Slide 1. April 2007

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical DevelopmentPharmaceutical Development

Slide 2. April 2007

Pharmaceutical DevelopmentPharmaceutical Development

Excipients

Presenter: Simon Mills

Email: Simon.n.mills@gsk.com

Slide 3. April 2007

IntroductionIntroduction

Overview of Excipients commonly used in Oral dosage forms

Role of Key Tablet Excipients– Diluents (fillers, bulking agents), Disintegrants, Binders, Lubricants, Glidants

Role of Key Oral Liquid/Suspension Excipients– Solvents/co-solvents , Buffering agents, Preservatives, Anti-oxidants,

Wetting agents, Anti-foaming agents, Thickening agents, Sweetening agents, Flavouring agents, Humectants

Paediatric Issues with Excipients and Excipient Quality

Slide 4. April 2007

ExcipientsExcipients

Drug products contain both drug substance (commonly referred to as active pharmaceutical ingredient or API) and excipients.

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.

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.

In addition, individual excipients can have different grades, types and sources depending on those different functional roles….

Slide 5. April 2007

Tablet ExcipientsTablet Excipients

….for example, there are various grades of lactose commercially available that have different physical properties, e.g. flow characteristics & particle size distribution. This permits selection of what is considered the most suitable grade for a particular need, e.g. with tablet development:

– Usually, fine grades of lactose are utilised when manufacturing tablets by the wet granulation route, as it utilises the binder more efficiently and permits better mixing and granule quality.

– In contrast, spray dried lactose is used for direct compression tablets, as it flows better and is more compressible.

In tablets, the key excipient types include:

– 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

Slide 6. April 2007

Tablet Diluents (Fillers)Tablet Diluents (Fillers)

Bulking agent– To make tablet weight practical for the patient: minimum tablet weight is typically

~50mg. Actual API doses can be as low as ~20µg, e.g. for oral steroids.

Compression aid– Deform readily to facilitate production of a robust tablet product.

Flow aid– Good flow of bulk powders is very important in tablet manufacture. Lactose can

exhibit poor flow characteristics, so is often supplemented with microcrystalline cellulose in wet granulation tablets, or is used as the spray dried version (particularly with direct compression formulations).

Slide 7. April 2007

Tablet DisintegrantsTablet Disintegrants

As an aid to de-aggregation of compacted tablets. Disintegrants cause rapid break up (disintegration) of the tablet compact 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 tablet increased.

Slide 8. April 2007

Tablet BindersTablet Binders

Binders act as an adhesive to ‘bind together’ powders or granules

– As a powder in dry granulation (roller compaction, slugging)– As a solution in wet granulation. Binder can be added either dry with other

excipients for granulation or already dissolved in the granulating fluid; water is the most common granulating fluid, very occasionally in a co-solvent system with, e.g. ethanol.

Binders can be:

– Insoluble in water, e.g. starch– Soluble in water e.g. HPMC– Soluble in water and ethanol e.g. Povidone

Slide 9. April 2007

Tableting LubricantsTableting Lubricants

Lubricants prevent adherence of granule/powder to punch die/faces and to 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

Just to illustrate the need for effective lubrication; high speed tablet presses can operate at: – 360,000 tablets/hour ≡ 6000 tablets/min– 30 stations ≡ 200 tablets/min/station ≡ ca. 3 tablets/second/station

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

Slide 10. April 2007

Tablet GlidantsTablet Glidants

E.g. colloidal silicon dioxide

Improve flow by reducing intra-particulate friction

Very low levels required (ca. <0.1%)

Very low bulk density (0.03 – 0.04g/cm3)– Difficult to work with (very voluminous)– Issues with dust exposure

Slide 11. April 2007

Excipients For Oral Suspension ProductsExcipients For Oral Suspension ProductsAgain, excipients are sub-divided into various functional classifications,

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

In Oral Liquid/Suspension products, the possible types of excipients include:– Solvents/co-solvents e.g. Aqueous Vehicle, Propylene Glycol, Glycerol– Buffering agents, e.g. Citrate, Gluconates, Lactates– Preservatives, e.g. Na Benzoate, Parabens (Me, Pr and Bu), BKC– Anti-oxidants, e.g. BHT, BHA, Ascorbic acid– Wetting agents, e.g. Polysorbates, Sorbitan esters– Anti-foaming agents, e.g. Simethicone– Thickening agents, e.g. Methylcellulose or Hydroxyethylcellulose– Sweetening agents, e.g. Sorbitol, Saccharin, Aspartame, Acesulfame– Flavouring agents, e.g. Peppermint, Lemon oils, Butterscotch, etc. – Humectants, e.g. Propylene Glycol, Glycerol, Sorbitol

Slide 12. April 2007

Solvents/Co-SolventsSolvents/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

Water miscible co-solvents are used to:– Enhance solubility, taste, anti-microbial effectiveness or stability– Reduce oral dose volume?– Or, conversely, optimise insolubility (if taste of API is an issue)– Examples: propylene glycol, glycerol, ethanol, low mol wt PEGs

Water immiscible co-solvents, e.g. – Emulsions / microemulsions using fractionated coconut oils

Slide 13. April 2007

Buffering AgentsBuffering Agents

Necessary to maintain pH of the formulation, thereby

– 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

Slide 14. April 2007

PreservativesPreservativesPreservatives used in multi-use cosmetic/pharmaceutical products (particularly

paediatric formulations) – prevents an increased risk of contamination by opportunistic microbial pathogens (from excipients or

introduced externally), resulting in potential health consequences

Ideally targeted for microbial cells - showing no toxicity/irritancy towards mammalian cells – In reality, the majority of effective GRAS preservatives are active against both microbial and

mammalian cells (non-specific cytoplasmic poisons)

There is a limited number of approved preservatives available for multi-use oral products, and options are even more limited for other routes of administration.

This restricted number can be further reduced by dose, pH-solubility profiles, incompatibilities, adsorption, toxicity and other relevant physico-chemical factors.

Slide 15. April 2007

Anti-OxidantsAnti-OxidantsUsed to control oxidation of API, e.g. lovastatin, preservative, e.g. K sorbate

or vehicle, e.g. oils or fats susceptible to β-oxidation

Sacrificial (more oxidisable than API, preservative, etc). Levels will reduce with time…. need to be monitored by specific assay

Need to assess regulatory acceptability (differs in different countries)

Efficacy can be affected by:– Compatibility with other excipients– Partitioning into micelles (from surfactants)– Adsorption onto surfaces (container, thickening agent and suspended particles)– Incompatibilities, e.g. with metal ions

Slide 16. April 2007

Wetting AgentsWetting Agents

To aid ‘wetting’ and dispersion of a hydrophobic API, preservative or antioxidant– Reduces interfacial tension between solid and liquid– Encourages deflocculation (stable colloidal dispersion)

Examples include – surface active agents, e.g. polysorbates, sorbitan esters

• But can cause excessive foaming (see anti-foaming agents)– hydrophilic colloids e.g. bentonite, tragacanth, alginates, cellulose derivative

Slide 17. April 2007

Anti-Foaming AgentsAnti-Foaming Agents

Foaming can be caused by the presence of surfactants and thixotropic thickening agents (which can entrap air in ‘gel-like’ structure) in the liquid formulation.

A typical example is Simethicone (polydimethylsiloxane-silicon dioxide), which is used at levels of 1-50ppm

Slide 18. April 2007

Thickening AgentsThickening 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• Quickly reforms ‘gel-like’ structure• Can impact on flocculation

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

Slide 19. April 2007

Sweetening AgentsSweetening AgentsNatural sweeteners

– Sucrose; soluble in water (vehicle), colourless, stable (pH 4-8), increases viscosity – Sorbitol (non-cariogenic - appropriate for paediatric formulations)

Artificial sweeteners– Regulatory review required– Much more intense sweeteners compared with sucrose– As a consequence the levels are much lower (<0.2%)– Can impart a bitter or metallic after-taste (hence used in combination with natural sweeteners),

e.g.• Saccharin, and it’s salts• Aspartame• Acesulfame -K

Slide 20. April 2007

Flavouring AgentsFlavouring AgentsSupplements and compliments 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

For instance:– If the product tastes salty then peach, apricot or liquorice can be used– If the product tastes bitter then mint, cherry or anise can be used– If the product tastes too sweet then vanilla can be used– If the product tastes sour then raspberry or liquorice can be used

Taste appreciation has a genetic element….. So it is difficult to formulate for global use– One person’s acceptable taste is another’s unacceptable taste

Regulatory acceptability of flavours needs to be checked– Different sources, different compositions, different flavour, e.g. there are >30 different “strawberry flavours”!

Slide 21. April 2007

HumectantsHumectants

Hygroscopic excipients that are added to prevent cap-locking caused by evaporation of formulation and subsequent condensation onto neck of container-closure, e.g. of a bottle after first opening

Retard evaporation of aqueous vehicle of dosage form

Examples include – propylene glycol– glycerol – sorbitol

Slide 22. April 2007

Paediatric Safety Issues with Common Excipients

Slide 23. April 2007

Solvents/SweetenersSolvents/Sweeteners Need for oral liquid preparations (that children typically find easiest to swallow) often

necessitates:– Taste-masking; which often relies on sweeteners– Addition of co-solvents to improve drug solubility

Most commonly used solvent/sweeteners are– Propylene glycol– Glycerine (Glycerol)

However, there are many historical precedence’s of adulteration of these excipients (e.g. with diethylene glycol: used in anti-freeze, brake and transmission fluids), often with tragic consequences:

– Sulphanilamide Elixir Tragedy (1935)– New low solubility antibiotic (sulphanilamide)– Need for a ‘child-friendly’ oral dosage form– Formulators used novel excipient, diethylene glycol– Impetus for formation of US Food & Drugs Administration– Federal Food, Drug and Cosmetic Act (1938) required toxicological testing for all new drugs

Genesis of cGMP’s

Slide 24. April 2007

SweetenersSweetenersAspartame Toxicity

– Aspartame is used as an intense sweetener in beverages, food products, and in pharmaceutical preparations

– It enhances flavour systems and can be used to taste-mask unpleasantly bitter tasting characteristics of common drugs

– A number of adverse events have been reported following the consumption of large quantities of aspartame in beverages (Golightly et al, 1988; Butchko and Kotsonis, 1989)

– Although, aspartame has been blamed for hyperactivity in children; a double-blind study of 48 pre-school children who were dosed with diets containing 38±13mg/kg body weight of aspartame for 3-weeks, showed no appreciable adverse behaviour or impact on cognitive function (Wolraich et al, 1994)

Slide 25. April 2007

SolventsSolvents

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

– 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– Some workers have 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

Slide 26. April 2007

Solvents/PreservativesSolvents/Preservatives

Propylene Glycol Toxicity

–The development of multi-dose oral liquid and parenteral preparations also necessitates the requirement for preservative(s) to prevent microbial contamination as serious microbial infections in the very young can often be fatal

–Propylene glycol is a general solvent and antimicrobial preservative used in a wide range of pharmaceutical preparations including oral liquid, topical and parenteral preparations

–In addition to risks associated with adulteration, its use in large volumes in children is discouraged, and it has been associated with CNS adverse events, especially in neonates

Slide 27. April 2007

PreservativesPreservatives

Benzyl Alcohol toxicity in neonates–Widely used as a preservative in cosmetics, foods and pharmaceuticals

(including injectables and oral liquids)–Toxic syndrome was attributed to the practice of “flushing out” umbilical

catheters with solutions containing benzyl alcohol, because of trace levels of benzaldehyde that were present

–FDA recommended discontinuation of practice and the use of medicinal products containing preservatives in neonates (1982)

Slide 28. April 2007

PreservativesPreservatives

Na 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

– Needs to be taken into account when formulating paediatric products

Thimerosal toxicity– Formerly widely used as a preservative in cosmetics, in soft contact lens solutions and

pharmaceuticals (including eye drops and vaccines)– Link with toxicity in eye drops – Strong links with toxicity in paediatric vaccines– Banned by EMEA and FDA in 1999 in paediatric vaccines– Linked with childhood autism, but not substantiated by EMEA (2004) and FDA (2006)

Slide 29. April 2007

Preservatives Preservatives

Lactic Acid toxicity (immature metabolism)–Lactic acid is used in beverages, food, cosmetics and pharmaceuticals–In topical cosmetics it is used as a skin softener–In food and beverages it is used as a preservative–It is usually present as the racemate (RS); but in some cases the S-isomer

predominates–Lactic acid is the naturally occurring endpoint of anaerobic metabolism of

carbohydrates; so is usually viewed as being non-toxic at the levels used in typical formulations

–However, there is evidence that neonates have difficulty metabolising the R-isomer; and hence this isomer and the racemate, should not be used in infant formulas for children less than 3 months old (WHO, 1974)

Slide 30. April 2007

Diluents/Fillers Diluents/Fillers

Lactose toxicity (immature metabolism)

– Lactose occurs widely in dairy products and is used in infant feed formulas– In pharmaceutical preparations it is widely used as a diluent in tablets and capsules, in lyophilised

powders, and as a carrier in dry powder inhalation products– Lactose intolerance occurs when there is a deficiency in the intestinal enzyme lactase– This enzyme is normally present at high levels at birth, declining rapidly in early childhood– Hypolactasia (malabsorption of lactose) can thus occur at an early age (4-8 years) and varies among

different ethic groups (Suarez and Saviano, 1997)– It is unlikely that severe gastrointestinal adverse events could result from ingestion of medicinal

products in adults, but it is less clear if this is equally applicable in infants

Slide 31. April 2007

Anti-oxidants Anti-oxidants

Propyl Gallate toxicity–Used as an anti-oxidant in cosmetics, food and wide range of pharmaceuticals–Strong sensitising potential in animals –Few reports of adverse events in humans; but do include methemoglobinemia

(met-Hb) in neonates (Nitzan et al, 1979)

Slide 32. April 2007

Suspending and Surfactant Agents Suspending and Surfactant Agents

– Carrageenan is a naturally occurring gel base or suspending agent derived from seaweed extracts

• Generally considered to be non-toxic and non-irritating, except in parenteral preparations• UK Food Advisory Committee did recommend the removal of carrageenan as an additive

in infant food formulas.. because of its ability to induce inflammatory responses in animals (MAFF, 1992)

– Docusate sodium, an anionic surfactant, is widely used in pharmaceutical preparations as a wetting agent, dissolution aid and as laxative and faecal softeners.

• Levels of docusate sodium should be strictly controlled in medicinal products to prevent diarrhoea, especially in infants. The adult dose (500mg) is over six times the amount administered to children of 6-months (75mg), and older (Guidott, 1996)

Slide 33. April 2007

Wetting Agents Wetting Agents

– Polyoxyethylene sorbitan fatty acid esters (polysorbates 20, 40 and 60) are used as emulsifying agents, non-ionic surfactants, solubilising agents, wetting, dispersing and as suspending agents

• Polysorbates are generally regarded as non-toxic and non-irritant materials• However, they have been associated with serious adverse events, including some deaths,

in neonates who were administrated with vitamin E intravenous preparations (Alade et al, 1986; Balistreri et al, 1986)

Slide 34. April 2007

Colorants Colorants

Tartrazine toxicity– Oral Liquid formulations are often complementarily coloured and flavoured to aid in paediatric

patient acceptance and long term compliance.– For instance, a paediatric formulation might be taste-masked using banana flavour (a particular

favourite of many young children), which would be complemented by the addition of a yellow colorant.

– One such colorant (FD&C Yellow No. 5 or tartrazine) has long been the subject of much controversy centred around its safety profile, and its possible link with hives and hyperactivity in children.

– In the US, any prescription drug containing tratrazine, is labelled:

“This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic reactions (including bronchial asthma) in certain susceptible persons.”

– Generally speaking, concerns over the safety profile of colorants in pharmaceuticals and foods are associated with hypersensitivity and hyperactivity.

Slide 35. April 2007

Lubricants Lubricants

Talc toxicity–Talc is commonly used as a dusting powder; and historically has been used as

both a glidant and lubricant• Although, generally regarded as non-toxic when orally ingested, inhalation

of talc causes irritation and severe respiratory distress in children

Slide 36. April 2007

SummarySummary

Overview of Excipients used in Tablets and Oral Liquid/Suspension dosage forms

– Functional role(s)– Paediatric Issues with Excipients

ANY QUESTIONS PLEASE?