A Review on Current Solid Oral Pediatrics Dosage Forms.pptx

Addis Ababa University
College of health science
School of Pharmacy
Department of Pharmaceutics and Social pharmacy
Presented by : Zerlealem Tsegaye
Date: July 21, 2021
A Review on Current Solid Oral
Pediatrics Dosage Forms
3/3/2024
1

Presentation outline
3/3/2024
2
 Introduction
 Pediatric Physiological consideration
 Formulation consideration
 Dosage form consideration
 Summary

Introduction
 The pediatrics population is divided, by age, into five or six
categories.
 In the ‘Note for guidance on clinical investigation of medicinal
products in the pediatrics population’ of the International
Conference of Harmonization (ICH),
 The groups of preterm newborns, newborns, infants and
toddlers, children and adolescents have been defined.
3/3/2024
3

Introduction
 Most conventional drug delivery systems aren’t acceptable for pediatric
patients as they differ in their developmental status and dosing
requirements from other subsets of the population.
 Advanced solutions are required to aid the development of age-
appropriate medicines to maximize patient acceptability while
maintaining safety, efficacy, accessibility and affordability
 The development of an age-appropriate formulation may be a
challenging task owing to the broad range of pharmaceutical and clinical
aspects that has got to be considered so as to make sure the quality,
safety and efficacy of the final product.
3/3/2024
4

Introduction
 Historically, drugs are developed with focus on mainly adult
population.
 Hence, information obtained for the drug molecule is not readily
applicable for direct use in pediatric population given the very
fact that nonlinearity exists on various aspects across pediatric
age range.
 The validated biomarkers that could be used for pediatric
population are limited in number.
 Therefore, application of the available adult biomarkers directly
to children to gather pediatric data is often carried out.
3/3/2024
5

Introduction
 Pediatrics formulations need to be appropriate for the child in
terms of dose, convenience and acceptability to ensure
compliance with the medication.
 There are differences in Pediatrics anatomy and physiology that
can impact upon the performance of a drug that is different from
that observed in adults.
 The design of a Pediatrics formulation needs to take these
differences in physiology into account to ensure that the
pharmacokinetic profile of the drug is not compromised
3/3/2024
6

Introduction
 Healthcare professionals and parents or caregivers are often
required to manipulate an adult medicine to obtain an
appropriate dose for a child, for example, by splitting a tablet to
provide a smaller dose or in more complex cases preparing a
suspension from a crushed tablet.
 Such manipulations increase the variability in the product by
inaccurate measurement, issues with stability, or errors in
instruction for manipulation
 The World Health Organization (WHO) estimates that
approximately 50% of the medicines prescribed for children are
not commercially available in pediatric form (Nahata & Allen Jr.,
2008).
3/3/2024
7

Introduction
 In the past children were largely denied access to
appropriate medicines that meet these criteria.
 Historically, children have not received medicines that
have been rigorously evaluated and have been given
medicines designed for adults.
 When medicines are adapted for children this is often
done informally and in the absence of evidence, using
measures such as cutting pills in half
3/3/2024
8

Introduction
 This review discuss the physiological considerations
and formulation consideration in pediatric oral
formulation.
 It provides an overview of currently available
innovative solid oral pediatric formulation and the
improvement in already accessible oral dosage
formulations.
3/3/2024
9

Pediatrics physiological
considerations
 Neonates in the early stage of less than 2 weeks could not
produce acid in the stomach (achlorhydria), which can
significantly affect the drug release and absorption of drugs.
 Gastric emptying time in these neonates is found to be
prolonged, irregular, and difficult to predict.
 This increased gastric emptying time may result in higher
degradation of the drug due to increased contact time with
gastric contents
 Pancreatic enzyme activity is low in early ages and develops
gradually
 Absorption of lipid-soluble drugs may also be decreased in
neonates due to the lower release of bile acids and lipase.
3/3/2024
10

considerations
 Infants have high ratio of total body water than adults generating
a large volume of distribution for hydrophilic drugs and low
volume of distribution for lipophillic drugs.
 Infants have decreased level of albumin, modified protein binding
characteristics and increased competition for binding
endogenous substances.
 A highly permeable blood brain (BBB) further allows increased
drug absorption.
 Tissue permeability, perfusion rate, tissue drug binding are major
factors affecting drug distribution.
 Decrease in liver volume, regional blood flow of liver reduces
drug (Ankita Mistry, 2015).
3/3/2024
11

considerations
 The drug metabolism in the liver is mostly carried by enzyme
cytochrome P-450.
 Less maturation of various metabolic pathways like these within infants
is a reason to have substantially slower drug metabolism among
pediatric population in infants in comparison to higher age children and
adults.
 The efficacy of the renal excretion of drug is the function of various
related processes, such as glomerular filtration, tubular secretion, and
tubular reabsorption determining the efficacy of renal excretion, which
are poorly developed in the 1st year of birth (Tréluyer et al., 2002).
 In infants, glomerular filtration rate is about 2–4 mL/minute/1.73 m2 ,
whereas the normal values for adults are largely over 60
mL/minute/1.73 m2 (Delanaye et al., 2012).
3/3/2024
12

Formulation considerations
Excipients for Pediatric Formulations
 Not all of Excipient can be considered safe for children.
 There is only limited knowledge available on the acceptability and safety of
formulation excipients in relation to the age and development status of the
child (European Medicines Agency, 2006)
 An adverse reaction in children due to the excipients used in the medicines
is an additional challenge which is not experienced by adults or is not seen
to the same extent.
3/3/2024
13

 Major problems with excipients in Pediatrics medicines, especially
when used to treat infants and neonates, have been reported
(Breitkreutz & Boos, 2007), e.g. medicines with benzyl alcohol, azo-
dyes, propylene glycol, ethanol and propyl paraben.
 A study on the exposure to benzyl alcohol and propylene glycol of
neonates receiving parenteral medication demonstrated a potential risk
of toxic doses, especially for neonates receiving continuous infusion
(Shehab et al., 2009).
 The toxicity of excipients to newborns and infants can be explained by
factors related to their physiological and metabolic development
(Gregory L. Kearns et al., 2003).
3/3/2024
14

Excipients for Pediatric
Formulations
 The amount of alcohol used as an excipient can cause toxic
effects in patients who have an idiosyncratic reaction to alcohol,
and in patients using drugs demonstrating a disulfiram-like effect.
 Drug formulations containing higher amounts of alcohol are
particularly toxic to children. Norvir®1 suspension, an anti-
retroviral preparation, contains high amounts of alcohol (Pawar &
Kumar, 2002).
3/3/2024
15

 Propylene glycol is another solvent used commonly in different for
formulation. However, it can accumulate in the body as pediatric
patients below 4 years have a limited metabolic pathway (alcohol
dehydrogenase).
 Depression of the central nervous system is the main toxic effect.
 laxative effects due to high osmotic pressure may be observed.
 Hence, the products containing high propylene glycol levels are not
suitable for children, especially below 4 years of age. Even topical use
of propylene glycol reported to cause contact dermatitis (European
Medicines Agency, 2006).
3/3/2024
16

 Sweeteners such as sucrose, fructose, sorbitol, xylitol, and
aspartame need to be cautiously used while considering some of
their effects.
 Formulations with high amount of sucrose should be avoided as
it lowers the pH of dental plaque which dissolves tooth enamel
and promotes dental caries.
 Similarly, fructose in high amounts can lead to laxative effects in
children.
 Sorbitol and xylitol may cause osmotic diarrhea though xylitol
offers the protection from dental caries (Raza et al., 2019).
3/3/2024
17

 Some colouring agents used in pediatrics medicines have
been associated with hypersensitivity.
 The number of colouring agents that are acceptable for use in
medicines is limited.
 Azo-dyes should be avoided in children’s medicines and
attention should be paid to the risk of allergic reactions
associated with natural colourants(WHO Expert Committee,
2012).
 With coating materials such as methacrylic acid and
ethacrylate copolymer, the cases of fibrosing colonopathy
have also been reported in children (European Medicines
Agency, 2006)
3/3/2024
18

 Taste and odor are important senses for the oral route of
administration and are developed at very early stage of the life.
 Newborns not only have taste buds but also they are more in
numbers compared to adults.
 However, their sensitivity to some taste such as salts develops
after 5 months.
3/3/2024
19

Dosage forms
Dispersible tablets
 Dispersible preparations are presented as solid formulations that are intended
to be dispersed or dissolved in water prior to administration.
 For the convenience of users, the formulations should disintegrate or dissolve
within a short time of being added to water, to yield a homogenous dispersion
or solution (Hannan P.A., Khan J.A., A. Khan, 2016).
 While these formulations require minimal preparation prior to use, health
literacy of caregivers may be an important factor to consider in their use.
 Clear instructions should detail appropriate diluents and volumes to dissolve or
disperse in, and caregivers should be instructed not to administer the solution
before effervescence has subsided, to minimise the ingestion of hydrogen
carbonate.
 If dispersible products are not reconstituted in an appropriate volume of liquid
then there is a risk of local tissue injury and a delay in the onset of action,
since the solid material needs to dissolve prior to absorption (Rose & Tobin,
1980).
 These reconstituted products also need to be taste-masked. 3/3/2024
20

Table 1: prequalified dispersible tablet formulations for
Pediatrics by WHO.
Product Manufacturer Age group Indication Date of
prequalification
Reference
Pyrimethamine/sulfadoxi
ne 12.5 mg/ 250mg
dispersible tablets
S Kant Healthcare Ltd In infants aged less than
12 months
Malaria 12 April 2021 (WHO, 2021f)
Dihydroartemisinin
/Piperaquine (as
phosphate) 30mg/240mg
/20/160 mg Dispersible
Tablets
Guilin Pharmaceutical
Co., Ltd
Children and infants 6
months and over and
weighing 5kg or more
25 November 2020 (WHO, 2021g)
Artemether/Lumefantrine
20mg/120mg Dispersible
Tablets
Novartis
Pharmaceuticals
Corporation
Children and infants
(body weight ≥5 kg)
Malaria 27 February 2009 (WHO, 2021e)
Ajanta Pharma Limited 19 December 2012. (WHO, 2021d)
Strides Pharma Science
Limited
12 December 2017 (WHO, 2021c)
Cipla limited 17 July 2017 (WHO, 2021a)
Levofloxacin 100 mg
Dispersible Tablets
Macleods
Pharmaceuticals Ltd
Dose of 15–20 mg/kg
aged up to 5 year and
dose 10–15 mg/ kg for
aged over 5 years
tuberculosis 22 February 2018 (WHO, 2018a)
Ethionamide 125 mg
Dispersible Tablet
Macleods
Pharmaceuticals Limited
Pediatrics dose of 15-20
mg/kg is recommended
30 May 2017 (WHO, 2020a)
Ethambutol
hydrochloride 100 mg
dispersible tablets
Macleods
Pharmaceuticals Ltd
Children younger than
15 years , The dose is
15-25 mg/kg body
weight, taken once daily:
14 March 2018. (WHO, 2021b)
Rifampicin/Isoniazid/Pyr
azinamide 75 mg/50
mg/150 mg Dispersible
Tablets
Macleods
Children weighing from 4
kg, no age restriction
12 December 2017 (WHO, 2018b)
Rifampicin/Isoniazid 75
mg/50 mg Dispersible
Tablet
Macleods
In children weighing less
that 25 kg
31 August 2017 (WHO, 2017)
Isoniazid 50 and 100 mg
Dispersible Tablets
Micro Labs Limited For all age groups no
age restriction
16 March 2020 (WHO, 2020c)
Moxifloxacin (as
hydrochloride) 100mg
Micro Labs Limited Children weighing less
than 30 kg and under 15
31 October 2018 (WHO, 2020b)
3/3/2024
21

Orodispersible tablets
 Orodispersible tablets are solid oral preparations that disintegrate
rapidly in the oral cavity, with an in-vitro disintegration time of
approximately 30 seconds or less. The products are designed to
disintegrate or dissolve rapidly on contact with saliva, thus eliminating
the need to chew the tablet, swallow an intact tablet, or take the tablet
with liquids ((CDER), 2008).
 According to the European Pharmacopoeia, orodispersible tablets
(ODTs) are uncoated tablets intended to be placed in the mouth where
they disperse rapidly before being swallowed. The European
Pharmacopoeia specifies a limit of 3 min for the in vitro disintegration in
water.
3/3/2024
22

Orodispersible tablets
 This dosage form is very much suitable for children having no primary teeth (Dey
& Maiti, 2010).
 A survey conducted in four European countries showed , more than two thirds of
the asked parents are willing to consider the use of ODT for allergy treatment of
their children (Valovirta & Scadding, 2009).
 Another trial was conducted evaluating the acceptability of
SoluPredOroDispersible (ODT with a prednisolone salt) amongst 56 children in
between 2 and 12 years of age. The results on semi qualitative verbal scale
show that 96.2% found the administration easy or very easy and more than 90%
would prefer the same product in case a new treatment is required (Slavkova &
Breitkreutz, 2015).
3/3/2024
23

Table 2 Examples of licensed and marketed orally dispersible
tablets
Product name Age Company Reference
Allegra (fexofenadine hydrochloride
orally disintegrating tablets)
For pediatrics 6 years
and older
Sanofi Aventis (FDA, 2000)
Claritin Reditabs (Loratadine 10 mg
orally disintegrating tablets)
and older
Bayer healthcare
LLC
(Llc, 2020)
Orapred ODT (Prednisolone orally
disintegrating tablets)
No age restriction Concordia
Pharms Inc
(FDA, 2020a)
Lamictal ODT (Lamotrigine orally
disintigating tablets)
and older
GSK (FDA, 2021a)
Imodium (loperamide) For pediatrics 12 years
and older
Janssen (FDA, 2017a)
3/3/2024
24

Multi-particulate dosage forms
 Multi-particulate dosage forms may offer a flexible dosing system that allows
covering a broad range of doses for different age groups.
 Since each individual unit contains a small amount of drug, dose adjustment
can be accurately done by means of dosing device e.g. multi-particulate
counting devices or volume/weight measuring devices.
 On the other hand a fast disintegrating system is the most convenient mode
of medicine administration for pediatric population and other patients with
dysphasia.
 Such dosage form can disintegrate and/or dissolve spontaneously in the
oral cavity, resulting in a solution or suspension that can be easily
swallowed (Hoang Thi et al., 2015).
 They can be used for immediate or modified release. They can be used in
different pharmaceutical dosage forms such as oral suspension (ready to
use, dry suspension), sachet, capsule, minitablets or orally disintegrating
tablets ‘ODTs)(Martinez Teran et al., 2017).
3/3/2024
25

Modified release dosage forms in Pediatrics
population
 The use of modified release oral formulations in children can
significantly reduce the dosing frequency and can be beneficial for
compliance especially in chronic diseases.
 Extended-release formulations can be useful for children who
need to take medication while at school or during night.
 Not only reducing the frequent drug administration is important, but
also providing a favorable pharmacokinetic profile of the drug with
keeping drug concentration at a constant therapeutic level(Trofimiuk
et al., 2019).
3/3/2024
26

Modified release dosage forms in Pediatrics
population
 MHRA approves Granupas 4g gastro resistant granules in 2014,
 Similarly Para-aminosalicylate sodium delayed-release granules 60% w/w was
approved by WHO.
 An FDA approved drug Moxatag which is an extended-release amoxicillin tablet.
 FDA approves Adzenys XR-ODT. It is an extended release orally disintegrating
amphetamine tablets,
 EMA, MHRA and FDA approved Viramune prolonged-release tablets (50, 100
and 400 mg).
 The other FDA approved Azulfidine EN delayed release tablets contain
sulfasalazine, 500mg for oral administration.
 Creon is a pancreatic enzyme formulated as delayed release mini tablets in a
capsule.
 Keppra XR is an extended release tablet formulation of Levetiracetam
 Dyanavel XR is an extended release suspension; Delsym an extended release
suspension of a drug dextromethorphan and extended release suspension Zmax
3/3/2024
27

Modified Release Orodispersible tablets
 An FDA approved PrevacidSoulTab is a delayed release
orally disintegrating tablet contains the active ingredient
lansoprazole , indicated for short-term treatment in adults and
pediatric patients 12 to 17 years of age (up to eight weeks)
and pediatric patients one to 11 years of age (up to 12 weeks)
for healing and symptom relief of all grades of erosive
esophagitis (FDA, 2020b).
 Another medicine methylphenidate extended-release oral
suspension was used to reduce symptoms of attention-deficit
hyperactivity disorder in children.
3/3/2024
28

Mini tablets for Pediatrics
 The small size makes them easier to swallow for young patients,
where the minitablets can be mixed with or sprinkled onto soft food
to assist with administration(Klingmann et al., 2015)
 In addition, multiple minitablets can be packaged into capsules for
ease of transport and administration to patients in older age groups
such as teenagers or even adults.
 Flexible dosing can also be accomplished by adjusting the number
of minitablets administered to different pediatric patient populations.
 In particular, the doses of different active ingredients can be varied
independently across different age groups in combination therapies.
 When compared to other oral pediatric dosage forms such as
liquids, minitablets retain the advantages of oral solid dosage forms,
such as easy to transportation and administeration, which make
minitablets an interesting choice for an ageappropriate pediatric
dosage form (Zhang et al., 2020). 3/3/2024
29

 A study carried out to evaluate the suitability of drug-free solid dosage forms (2 mm
mini-tablets) as an alternative administration modality in neonates in comparison with
syrup (Klingmann et al., 2015).
 A similar study was conducted to evaluate acceptability of 2 mm solid dosage forms
(mini-tablets) as an alternative administration modality in young children in comparison
with syrup. (Klingmann et al., 2013).
 Another study has been conducted to assess the acceptability and swallowability of
several minitablets when administered as a unit dose compared with an equivalent
dose of syrup in children aged 6 months to 5 years.
 Administration of ≥25 minitablets is well-tolerated, feasible, and safe in children
aged from 6 months, and was superior to the equivalent dose of syrup.
 Children aged >1 year accept ≤400 minitablets even better than the equivalent
dose of syrup (Klingmann et al., 2018).
3/3/2024
30

3/3/2024
31
 Recently a small number of medicines emerge to
have been marketed. Orfiril long is an extended
mini tablets provided in hard capsule or single
sachet form.
 It is licensed in different European member countries for the
treatment of epilepsy in pediatrics patients age greater than
or equals to six years.
 FDA approved a new dosage form – oral
granules, of Kalydeco (ivacaftor).
 The drug product ivacaftor granules is an immediate release
dosage form for oral administration intended for the
treatment of cystic fibrosis in patients age 2 years and older.

Summary
 During the past decade, a crucial number of age-appropriate solid oral
formulations are investigated, developed and some have gained marketing
authorization.
 The present approaches for the preparation of age-appropriate oral drug delivery
systems are reviewed all through this document.
 It’s unlikely that one formulation approach is going to be acceptable for all
pediatric patients.
 The choice of an appropriate formulation approach for a targeted population
group must be carefully considered.
 Further study all through this field is desired to allow link between formulation
technological aspects and pediatric population.
3/3/2024
32

Acknowledgments
3/3/2024
33
 I would like to express my gratitude to my advisor
Dr. Anteneh Belete for providing invaluable
guidance, comments and suggestions.
 I also thank Dr. GebremariamBrhanu and the
department for giving an opportunity to learn and
present the seminar.

A Review on Current Solid Oral Pediatrics Dosage Forms.pptx

Recommended

Recommended

More Related Content

Similar to A Review on Current Solid Oral Pediatrics Dosage Forms.pptx

Similar to A Review on Current Solid Oral Pediatrics Dosage Forms.pptx (20)

Recently uploaded

Recently uploaded (20)

A Review on Current Solid Oral Pediatrics Dosage Forms.pptx