Pharmaceutical Development with Focus

on Paediatric formulations
WHO/FIP Training Workshop
Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 2 May 2008

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Simon Mills | April 2008

Pharmaceutical Development with Focus

on Paediatric formulations
Pharmaceutical excipients an overview
including considerations for paediatric dosing

Presented by:
Name: Simon Mills
Contact details:
[email protected]

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Simon Mills | April 2008

Introduction
Overview of excipients commonly used
(particularly in oral dosage forms)

Role of Key Solid Dose Excipients

Diluents (fillers, bulking agents), Disintegrants, Binders, Lubricants , Glidants

Role of Key Solution/Suspension Excipients

Solvents/co-solvents , Buffering agents, Preservatives, Anti-oxidants,
Wetting agents, Anti-foaming agents, Thickening agents, Sweetening
agents, Flavouring agents, Humectants

Paediatric considerations with regard to excipients

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Simon Mills | April 2008

Solid dosage forms for paediatrics

Dose
Sipping
Technology

Confidential

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Liquid dosage forms for paediatrics

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Excipients an overview
Drug products contain both drug substance (commonly referred to as active
pharmaceutical ingredient or API) and excipients. Formulation of API with excipients is
primarily to:

Ensure an efficacious drug product with desired properties and a robust manufacturing process

The resultant biological, chemical and physical properties of the drug product are
directly affected by the excipients chosen, their concentration and interactions with the
API:
Consistency of drug release and bioavailability
Stability including protection from degradation
Ease of administration to the target patient population(s) by the intended route

Excipients are sub-divided into various functional classifications, depending on the role
that they are intended to play in the resultant formulation.
Certain excipients can have different functional roles in different formulation types,
e.g. lactose; widely used as:
a diluent, filler or bulking agent in tablets and capsules
a carrier for dry powder inhalation products (DPIs).

Furthermore, individual excipients can have different grades, types and sources
depending on those different functional roles.
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Simon Mills | April 2008

Excipients an overview
.for example, there are various grades of lactose commercially available that
have different physical properties, e.g. flow characteristics & particle size
distributions. This permits selection of what is considered the most suitable
grade for a particular need.
Wet Granulation: usually, finer grades of lactose are utilised as the binder is utilised more efficiently and
this permits better mixing and granule quality.
Direct Compression: in contrast here, spray dried lactose is used as it flows better and is more
compressible.
..And then for dry powder inhalers: crash-crystallisation fine-milled lactose with a coarser fraction for flow
and a finer fraction to enhance API aerosolisation and delivery to the lungs

In solid dosage forms, the key excipient types include:

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Diluents, e.g. lactose, microcrystalline cellulose

Disintegrants, e.g. sodium starch glycolate, croscarmellose sodium
Binders, e.g. PVP, HPMC
Lubricants, e.g. magnesium stearate
Glidants, e.g. colloidal SiO2

Simon Mills | April 2008

Diluents (Fillers)
Bulking agent
E.g. to make a tablet weight practical for the patient: minimum tablet weight is
typically ~50mg.
Actual API doses can be as low as ~20g, e.g. for oral steroids.

Compression aid
Deforms and/or fragments readily to facilitate robust bonding in tablet
compacts, e.g. microcrystalline cellulose.

Good bulk powder flow.diluents have a strong influence

Good flow of bulk powders is very important in designing a robust commercial
tablet product.
Favoured combinations: Lactose is an excellent choice of filler in many
respects but can exhibit poor flow characteristics, so is often combined with
free-flowing microcrystalline cellulose in wet granulation formulations.

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Simon Mills | April 2008

Disintegrants

As an aid to de-aggregation of solid dosage forms. Disintegrants cause

rapid break up (disintegration) of solid dosage forms upon exposure to
moisture.

Generally, disintegration is viewed as the first stage in the dissolution

process, although dissolution does occur simultaneously with
disintegration.

Mode of action:
In many cases water uptake alone will cause disintegration, by rupturing the
intra-particle cohesive forces that hold the tablet together and resulting in
subsequent disintegration.
If swelling occurs simultaneously with water uptake, the channels for
penetration are widened by physical rupture and the penetration rate of water
into the dosage form increased.

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Simon Mills | April 2008

Binders
Binders act as an adhesive to bind together powders, granules and
tablets to result in the necessary mechanical strength:
As a dry powder with other excipients in dry granulation (roller compaction, slugging) or as an
extra-granular excipient in a wet granulation tablet formulation.
As a dry powder with other intra-granular excipients in wet granulation. When the granulating
fluid is added, the binder may dissolve partially or completely to then exhibit adhesive binding
properties in helping granules to form.
Most commonly in wet granulation, the binder is added already dissolved in the granulating fluid
to enable a more effective and controllable granule formation.

Water is the most common granulating fluid, very occasionally in a co-solvent system with, e.g.
ethanol.

Examples:
Dry binders:
Solution binders:
Soluble in water/ethanol mix:

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Microcrystalline cellulose, cross-linked PVP

HPMC, PVP
PVP

Lubricants
Compression lubricants prevent adherence of granule/powder to punch
die/faces and promote smooth ejection from the die after compaction:
Magnesium stearate is by far the most extensively used tableting lubricant
There are alternatives, e.g. stearic acid, sodium stearyl fumarate, sodium behenate
Lubricants tend to be hydrophobic, so their levels (typically 0.3 2%) need to be
optimised:
Under-lubricated blends tend to flow poorly and show compression sticking
problems
Over-lubricated blends can adversely affect tablet hardness and dissolution rate

Lubricants can also be used when compression isnt involved, e.g.

In powder blends for filling into capsules to prevent adherence of granule/powder to
equipment surfaces and dosator mechanisms
Coating the surface of multi-particulate dosage forms (including intermediate product)
to inhibit agglomeration of individual particles

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Simon Mills | April 2008

Glidants
Most commonly; colloidal silicon dioxide (traditionally, talc was used)
Good bulk powder flowability is especially important during high speed
processing
Glidants improve flow by adhering to particles and so reducing
inter-particulate friction
Most common in dry powder formulations, e.g. direct compression tablets
Can also be added to granules to improve flow prior to compression
NB: can get undesirable flooding if flow is too good

Very low levels required (ca. <0.2%)

Control can be challenging with blends sensitive to levels

Very low bulk density (0.03 0.04g/cm3)

Difficult to work with (very voluminous) not a standard excipient, only added if
needed
Issues with dust exposure

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Simon Mills | April 2008

Excipient challenges (ARVs)

Anti-retroviral (ARV) and anti-tuberculosis drugs have a common challenge in being high dose.
There is also a patient preference for the drug cocktails associated with these diseases to be
presented as a fixed dose combination tablet rather than multiple single-API tablets. FDCs also
simplify the treatment and management of drug supply, which may help impede the emergence of
drug resistance.
This poses certain technical challenges, specifically for the paediatric market, because the tablets
must be swallowable.

Formulation design approach:

Understand variability in API(s) characteristics and minimize if possible, through processing
(granulation/slugging) if necessary
Choose excipients and appropriate grades that will, with minimal extra weight additional to the
API loading:
Enable development of a robust formulation and manufacturing process
Provide tablets with desired and consistent physical characteristics, stability profile and bioavailability

Consider a breakline (on top and bottom of tablet) to enable splitting of tablet to ease swallowing
and/or provide flexibility of dosing; each fragmented half will need to incorporate the appropriate
half-dose within specified limits

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Oro-dispersible tablets (ODT)

Tablets that rapidly disintegrate without chewing, when placed on top of tongue.
No water required for administration. Two main types of ODT:
Lyophilised units

Carrier excipient predominantly sucrose

Disintegrate in <5 seconds
Only low drug loading possible (~5-10mg)
Prone to friability packed into blisters

Conventional tablets
Standard tabletting processes; can involve novel/modified conventional and/or combination
excipients
Disintegrate in 20-60 seconds
Larger drug loading possible (up to ~500mg)
More robust can be packed into bottles as well as blisters

Issues:
Novelty of some excipients
Taste masking is a challenge and can be an expensive technical hurdle using excipients with little or
no paediatric safety information

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Excipients For Solution/Suspension Products

Again, excipients are sub-divided into various functional

classifications, depending on the role that they play in
the resultant formulation.

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Solvents/Co-Solvents
Water is the solvent most widely used as a vehicle due to:
Lack of toxicity, physiological compatibility, and good solubilising power (high dielectric
constant), but
Likely to cause instability of hydrolytically unstable drugs
Good vehicle for microbial growth

Sorbitol, dextrose, etc. are often added as solubilisers, as well

as base sweeteners
Similar pros and cons to water alone

Water-miscible co-solvents are used to:

Enhance solubility, taste, anti-microbial effectiveness or stability

Reduce dose volume (e.g. oral, injections)
Or, conversely, optimise insolubility (if taste of API is an issue)
Examples: propylene glycol, glycerol, ethanol, low molecular weight PEGs

Water-immiscible co-solvents, e.g.

Emulsions / microemulsions using fractionated coconut oils
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Buffering Agents
Can be necessary to maintain pH of the formulation to:

Ensure physiological compatibility

Maintaining/optimising chemical stability
Maintaining/optimising anti-microbial effectiveness
Optimise solubility (or insolubility if taste is an issue)
But, optimum pH for chemical stability, preservative
effectiveness and solubility (or insolubility) may not be the
same
Compromises need to be made

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Simon Mills | April 2008

Anti-microbial Preservatives
Preservatives are used in multi-use cosmetic/pharmaceutical products (including
paediatric formulations)
Prevents an increased risk of contamination and proliferation by opportunistic microbes (from
excipients or introduced externally), that would result in potential health issues
Avoid use wherever possible, especially in products aimed at younger paediatric patients
e.g. not required for sterile, single-dose products (as recommended for neonates)

Ideally targeted for microbial cells - showing no toxicity/irritancy towards

mammalian cells
Challenge is that the active groups involved are usually harmful to all living tissue

There are a limited number of approved preservatives available for multi-use oral
products, and options are even more limited for other routes of administration
Should not use in parenteral infusions
Must avoid access to cerebrospinal fluid and retro-ocular administration

This restricted number can be further reduced by consideration of factors such

as levels required (dose), pH-solubility profiles, API & excipient incompatibilities,
adsorption, irritancy and toxicity.
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Simon Mills | April 2008

Anti-Oxidants
Used to control oxidation of:

API
Preservative, e.g. potassium sorbate
Vehicle, e.g. oils or fats susceptible to -oxidation (rancidification)
Colourants (ageing discolouration)

Sacrificial (more oxidisable than API, preservative, etc). Levels will reduce
with time. need to be monitored by specific assay
Light exposure and metal ion impurities can accelerate oxidative degradation and hence
depletion of antioxidant

Need to assess regulatory acceptability (differs in different countries)

Efficacy can be affected by:

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Compatibility with other excipients

Partitioning into micelles (from surfactants)
Adsorption onto surfaces (container, thickening agent and suspended particles)
Incompatibilities, e.g. with metal ions

Simon Mills | April 2008

Wetting Agents
To aid wetting and dispersion of a hydrophobic API, preservative or
antioxidant
Reduce interfacial tension between solid and liquid during manufacture or
reconstitution of a suspension
Not all are suitable for oral administration
Examples include:
Surface active agents, e.g.
Oral: polysorbates (Tweens), sorbitan esters (Spans)
Parenteral: polysorbates, poloxamers, lecithin
External: sodium lauryl sulphate
.but these can cause excessive foaming (see anti-foaming agents) and can lead to
deflocculation and undesirable physical instability (sedimentation) if levels too high
Hydrophilic colloids that coat hydrophobic particles, e.g. bentonite, tragacanth,
alginates, cellulose derivatives. Also used as suspending agents, these can
encourage deflocculation if levels are too low.

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Simon Mills | April 2008

Anti-Foaming Agents
The formation of foams during manufacturing processes or when
reconstituting liquid dosage forms can be undesirable and disruptive.
Anti-foaming agents are effective at discouraging the formation of
stable foams by lowering surface tension and cohesive binding of the
liquid phase.
A typical example is Simethicone (polydimethylsiloxane-silicon dioxide),
which is used at levels of 1-50ppm.
Of course, a foam is also a very valid dosage form option for certain
situations, e.g. for topical administration and in wound dressings.
In addition, wet granulation using a foam rather than aqueous
granulation fluid is gaining popularity.

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Simon Mills | April 2008

Thickening Agents
Suspension stabilisers: prevent settling/sedimentation (particularly if a
wetting agent present)
They usually modify viscosity and are often thixotropic (where viscosity
is dependent on applied shear and exhibits shear thinning)
Easily poured when shaken
Must permit accurate dosing with chosen method (e.g. graduated
syringe, spoon)
Quickly reforms gel-like structure
They can impact on flocculation at low levels
Work by entrapment of solid particles, e.g. API, in a viscous or even
gel-like structure
Can be either water-soluble, e.g. methylcellulose or hydroxyethylcellulose
Or water-insoluble, e.g. microcrystalline cellulose

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Simon Mills | April 2008

Sweetening Agents
Natural sweeteners
Sucrose; soluble in water (vehicle), colourless, stable (pH 4-8), increases viscosity;
Arguably the best taste/mouthfeel overall but cariogenic & calorific avoid in
paediatrics?
Sorbitol (non-cariogenic, non-calorific - appropriate for paediatric formulations), but
lower sweetness intensity than sucrose (so you need more) & can cause diarrhoea

Artificial sweeteners
Regulatory review required often restricted territories
Much more intense sweeteners compared with sucrose
As a consequence the levels are much lower (<0.2%) but still need to refer to WHO
Acceptable Daily Intakes (ADIs)
Can impart a bitter or metallic after-taste (hence used in combination with natural
sweeteners), e.g.

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Saccharin, and its salts

Aspartame
Acesulfame K
Sucralose excellent sweetness, non-cariogenic, low calorie, wide & growing
regulatory acceptability but relatively expensive

Simon Mills | April 2008

Flavouring Agents
Supplement and complement a sweetening agent

Ensures patient compliance (especially in paediatric formulations a big issue)

Can be natural, e.g. peppermint, lemon oils,
Or artificial e.g. butterscotch, tutti-frutti flavour
Instability can be an issue combinations can be used to cover intended product shelf-life

Taste appreciation is not globally consistent

Genetic element: one persons acceptable taste is anothers unacceptable taste

Territorial (cultural?) differences in preference; e.g. US vs. Japan vs. Europe
Affected by age (paediatric perception and preferences are different from adult)
Can be affected by certain disease states, e.g. during cancer chemotherapy

Regulatory acceptability of flavours needs to be checked

Different sources, different compositions, different flavour, e.g. there are >30 different
strawberry flavours!
Usually complex of composition (so refer to internationally recognised standards)

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Simon Mills | April 2008

Humectants
Hygroscopic excipients used at ~5% in aqueous
suspensions and emulsions for external application.
Their function is to retard evaporation of aqueous vehicle of
dosage form:
To prevent drying of the product after application to the skin
To prevent drying of product from the container after first opening
To prevent cap-locking caused by condensation onto neck of containerclosure of a container after first opening

Examples include:
propylene glycol
glycerol
PEG

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Paediatric Issues with Common Excipients

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Overview thoughts for paediatric dosage forms

Technical Challenges:
Good taste and mouth feel (oral liquids, chewable/dispersible/melt-in-mouth units,
inhaled, intranasal)
Inability to swallow solid dosage forms; needing an alternative option
Constraints of dosage form size and volume related to dose required, e.g. drug solubility
in small injection volumes
Dosing flexibility
Physical, chemical and, where appropriate, anti-microbial stability
Accuracy of dosing potentially more of a challenge with lower doses & dose volumes
Parenterals: needlephobia, small veins needing small needles & injection volumes
Important routes: oral, topical, inhaled, rectal, eye drops & nose drops/spray, injectables

Influence of target age population..

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Paediatric Dosage Forms of Choice (1)

EMEA Reflection Paper, Formulations of Choice for the Paediatric Population (2005)

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Paediatric Dosage Forms of Choice (2)

EMEA Reflection Paper, Formulations of Choice for the Paediatric Population (2005)

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Simon Mills | April 2008

Overview thoughts for paediatric dosage forms

So..
A quite wide range of excipients and dosage forms
needs to be considered
Key considerations for paediatric formulations are to
minimize the use of excipients, understand the
limitations of those types of excipient that can and
are used and be able to justify their use at the dose
levels involved.
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Simon Mills | April 2008

General philosophy regarding excipients for

paediatric dosage forms

Choose the appropriate dosage form for the target population(s)

Avoid health hazards apply a benefit vs. risk balance assessment:

Minimum age of target population
Maximum duration of therapy
Double-check age-related safety of established (adult dosage form?) excipients
Novel excipients need comprehensive safety testing

Justify inclusion and minimise number of excipients and quantity to

be used:

Especially younger age groups

Choose dosage forms that achieve this
Not for aesthetic or cosmetic purposes
Avoid sugar for long-term use
Can any taste issue be reduced without resorting to the use of additives? e.g. through dilution, pH control,
API version selection (does reduced API solubility resolve the issue?)
Avoid biologically active excipients e.g. preservatives, anti-oxidants, unless dosage flexibility warrants
inclusion. Use lowest feasible levels.
Compliance with relevant regulations and be alert to the latest guidance

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Simon Mills | April 2008

Solvents/Solvent sweeteners
Need for oral liquid preparations (that children typically find easier to
swallow) often necessitates:
Taste-masking; which often relies on sweeteners
Addition of co-solvents to improve drug solubility if a solution is wanted (elegance/mouth feel vs.
taste)

Most commonly used solvent sweeteners are

Propylene glycol
Glycerine (Glycerol)

However, note that it was historical adulteration of oral medicine with the
orally toxic diethylene glycol (used in anti-freeze, brake and transmission
fluids) that led to tragic consequences:
Impetus for formation of US Food & Drugs Administration
Genesis of cGMPs

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Simon Mills | April 2008

Solvents/Preservatives
Propylene Glycol Toxicity
Propylene glycol (PG) is a general solvent with anti-microbial
properties used in a wide range of pharmaceutical preparations
including oral liquids, topicals and parenteral preparations
However, its use in large volumes in children is very much
discouraged:
PG has been associated with cardiovascular, hepatic, respiratory and CNS
adverse events, especially in neonates where the biological half-life is
prolonged (~17h) compared with adults (5h).
I.V. parenterals containing PG must be infused slowly
PG also has a laxative action at high oral doses through high osmotic
pressure effects.

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Simon Mills | April 2008

Solvents
Ethanol Toxicity
Widely used as a co-solvent to aid solubility
In US, maximum permitted quantities in OTC products:
<0.5% for children under 6-years
<5% for children 6-12-years
<10% for children over 12-years
Acute (overdose) or chronic (long-term use) toxicity is possible
May cause adverse symptoms of intoxication, lethargy, stupor, coma,
respiratory depression and cardiovascular collapse

Peanut Oil Toxicity

Peanut oil is used as a food additive and as a solvent in intra-muscular
injections
It has been suggested that the use of peanut oil in childhood (infant formula and
topical preparations) can lead to later episodes of hypersensitivity, and
therefore should be discontinued

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Simon Mills | April 2008

Sweeteners
Saccharin
Restricted regulatory acceptability
Poor aftertaste
Hypersensitivity reactions; mainly dermatologic
Paediatrics with allergy to sulphonamides should avoid saccharin

Aspartame Toxicity
Source of phenylalanine possibly an issue for phenylketoneurics
Aspartame has been blamed for hyperactivity in children but as yet unproven

Sorbitol
Can induce diarrhoea

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Simon Mills | April 2008

Anti-microbial Preservatives
Benzyl Alcohol toxicity in neonates
Widely used as a preservative in cosmetics, foods and pharmaceuticals
(including injectables and oral liquids)
Toxic syndrome observed in neonates it was attributed to the practice of
flushing out umbilical catheters with solutions containing benzyl alcohol
(BA), because of trace levels of benzaldehyde that were present
Dilution of nebulisation solutions with BA-preserved saline led to severe
respiratory complications and even death in neonates. Attributed to
accumulation of BA due to an immature metabolic capability.
Only dilute inhaled solutions with non-preserved, sterile diluents

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Simon Mills | April 2008

Anti-microbial Preservatives
Sodium Benzoate toxicity
Widely used as a preservative in cosmetics, foods and pharmaceuticals
(including injectables and oral liquids)
Injectable combinations of Na Benzoate and Caffeine should not be used in
neonates; found to elicit non-immunological contact reactions, including
urticaria and atopic dermatitis
Limitation on dosing of NA benzoate to neonates - 10mg/kg/day due to
immature metabolic capability

Thimerosal toxicity
Formerly widely used as a preservative in cosmetics, in soft contact lens
solutions and pharmaceuticals (primarily vaccines)
Being phased out from most paediatric vaccines as better options emerge
Possible links with toxicity in paediatric vaccines, e.g. linked with childhood
autism but not proven

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Simon Mills | April 2008

Diluents/Fillers
Lactose toxicity (immature metabolism)
Lactose occurs widely in dairy products and is used in infant feed formulae.
In pharmaceutical preparations it is widely used as a diluent in tablets and capsules,
in lyophilised powders, as a sweetener in liquid formulations and as a carrier in dry
powder inhalation products.
Lactose intolerance occurs when there is a deficiency in the intestinal enzyme
lactase, leading to GIT build-up of lactose. There is then the risk of abdominal
bloating and cramps.
Lactase is normally present at high levels at birth, declining rapidly in early childhood
(4-8 years) . Hypolactasia (malabsorption of lactose) can thus occur at an early age
and, furthermore, this varies among different ethic groups.
Significant lactose intolerance can also occur in adults but this is rare.
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Simon Mills | April 2008

E number Additives
(Colourants, preservatives, stabilisers, anti-oxidants, etc.)
Current high profile concerns...
Some opinion that additives in processed foods are linked to children's allergies.
Particular attention has been paid to infants and children's products because their immature
organs are less efficient at removing such toxins from their systems.
Certain combinations of the following artificial food colours: sunset yellow (E110), quinoline
yellow (E104), carmoisine (E122), allura red (E129), tartrazine (E102) and ponceau 4R (E124)
have been linked to a negative effect on childrens behaviour.

Basic message: maintain good awareness of regulatory status of

these materials in designing your paediatric drug formulation and
dont use them if you cannot justify it.

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Simon Mills | April 2008

Summary
Overview of Excipients used in Tablets and
Liquid/Suspension dosage forms
Functional role(s)
A review of specific paediatric considerations with
excipients

?ANY QUESTIONS PLEASE

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Simon Mills | April 2008