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International Journal of Pharmaceutics 469 (2014) 249250

Contents lists available at ScienceDirect

International Journal of Pharmaceutics


journal homepage: www.elsevier.com/locate/ijpharm

Mini review

How do Japanese children take their medicines, and what are


pharmacists and paediatricians doing about it?
Hidefumi Nakamura a, * , Yoichi Ishikawa b
a
b

Division for Clinical Trials, National Centre for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
Department of Pharmacy, National Centre for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 26 February 2014
Received in revised form 28 March 2014
Accepted 28 March 2014
Available online 1 April 2014

In Japan, powders for reconstitution are often dispensed in sachets, and parents add small amount of
water or syrups to make the powders paste-like or condensed syrup and have their children take the
medicines. Compounding is common just like any other parts of the world. According to the survey in
2005, most commonly compounded medicines include warfarin, digoxin and enalapril. Crushed tablets
or capsules are often mixed with sucrose or starch and kept in bottles at pharmacy departments for
regular use. There is no regulation so far to mandate pediatric drug/formulation development in Japan.
The pediatric premium can be given to drugs whose indications and dosage are clearly for children, but
this is not sufcient for many drug companies especially when their drug prices are cheap. In 2013, new
MHLW grant-supported project for regulatory science in pediatric drug development started, and
discussion on key issues related to pediatric drug development including formulations, modeling and
simulation and neonatal drug evaluation is ongoing including the possible change on legal framework to
facilitate pediatric drug development in the country. Initiation of international collaboration with global
partners including the European Paediatric Formulation Initiative is to be expected.
2014 Elsevier B.V. All rights reserved.

In Japan, medicines for children often are liquids, powders or


small granules. Compounding is common just like any other parts
of the world. When dry syrups (powders for reconstitution) are
dispensed, it is commonly put and dispensed in a sachet for each
dose rather than adding sterile water at each pharmacy. Most
pharmacies have a powder packing machine to evenly put each
dose of powder, dry syrup or granules in sachets as shown in Fig. 1.
Parents often add small amount of water or syrup to make dry
syrup paste-like or condensed syrup to help children swallow.
With the poor taste of drugs, parents also use different foods with
different tastes and avours including chocolate cream, jam,
condensed milk, ice cream, jelly, cocoa, maple syrup, peanut butter
to make the medicine easier to be taken. There are also
commercially available jellies with different avours.
In 2005, Kato investigated the incidences of dosage forms
changes at 32 institutions in one month period (Kato, 2006). In
1227 occasions, powders were made by crushing tablets/capsules

* Corresponding author at: Division for Clinical Trials, Deparment of Development Strategy, Centre for Social and Clinical Research, National Centre for Child
Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Tel.:
+81 3 3416 0181x5373; fax: +81 3 3417 5691.
E-mail address: nakamura-hd@ncchd.go.jp (H. Nakamura).
http://dx.doi.org/10.1016/j.ijpharm.2014.03.053
0378-5173/ 2014 Elsevier B.V. All rights reserved.

and by often adding sucrose or starch to make the amount


measurable by packing machines. The top 10 drugs for dosage form
changes on prescription number basis are listed in Table 1. Most of
these medicines are still compounded at each pharmacy even now.
Some of these medicines are kept in bottles at pharmacy
departments for regular use after being crushed and mixed with
sucrose or starch (Fig. 2). For some powders, one concentration is
sufcient for certain age group, but too much or too little for other
age groups. In that case, powders with different concentrations are
also prepared.
In case of tacrolimus, granules are commercially available either
as 0.2 mg or 1.0 mg in a sachet. As small children need more minute
dosage change, 0.1 mg sachet is also compounded in the pharmacy
and kept in a refrigerator at the National Centre for Child Health
and Development (Fig. 3).
Warfarin is known to be unstable under light. Some pharmacies
fail to protect the medicine from light which could be a cause of
treatment failure in some patients. In December 2011, Eisai
developed 0.2% coated warfarin granule stable exposed to light.
There are also some other drug companies trying to develop better
pediatric formulations. But, there is no regulation to mandate
pediatric drug/formulation development in Japan, and formulation
development for children is at each drug companys discretion.

250

H. Nakamura, Y. Ishikawa / International Journal of Pharmaceutics 469 (2014) 249250

Fig. 1. Powder packing machine at the National Centre for Child Health and
Development.
Table 1
Top 10 drugs for dosage form changes on prescription number basis at 32
institutions in 2005 (Kato, 2006).

1
2
3
4
5
6
7
8
9
10

Drug names

Form

Prescription numbers/month

Warfarin
Digoxin
Enalapril
Dantrium
Lisinopril
Beraprost
Hydrocortisone
Bacrofen
Chloral hydrate
Propranolol

Tablet
Tablet
Capsule
Tablet
Tablet
Tablet
Tablet
Tablet
Powder
Tablet

1052
568
550
482
456
444
406
374
364
356

Fig. 3. 0.1 mg tacrolimus is premixed with sucrose and kept in a refrigerator at


National Centre for Child Health and Development.

Some incentives exist as a drug price premium for pediatric


formulation development. The pediatric premium (520% increase) can be given to drugs whose indications and dosage are
clearly for children. This 520% is appealing for the development of
some drugs, but this is not too attractive for many drug companies
to develop pediatric formulations especially when the price is
cheap.
In 2013, new Ministry of Health, Labour and Welfare (MHLW)
grant-supported project for regulatory science in pediatric drug
development started. This project focuses on some of the key
issues related to pediatric drug development including formulations, modeling and simulation and neonatal drug evaluation.
Discussion with representatives from academia, industries and the
regulatory agency started. Possible change of legal framework to
facilitate pediatric drug development in Japan is also in the scope
of the discussion. Representatives from the Japan Society of
Developmental Pharmacology and Therapeutics and the Academy
of Pharmaceutical Science and Technology are starting to discuss
the development of better pediatric formulations from a technical
and clinical standpoint. With all these efforts combined, initiation
of international collaboration with other global partners including
the European Paediatric Formulation Initiative, the Global Research in Paediatrics, and the Global Alliance for Pediatric
Therapeutics is to be expected.
References

Fig. 2. Bottles of pre-prepared powders at pharmacy departments for regular use.

Kato, H., 2006. Survey of paediatric dosage form changes in Japan. In: Ishikawa, Y.
(Ed.), The Annual Report of MHLW Grant Supported Project Research on Data
Network for Paediatric Therapeutics (In Japanese), pp. 1932 (Not available
online).