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Teknologi Farmasi ICair dan Semi Padat

Najma Annuria FithriGanjil 2013

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Self Introduction

Najma Annuria Fithri

Education- SMP Al-Kautsar, Bandar Lampung

- SMA Al-Kautsar , Bandar Lampung

- S1 Farmasi Sains dan Industri UGM 2006

- Apt Fak. Farmasi UGM 2010

- S2 Ilmu Farmasi Sains dan Teknologi UGM 2011 CP

- email: empith@gmail.com

- HP : 081931769304 / 082325780787

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Syllabus

Liquid excipients

Semi solid excipients

Tools and equipments in manufacture Methods of manufacture liquid

Methods of manufacture semi solid

Quality control and evaluations Quality control and evaluations (Task)

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Scoring system

Final test (50%

Quizes (20%)

Tasks (20%)Involvement in class (10%)

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Types of LDF

Solutions

- Aqueous solutions + SugarSyrup

- HydroalcoholicElixir

- Aromatic alcoholic solutionsSpirit

- Aromatic aqueous solutionsAromatic water

- Extracted liquids from crude productsTincture

Emulsions

Suspensions

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Type of excipients

Solvents/Co-solvents

Buffering agents Anti microbial preservatives

Anti oxidants

Sequestering agents Wetting agents

Anti foaming agents

Thickening agents Sweetening agents

Colouring agents

Flavouring agents

Humectant

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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, et c. are often added as solubilisers, aswell 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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Some solvents for liquid preparations

Alcohol, Ethyl alcohol (ethanol)C2H5OH1. Next to water, alcohol is the most useful solvent in pharmacy. It is used as a primary

solvent for many organic compounds.

2. It forms hydroalcoholic mixture with water that dissolves both alcohol-soluble andwater-soluble substances

3. Alcohol has been well recognized as a solvent and excipient in the formulation of oral

pharmaceutical products. Alcohol is often preferred because of its miscibility withwater and its ability to dissolve many water-insoluble ingredients, including drugsubstances, flavorants, and antimicrobial preservatives.

4. It is also used in liquid products as an antimicrobial preservative alone or withparabens, benzoates, sorbates, and other agents.

5. Toxicity of ingested alcohol particularly for children. For OTC oral products intendedfor children under 6 years of age, the recommended alcohol content limit is 0.5%, forproducts intended for children 6 to 12 years old, the recommended limit is 5% and forchildren over 12 years and adults, the recommended limit is 10%.

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Diluted alcohol

- Is prepared by mixing equal volumes of alcohol and purified water (50%).- Diluted alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes

and preparations.

Alcohol, Rubbing (alcohol rubbing compound)

- It contains about 70% ethyl alcohol by volume.

- It is employed as a rubefacient externally and as soothing rub for bedridden patients, a

germicide for instruments

- As vehicle for topical preparation

- As skin cleanser before injection

Isopropyl rubbing alcohol- It has the advantage over ethyl alcohol in that the commonly available product contains

not over 1% of water, while ethyl alcohol contains about 5% water, which often a

disadvantages.

-Is about 70% by volume isopropyl alcohol, with or without colour additives, stabilizers and

perfume oils

- It is used externally as a rubefacient and soothing rub and for topical products

- The commercially available 91% isopropyl alcohol solution are commonly employed by

diabetic patients in preparing needles and syringes for hypodermic injections of insulin

and for disinfecting the skin.

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Glycerin, Glycerol- It is a clear syrupy liquid with sweet taste- It is miscible with water and alcohol

- As solvent it is comparable with alcohol, but because ofits viscosity, solutes are slowly soluble in it unless it isrendered less viscous by heating.- It is used as a stabilizer and as auxiliary solvent in

conjunction with water or alcohol.- It has preservative qualities- It is used in internal preparations- It dissolves the fixed alkalies, a large number of salts

and vegetable acids, pepsin, tannin, some activeprincipals of plants, etc.

- It also dissolves gum, starch, etc.

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Propylene glycol- A viscous liquid, miscible with water, with acetone and with chloroform in allproportions.- It is soluble in ether and will dissolve many essential oils but is immiscible withfixed oils.- It is a useful solvent with wide range of application

- It is substituted for glycerol in modern pharmaceutical preparations- It is used for formulation of digoxin, diazepam, phenobarbital injection- As diluent for ear drops

Polyethyleneglycol, PEG 400- It is miscible with water, acetone, alcohol and other glycols.- It dissolves many water-soluble organic compounds as well as certain waterinsoluble substances such as acetylsalicylic acid and theophyllin.- Is used as a solvent in topical solution- Used as co-solvent with alcohol and water- Can be used for extraction processes- In the formulation of veterinary solutions

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Role of co-solvencyWeak electrolytes and non-polar molecules frequently have poor

water solubility

Their solubility usually can be increased by the addition of a water-

miscible solvent in

which the drug has good solubility.

This process is known as co-solvency, and the solventsused in combination to

increase the solubility of the solute are known as co-

solventCo-solvents are employed not only to affect solubility of the

drug, but also to improve the solubility of volatile constituents

used to impart a desirable flavor and odour to the product.

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Types of pharmaceutical water

Purified water, USPWater for injection

Aromatic water

Physiological compatibility

Lack of toxicity

Possesses a high dielectric constantensuring the dissolution of a wide range of ionizable

materials

Lack of selectivity

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Water is used both as vehicle and as a solvent for the desiredflavoring or medicinal ingredients.

Advantages: Tasteless, odourless, lack of pharmacological

activity, neutral and very cheap

Tap Water It is not permitted to use tap water for the dispensing of

pharmaceutical dosage forms due to its possible bacterialcontamination and the presence of dissolved salts that destroythe active ingredients or enhance their decomposition.

Freshly Boiled and Cooled Water

Boiling is seldom used to destroy vegetative bacteria. But, onstorage for long time spores may yield vegetativemicroorganism.

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Purified Water Must be used for most pharmaceutical operations and in all the

tests and assays.

Such water is prepared by distillation, deionization (ionexchange method) or reverse osmosis.

"Hard" waters are those that contain the Ca and Mg cations. Alkaline" waters are those that contain bicarbonates as the

major impurity. Ultraviolet energy, heat or filtration (Millipore filtration) can beused to remove or kill the microorganisms present in the water.

Water for injection Must be used for the formulation of parental solutions. It is obtained by sterilizing pyrogen-free distilled water.

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Aromatic Waters

Aromatic waters (medicated waters) are clear, saturated aqueoussolution of volatile oils or other aromatic or volatile substances.

They are used principally as flavored or perfumed vehicles. Volatile oils solutions represent an incompatibility problem of

salting out. This occurs after the incorporation of a very solublesalt in their solution.

Aromatic water will deteriorate with time therefore:- should be made in small quantities- protected from intense light and excessive heat by storing in airtight, light resistant containers.

- If they become cloudy or otherwise deteriorate; they should bediscarded. Deterioration may be due to volatilization,decomposition or mould growth.

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The strengths of pharmaceutical preparations are usually expressed in terms of percentstrength, although for very dilute preparations, expressions of ratio strength may be

used.

Percentage (%)

% w/v (e.g., 1%w/v =1g constituent in 100 mL preparation) %v/v (e.g., 1%v/v = 1mL constituent in 100 mL preparation) % w/w (e.g.,1%w/w=1 g constituent in 100 g preparation)

Ratio strength weight in volume (e.g., 1:1000 w/v= 1g constituent in 1000 mL

preparation) volume in volume (e.g., 1:1000 v/v = 1ml constituent in 1000

mL preparation) weight in weight (e.g., 1:1000 w/w = 1 g constituent in 1000 gpreparation)

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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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Ex: carbonates, citrates, phosphate, lactates,gluconates, tartarates, borates (external). Itspresence in solution resists any changes in pH

upon dilution or addition of small quantities ofacid or base. The usual buffering agents used inoral liquid preparations are acetate and

phosphate buffer. The buffer increase

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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 potentialhealth issues Avoid use wherever possible, especially in products aimed at younger paediatric

patientse.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 otherroutes 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 offactors such as levels required (dose), pH-solubility profiles, API &excipient incompatibilities, adsorption, irritancy and toxicity.

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Choice of Preservative The preservative selected should have the following

properties : 1. It should be effective against a wide range of

microorganisms. 2. It should be compatible with other ingredients of the

formulation. 3. It should be soluble in aqueous phase when used in

emulsions. 4. It should be nontoxic. 5. It should be free from odour and taste. 6. It should preserve the preparations and remain stable

for the shelf life of the product. No singly preservative possesses all the qualitiestherefore it becomes necessary to use a combination ofpreservatives to prevent the growth of microorganisms.The most commonly used preservatives are as follows:

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1. Benzoic acid and sodium benzoate 0.1 to 0.2%.2. Salicylic acid 0.1%.3. Phenol 0.2 to 0.5%.4. Chlorocresol 0.05 to 0.1%.5. Alcohol 15 t 20%.

6. Chlorbutanol 0.5%.7. Phenylmercuric nitrate 0.002 to 0.005%.8. Sorbic cid and its salts 0.05 to 0.2%.

9. Benzalkonium chloride 0.004 to 0.02 %.10. Methyl paraben and propyl paraben 0.1% to0.2%.

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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). Levelswill 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 differentcountries)

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

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Sequestering/Chelating agentsChelating agent excipients are used in chelation therapy todetoxify poisonous metal agents such as mercury [Hg],

arsenic [As], and lead [Pb] by converting them to achemically inert form that can be excreted without furtherinteraction with the body.

Chelating agents inhibits auto oxidations by metal ions

Metal ions are a catalyst to auto oxidation process

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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) iflevels too high

Hydrophilic colloids that coat hydrophobic particles, e.g. bentonite, tragacanth,alginates, cellulose derivatives. Also used as suspending agents, these canencourage deflocculation if levels are too low.

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Anti-Foaming Agents The formation of foams during manufacturing processes or

when reconstituting liquid dosage forms can be undesirableand disruptive.

Anti-foaming agents are effective at discouraging theformation of stable foams by lowering surface tension andcohesive 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 forcertain situations, e.g. for topical administration and in

wound dressings.

In addition, wet granulation using a foam rather than aqueousgranulation fluid is gaining popularity.

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Thickening Agents Suspension stabilisers: prevent settling/sedimentation

(particularly if a wetting agent present)

They usually modify viscosity and are often thixotropic (whereviscosity is dependent on applied shear and exhibits shearthinning)

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 oreven

gel-like structure Can be either water-soluble, e.g. methylcellulose orhydroxyethylcellulose

Or water-insoluble, e.g. microcrystalline cellulose

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Example:

semi-synthetic: thickening agents-methylcellulose, carboxy methyl cellulose,hydroxypropyl cellulose, synthetic polymers and

gelatin. Sodium carboxy methyl cellulose (3.5%)is used in injectable suspensions.

Clays: hydrated aluminium silicate or

magnesium silicate Non-ionic: sorbitol, glycerin, sugar orpolycthylene glycols

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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 inpaediatrics?

Sorbitol (non-cariogenic, non-calorific - appropriate for paediatric formulations),but lower sweetness intensity than sucrose (so you need more) & can causediarrhoea

Artificial sweeteners Regulatory review required often restricted territories

Much more intense sweeteners compared with sucrose As a consequence the levels are much lower (

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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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Colouring agents

Colouring agents may be defined as the substances used toimpart colour to foods, drugs and cosmetics to increase theirorganoleptic properties. In pharmaceutical preparationsthey may be used to increase their acceptability by thepatients, to give warning, or to produce standardpreparations.

The examples of mineral colours are ferric oxide (yellowand red), carbon black, titanium dioxide and ultramarine.

Only the permitted colours are used in food andpharmaceutical preparations. Caramel or burnt sugar, anartificial colour is used to produce brown colour in coughsyrups. elixirs and other oral liquid preparation.

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Certified color additives are classified according totheir approved use: (a) FD&C color additives,

which may be used in foods, drugs, and cosmetics;(b) D&C color additives, some of which areapproved for use in drugs, some in cosmetics, and

some in medical devices; and (c) external D&Ccolor additives, the use of which is restricted toexternal parts of the body, not including the lips

or any other body surface covered by mucousmembrane

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Humectants Hygroscopic excipients used at ~5% in aqueous

suspensions and emulsions for external application.

Their function is to retard evaporation of aqueousvehicle 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

container-closure of a container after first opening

Examples include: propylene glycol glycerol PEG

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Overview thoughts for paediatric dosage forms

So..

A quite wide range of excipients and dosage formsneeds to be considered

Key considerations for paediatric formulations are

tominimize 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 doselevels involved.

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General philosophy regarding excipients forliquid dosage forms

Choose the appropriate dosage form for the targetpopulation(s)

Avoid health hazards apply a benefit vs. risk balanceassessment: 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 andquantity tobe 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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Solvents/Preservatives

Propylene Glycol Toxicity

Propylene glycol (PG) is a general solvent with anti-microbial properties used in a wide range ofpharmaceutical preparations including oral liquids,topicals and parenteral preparations

However, its use in large volumes in children isvery much discouraged:

PG has been associated with cardiovascular, hepatic, respiratory andCNS 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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Solvents

Ethanol Toxicity Widely used as a co-solvent to aid solubility

In US, maximum permitted quantities in OTC products:

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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 yetunproven

Sorbitol Can induce diarrhoea

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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)

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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 practiceof flushing out umbilical catheters with solutions containing benzylalcohol (BA), because of trace levels of benzaldehyde that were present

Dilution of nebulisation solutions with BA-preserved saline led tosevere respiratory complications and even death in neonates.Attributed to accumulation of BA due to an immature metaboliccapability.

Only dilute inhaled solutions with non-preserved, sterile diluents

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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 beused 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 optionsemerge

Possible links with toxicity in paediatric vaccines, e.g. linked withchildhood autism but not proven

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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 andcapsules, in lyophilised powders, as a sweetener in liquid formulations andas a carrier in dry powder inhalation products.

Lactose intolerance occurs when there is a deficiency in the intestinalenzyme 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 earlychildhood (4-8 years) . Hypolactasia (malabsorption of lactose) can thusoccur at an early age and, furthermore, this varies among different ethicgroups.

Significant lactose intolerance can also occur in adults but this is rare.

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E numberAdditives(Colourants, preservatives, stabilisers, anti-

oxidants, etc.) Current high profile concerns...

Some opinion that additives in processed foods are linked to children'sallergies.

Particular attention has been paid to infants and children's productsbecause their immature organs are less efficient at removing suchtoxins from their systems.

Certain combinations of the following artificial food colours: sunsetyellow (E110), quinoline yellow (E104), carmoisine (E122), allura red(E129), tartrazine (E102) and ponceau 4R (E124) have been linked to anegative effect on childrens behaviour.