children need doses of between 150 and 300 mg/kg/
day, entire sachets must be opened, and weighing out 
the granules can be labor-intensive. 
On 17 December 2010, orphan designation (EU/3/ 
10/826) was granted by the European Commission 
to Lucane Pharma, Paris, France, for Paser for the 
S U M M A R Y
2 The  International  Journal  of  Tuberculosis  and  Lung  Disease
treatment of TB. Lucane, which has a history of work-
ing with other designated orphan drugs, was asked to 
develop a pediatric delivery system for Paser for use 
in Europe.
Dosing spoon intervention
Lucane determined that the adult granular formula-
tion of PAS (Paser) was amenable to adaptation for 
pediatric use. Their development strategy found that 
granule formulations are well suited for the dosing of 
infants and children for several reasons. First, doses 
can be calibrated to body weight. Furthermore, gran-
ules allow the unpleasant taste of many medicines to 
be masked, which can be diffi cult to achieve with liq-
uid forms. Granule forms are also often more stable 
than liquids, making them easier to distribute and 
store safely in more inaccessible locations. Finally, al-
though 4 g is the dose of active ingredient to be deliv-
ered, the actual weight of the Paser granules can be 
higher; the dosing spoon takes this into account and 
allows the correct dose of the active ingredient to be 
delivered.
To ease dispensing of PAS for children, Lucane de-
veloped a pediatric ‘dosing spoon’, calibrated specifi -
cally for Paser. The spoon allows providers to dis-
pense Paser in dosing ranges acceptable for children, 
and has cut-off marks for the different doses of PAS 
based on weight-band doses (Figure). The spoon has 
been purchased in small quantities by Médecins Sans 
Frontières for some of its project sites. It is now avail-
able from Lucane and will be included in all Euro-
pean Union packs if the product is granted marketing 
authorization. 
Development
To facilitate the development of pediatric PAS, Lu-
cane did not change the adult formulation. Rather, 
they worked with the existing formulation and came 
up with a novel method for dosing, i.e., a pediatric 
delivery system. Lucane encountered some challenges 
in creating this pediatric delivery system. It took al-
most 9 months to develop and validate the device. 
Furthermore, the number of MDR-TB patients in Eu-
rope is relatively small, and the number of children 
requiring Paser in Europe is unlikely to exceed 200 
per year. This small market made registering the de-
vice in Europe more diffi cult. Finally, there are issues 
with the level of calibration and accuracy that can be 
achieved with these spoons. The spoon is operator-
dependent, and requires that the dispenser be famil-
iar with the marking system. Dispensing doses be-
tween those calibrated on the spoon (e.g., 750 mg) 
requires special attention. Despite these limitations, 
the dosing spoon developed by Lucane is one of the 
few pediatric-friendly delivery systems for second-line 
anti-tuberculosis drugs available and the only one of 
its kind in use today.
DISCUSSION
The lack of child-friendly formulations for second-
line anti-tuberculosis medications greatly hinders ac-
cess to MDR-TB treatment for thousands of children 
around the world. While some of the second-line 
medications come as syrups (e.g., linezolid, levofl oxa-
cin), they can be cumbersome, diffi cult to store and 
require large volumes to be administered daily. Other 
medications come as injectables (e.g., capreomycin, 
the aminoglycosides), and while it may be possible to 
adjust injection doses for children, this mode of deliv-
ery can be painful. This case study presents one way in 
which the pharmaceutical industry has responded to 
the need for pediatric delivery systems for second-line 
medications, drugs for which there is a limited market. 
Similar action is needed for other second-line anti-
t uberculosis drugs—particularly medications such as 
cycloserine (CS) and ethionamide (ETH), for which 
no such delivery systems exist—to improve the global 
management of pediatric MDR-TB.
The pediatric pharmaceutical community is aim-
ing for dispersible FDCs as a way of providing safe 
and effective treatment for children with TB and 
MDR-TB. However, due to the lack of certainty re-
garding the dosages required for MDR-TB in children 
and the number of drugs involved, the development 
of an FDC for MDR-TB is still some time away. The 
development of granules and dosing spoons offers 
an alternative to the standard FDC approach. Other 
medications such as CS or ETH could be developed 
into granular formulations with spoon delivery sys-
tems at a minimal cost. The granular approach to pe-
diatric dosing has the potential to address the urgent 
need for pediatric-friendly formulations of and deliv-
ery systems for other second-line anti-tuberculosis 
medications, and it should be pursued in future drug 
development plans.
Acknowledgements
The authors of this article are grateful to Lucane Pharma—notably 
P Mambrini and P Lewis—for their assistance with this work and 
their careful reading of this manuscript.
Confl ict of interest: none declared.
References
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Pediatric  delivery  system  for  PAS i
Des dizaines de milliers d’enfants sont atteints de formes 
multirésistantes de tuberculose (TB-MDR), mais des 
systèmes de fourniture des médicaments de deuxième 
ligne adaptés aux enfants n’existent que de manière li-
mitée. Cette étude de cas expose l’élaboration d’un sys-
tème de délivrance de l’acide para-aminosalicylique aux 
enfants au moyen d’une cuillère permettant le dosage de 
granulés. Cet instrument est le premier dans son genre 
pour la TB-MDR et pourrait servir de modèle pour 
l’élaboration d’autres systèmes de délivrance pédiatrique 
nécessaires d’urgence pour les médicaments antituber-
culeux de deuxième ligne.
Decenas de miles de niños sufren de formas multidrogo-
resistentes de tuberculosis (TB-MDR), pero se cuenta 
con muy pocos sistemas de administración de medica-
mentos de segunda línea que sean adaptados para los 
niños. En el presente análisis casuístico se presenta el 
desarrollo de un sistema de administración de ácido 
p-aminosalicílico en gránulos con cuchara dosificadora 
para niños. Este producto es el primero en su género 
para el tratamiento de la TB-MDR y podría servir como 
modelo en otros sistemas de administración de medica-
mentos de segunda línea que se necesitan con urgencia 
en pediatría.
R É S U M É
R E S U M E N


Novel pediatric delivery systems for second-line anti-tuberculosis medications: a case study

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Novel pediatric delivery systems for second-line anti-tuberculosis medications: a case study

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