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Pharmaceutical Excipients

20. Pharmaceutical Excipients

What are Excipients?

Medicinal products contain one or more pharmacologically active compounds which are responsible for the product’s therapeutic potential. Excipients are all the other parts of the formulation. Collectively these stabilise the formulation, help with the manufacturing process, aid dispersion of the or make the product more appealing to the patient. Two oral formulations are described in detail below as examples:

® ® Ciproxin Tablets Lanoxin PG The body of the contains: The elixir contains: • Ciprofloxacin (the active ingredient). • Digoxin (the active ingredient). • Microcrystalline (used as a • Methyl Hydroxybenzoate (). binder which holds the tablet together, • or Syrup BP (sweetener and and as a diluent which bulks up the thickener). tablet). • 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 (binder, diluent and helps to maintain desired pH). disintegrant). • Quinine Yellow (colour). • Silica colloidal anhydrous (improves flow • (solvent). of through tabletting machine). • (solvent with some • Magnesium stearate (lubricant in preservative properties). tabletting process). • Purified (solvent). • Lime No. 1 NA HSE (flavour). The tablet film-coat consists of a mixture of: • Hypromellose (main ingredient of coat). • 4000 (makes the coating more soluble 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 medicinal product they do, in many cases, have pharmacological activity. This means they can cause side effects in their own right. Sometimes an unexpected reaction to a pharmaceutical can be explained by considering the potential effects of excipients. On other occasions patients or professionals know about a problem with specific excipients and may ask you to check new to make sure that a particular excipient is not present.

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Pharmaceutical Excipients

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 may not be declared. Different manufacturers may also list excipients in different parts of the SPC. If it is crucial to be sure about excipient content, the only option is to ring manufacturers individually. For excipients that present particular problems in children refer to Tutorial 11. 1. – lactose intolerance is caused by a deficiency of the gut enzyme lactase which normally breaks lactose down into simple . Deficiency may be a temporary situation (e.g. after gastroenteritis) or permanent (genetic deficiency). In the absence of lactase, flora in the lower bowel convert lactose to irritant substances which can cause symptoms such as diarrhoea, flatulence and abdominal pain. Lactose is commonly used in tablets and capsules as a diluent in small amounts, but it may need to be avoided by patients with severe intolerance. 2. Gluten – a protein derived from wheat which exacerbates the gastrointestinal symptoms of coeliac disease and related conditions. Maize (or ‘corn’) starch does not cause this problem. 3. – allergy to these can sometimes be demonstrated and further exposure should subsequently be avoided if possible. Examples include (methyl, ethyl and propyl hydroxybenzoates used in oral liquids and topical products); thiomersal (mainly in ); cetyl alcohol (principally used in topical products and dressings). 4. Phenylalanine – this, and the chemically-related aspartame , should be avoided in patients with phenylketonuria. These patients are unable to metabolise phenylalanine and suffer a range 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 it could theoretically contaminate the drug solution. Consequently, parenterals with latex bungs are best avoided in those with latex allergy. 6. Peanuts – the arachis oil used in pharmaceuticals should not cause problems in patients with peanut allergy (see example enquiry below). However, patients affected may prefer to avoid it and it is easy to do so. 7. Glucose and Sucrose – the amount of in some medicines might occasionally be significant enough to affect blood sugars in some diabetic patients. High sugar content liquid medicines can also cause tooth decay. 8. – 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 with hypertension). Some , for example, contain quite high amounts (e.g. Gaviscon liquid). 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 further exposure. 11. Animal origins – sometimes patients may wish to avoid excipients of animal origin for personal or religious reasons. For example, some vegans may wish to avoid , and Jehovah’s Witnesses may wish to avoid vaccines containing albumin from a human source.

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Pharmaceutical Excipients

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 standard way of identifying additives across Europe. Examples of pharmaceutical excipients that might also 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 pharmaceutical excipient it is helpful to check if the excipient has an E number so that the patient can avoid further exposure via food. The Food Additives and Ingredients Association provides a comprehensive list of E numbers and 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 were completely harmless. However, some excipients are not absorbed from the gut at all, and so their 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 amounts used in pharmaceuticals do not represent a hazard (e.g. citric acid, albumin). Others do not have 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 not recommended for purchase by local MI centres. However, regional centres may have access.

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Pharmaceutical Excipients

Further Reading

 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).

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Pharmaceutical Excipients

Test Yourself!

1. What is the difference between an excipient and an additive?

2. Why should you be careful about prescribing oral liquid medicines with a high sorbitol 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 the contents of a product in response to an enquiry, where would you go to find out more about it?

5. Why is maize starch in an oral formulation not likely to be the cause of a patient’s allergic rash?

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Pharmaceutical Excipients

Example Enquiry

Below is an e-mail exchange between a consultant dermatologist and a medicines information pharmacist.

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Pharmaceutical Excipients

Real Enquiries

This section helps you to think about the enquiry answering process. Below are given the details of two real enquiries, as received by a regional MI centre. Decide with your tutor which of 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 full answer using MiDatabank Trainer on MiCAL to document it, but discuss this with your tutor first. 1. Calcium supplement in child with multiple additive allergy

A dietician rings for advice on choice of calcium supplement in a child with allergy to oranges and lactose intolerance.

Further questions for enquirer Sources to use

2. Changing formulation associated with allergic reaction

A GP rings to ask you about a patient who has developed an allergic rash after starting cefaclor capsules . The patient has had cefaclor syrup before on two occasions without a problem and the GP asks you to check for any additives in the capsules that might be the cause of the problem.

Further questions for enquirer Sources to use

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Pharmaceutical Excipients

Notes

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