Medicinal products contain one or more pharmacologically active compounds which areresponsible for the product’s therapeutic potential. Excipients are all the other parts of theformulation. Collectively these stabilise the formulation, help with the manufacturing process,aid dispersion of the drug or make the product more appealing to the patient. Two oralformulations are described in detail below as examples:
Ciproxin®Tablets Lanoxin PG® ElixirThe body of the tablet contains: The elixir contains:• Ciprofloxacin (the active ingredient). • Digoxin (the active ingredient).• Microcrystalline cellulose (used as a • Methyl Hydroxybenzoate (preservative).binder which holds the tablet together, • Sucrose or Syrup BP (sweetener andand as a diluent which bulks up the thickener).tablet). • Citric Acid Monohydrate (lowers pH,
• Crospovidone (disintegrant, which helps where the formulation is most stable).tablets break up in the stomach). • Anhydrous Sodium Phosphate (a buffer –
• Maize starch (binder, diluent and helps to maintain desired pH).disintegrant). • Quinine Yellow (colour).
• Silica colloidal anhydrous (improves flow • Ethanol (solvent).of powder through tabletting machine). • Propylene Glycol (solvent with some
• Magnesium stearate (lubricant in preservative properties).tabletting process). • Purified Water (solvent).
• Lime No. 1 NA HSE (flavour).The tablet film-coat consists of a mixture of:• Hypromellose (main ingredient of coat).• Macrogol 4000 (makes the coating moresoluble so it dissolves in the stomach).
• Titanium dioxide (white pigment).
Oral formulations tend to contain more excipients than preparations given by other routes.
Why Do You Need to Know About Them?
Although excipients are not the principal pharmacologically active constituents of a medicinalproduct they do, in many cases, have pharmacological activity. This means they can cause sideeffects in their own right. Sometimes an unexpected reaction to a pharmaceutical can beexplained by considering the potential effects of excipients. On other occasions patients orprofessionals know about a problem with specific excipients and may ask you to check newmedication to make sure that a particular excipient is not present.
What Are the Common Excipients Which Cause Problems?
Note that manufacturers’ SPCs can be an unreliable source of information about excipients.SPCs do NOT always list all excipients; in particular excipients present in ‘trace’ amounts maynot be declared. Different manufacturers may also list excipients in different parts of the SPC. Ifit is crucial to be sure about excipient content, the only option is to ring manufacturersindividually. For excipients that present particular problems in children refer to Tutorial 11.1. Lactose – lactose intolerance is caused by a deficiency of the gut enzyme lactase which
normally breaks lactose down into simple sugars. Deficiency may be a temporarysituation (e.g. after gastroenteritis) or permanent (genetic deficiency). In the absence oflactase, flora in the lower bowel convert lactose to irritant substances which can causesymptoms such as diarrhoea, flatulence and abdominal pain. Lactose is commonly used intablets and capsules as a diluent in small amounts, but it may need to be avoided bypatients with severe intolerance.
2. Gluten – a protein derived from wheat which exacerbates the gastrointestinal symptomsof coeliac disease and related conditions. Maize (or ‘corn’) starch does not cause thisproblem.
3. Preservatives – allergy to these can sometimes be demonstrated and further exposureshould subsequently be avoided if possible. Examples include parabens (methyl, ethyland propyl hydroxybenzoates used in oral liquids and topical products); thiomersal(mainly in vaccines); cetyl alcohol (principally used in topical products and dressings).
4. Phenylalanine – this, and the chemically-related aspartame, should be avoided in patientswith phenylketonuria. These patients are unable to metabolise phenylalanine and suffer arange of symptoms, including mental retardation, as a consequence of its accumulation.
5. Latex – this is sometimes used as part of the bung in many parenteral products and itcould theoretically contaminate the drug solution. Consequently, parenterals with latexbungs are best avoided in those with latex allergy.
6. Peanuts – the arachis oil used in pharmaceuticals should not cause problems in patientswith peanut allergy (see example enquiry below). However, patients affected may preferto avoid it and it is easy to do so.
7. Glucose and Sucrose – the amount of sugar in some medicines might occasionally besignificant enough to affect blood sugars in some diabetic patients. High sugar contentliquid medicines can also cause tooth decay.
8. Sorbitol – this excipient is a popular sweetener in oral liquids, but it can cause diarrhoea.9. Sodium content – the sodium content of certain pharmaceuticals may be high enough for
them not to be recommended for patients on a restricted salt diet (e.g. those withhypertension). Some antacids, for example, contain quite high amounts (e.g. Gavisconliquid).
10. Colourants – some patients claim a link between colourants and behavioural illness (e.g.hyperactivity in children) or physical illness (e.g. eczema) and may wish to avoid furtherexposure.
11. Animal origins – sometimes patients may wish to avoid excipients of animal origin forpersonal or religious reasons. For example, some vegans may wish to avoid gelatin, andJehovah’s Witnesses may wish to avoid vaccines containing albumin from a humansource.
What’s the Difference Between Excipients and ‘E’ Numbers?
Some excipients found in pharmaceuticals are also used in foods, where they are usually called‘additives’. The ‘E’ number system was devised by the EU so that there would be a standardway of identifying additives across Europe. Examples of pharmaceutical excipients that mightalso occur as food additives include sorbitol (E420), titanium dioxide (E171), sodium benzoate(E211) and tartrazine (E102). If a patient has a suspected sensitivity to a pharmaceuticalexcipient it is helpful to check if the excipient has an E number so that the patient can avoidfurther exposure via food.The Food Additives and Ingredients Association provides a comprehensive list of E numbersand also describes their uses. See: www.faia.org.uk/
Are Any Excipients ‘Harmless’?
Given the natural caution of MI pharmacists, it would be unwise to say that any werecompletely harmless. However, some excipients are not absorbed from the gut at all, and sotheir potential for causing systemic reactions would seem to be zero after oral administration(e.g. titanium dioxide, talc). Some excipients are natural to the human body and in the amountsused in pharmaceuticals do not represent a hazard (e.g. citric acid, albumin). Others do nothave significant side effects in the concentrations normally used in pharmaceuticals (e.g.magnesium stearate, maltose).
Questions to Ask an Enquirer
� What is the reason for asking about excipients? Does the patient have a known problem,or is one suspected?
� What is the nature of any known or suspected reactions to excipients?� How long has the patient been taking any medication that might be the source of the
problem?� What other medication is the patient taking?
Example Sources to Use in Answering Enquiries
� SPCs or manufacturers’ Medical Information departments are often very helpful.� Medline and Embase enable retrieval of case reports and reviews of excipient side effects.� Check MiDatabank to see if you have been asked similar questions before.� There are a series of UKMi Q and As on NICE Evidence Search about prescribing in
lactose intolerant patients.� Martindale often has a description of major excipients with known problems.� Pharmaceutical Excipients by Rowe, Sheskey and Quinn (Pharmaceutical Press). Available
as a book or online via Medicines Complete, it is expensive and therefore notrecommended for purchase by local MI centres. However, regional centres may haveaccess.
� Anon. What are excipients doing in medicinal products? DTB 2009; 47:81-84.
Exercises
� Try the ‘Test Yourself!’ questions (page 20.5).� Look at the example enquiry (page 20.6).� Attempt the real enquiries as guided by your tutor (page 20.7).
1. What is the difference between an excipient and an additive?
2. Why should you be careful about prescribing oral liquid medicines with a highsorbitol content to patients with a short bowel?
3. Where can you find out which antacids contain low amounts of sodium?
4. If you found an excipient that you were not familiar with when checking thecontents of a product in response to an enquiry, where would you go to find outmore about it?
5. Why is maize starch in an oral formulation not likely to be the cause of a patient’sallergic rash?
This section helps you to think about the enquiry answering process. Below are given thedetails of two real enquiries, as received by a regional MI centre. Decide with your tutor whichof these enquiries to do. Then for each one describe:(a) Any further questions you would like to ask the enquirer.(b) The top sources that you would use to answer the enquiry.Your tutor will go through these with you when you have finished. If you like, research a fullanswer using MiDatabank Trainer on MiCAL to document it, but discuss this with your tutorfirst.
1. Calcium supplement in child with multiple additive allergy
A dietician rings for advice on choice of calcium supplement in a child with allergyto oranges and lactose intolerance.
Further questions for enquirer Sources to use
2. Changing formulation associated with allergic reaction
AGP rings to ask you about a patient who has developed an allergic rash afterstarting cefaclor capsules. The patient has had cefaclor syrup before on two occasionswithout a problem and the GP asks you to check for any additives in the capsulesthat might be the cause of the problem.
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