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What are excipients doing in medicinal products?

Abstract

Medicinal products contain not only active drugs but also other ingredients included for a variety of purposes and collectively known as excipients (from the Latin word excipere, meaning ‘to take out or receive’).1,2 Prescribers may wrongly overlook or dismiss excipients on the assumption that these are inactive. In reality, such substances are not always inert and may have risks.3 Here we consider why excipients are present in medicines, their potential unwanted effects, how they are regulated and where to find out more about them.

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Functions of excipients

Product manufacture and identification

Some excipients are used in the manufacture of medicines (e.g. to ensure homogeneity of powders, flow of granules, compression of tablets).1 Examples include lubricants which may be either water-soluble (e.g. sodium lauryl sulphate, polyethylene glycol 4000 or 6000) or water-insoluble (e.g. hydrogenated vegetable oil). Anti-adherents include talc and corn starch. Binders (e.g. ethylcellulose, gelatin) increase cohesion and aggregation of powders in tablets. Maltodextrin helps to avoid crystallisation of syrups.

Colouring agents may help in product identification; they include organic substances (e.g. beta-carotene, indigo carmine, sunset yellow, tartrazine, flavones), minerals (e.g. red and yellow ferrous oxides), and synthesised compounds.1

Stability and preservation of medicines

The inclusion of antioxidants (e.g. ascorbic, fumaric and maleic acids; sodium edetate) can help to delay oxidation of active substances and other excipients that might otherwise reduce the medicine's potency or increase its unwanted effects.1 To further inhibit oxidation, antioxidant synergists may also be used (e.g. edetic acid plus edetates).1,2 Film-coating a tablet (e.g. using cellulose derivatives and sugar) can protect the active ingredient from the environment (e.g. light, air, moisture) and increase the mechanical strength of the product.1 Insoluble pigments such as iron oxides in tablet coatings may help to protect light-sensitive ingredients.1

Preservatives are added primarily to prevent or inhibit microbial proliferation, if this could risk infection or degradation of the medicinal product, a particular risk in multi-dose preparations.2 Examples of preservatives include benzoic acid (in oral liquid preparations); benzalkonium chloride (in eye drops); and cetrimide (in creams and emulsions).1 Parabens are broad-spectrum antimicrobial esters of 4-hydroxybenzoic acid used singly or in combination as preservatives.4

Making medicines acceptable

Ingredients typically added to make medicines more acceptable to patients include colourings (e.g. tartrazine); flavourings (e.g. peppermint, lemon oil); sugars (e.g. sucrose, glucose); and artificial sweeteners (e.g. saccharin, sodium cyclamate, aspartame).3 Coating tablets with water-soluble cellulose derivatives may make them less likely than uncoated products to stick to the oesophageal mucosa.1 Medicines may include buffers (acidifying agents such as citric acid; alkalising agents such as sodium bicarbonate) and tonicity agents (e.g. dextrose, sodium chloride, mannitol) to aid tolerability when the drug is delivered to the systemic circulation or to a localised area (e.g. mucous membranes).1

Delivering the drug

Some medicines contain excipients known as carriers, which are vehicles for delivering the active ingredient to its site of action. Examples of these include solvents (e.g. benzyl alcohol, glycerol, propylene glycol) and ointment bases (e.g. polyethylene glycols, ethyl oleate).1,5 Also, diluents (e.g. lactose) may be added to make administration easier.1,5,6 The inclusion within sustained-release preparations of polymers (e.g. xanthan gum) with restricted water solubility or permeability allows control of the release of the drug from the formulation.1 Propellants (e.g. chlorofluorocarbons [CFCs]) disperse liquid or solid colloidal particles when the drug is intended for inhalation.1 Because of their adverse effect on the environment, CFCs have largely been replaced by hydrofluoroalkanes (HFA; e.g. in asthma inhalers).7 To facilitate breakdown in the gastrointestinal tract, medicines may contain disintegrants (e.g. maize or potato starch, aluminium magnesium silicate, sodium alginate).1 Also, the inclusion of permeation enhancers and solubilisers (e.g. alkyl amines, pyrrolidones, sulfoxides, terpenes) can modify the penetration of active substances through the skin or aid oral drug absorption.2,8

Enhancing the drug effect

Medicines may contain adjuvants (e.g. aluminium phosphate or hydroxide in vaccines) to enhance the efficacy of the active drug or increase the ability of an antigen to stimulate the immune system.2

What harm can excipients do?

Allergic reactions and anaphylaxis

Examples of excipients that can cause allergic reactions include common preservatives used in topical preparations (e.g. benzalkonium chloride 0.1%, benzethonium chloride, propylene glycol, sorbitol); azo colouring agents (e.g. tartrazine [E102]), methylhydroxybenzoate [E218], propylhydroxybenzoate [E216]; cetyl and stearyl alcohol; and polysorbate 80, a solvent.911 Vaccines may also cause allergic reactions that are responses to excipients such as egg, antibacterials (e.g. neomycin, gentamicin) and other substances (e.g. gelatin).3 Polyoxyl castor oils, used as vehicles in intravenous injections, have been associated with severe anaphylactoid reactions.3 Some people have a severe, life-threatening allergic reaction following exposure to peanut allergens and this raises concerns about medicines containing such substances as excipients.12 For example, the presence of arachis (peanut) oil in a medicine may be associated with warnings in the summary of product characteristics (SPC) about never using the product in patients allergic to peanuts.13 However, the inclusion within medicinal products of refined peanut oil (a neutralised, bleached, deodorised product containing no proteins) is considered by the Department of Health to be without risk even to sensitised individuals.12

Examples of excipients in topical preparations that can cause sensitisation include beeswax, parabens, isopropyl palmitate, sorbic acid and wool fat and related substances including lanolin.3 Sensitisation to peanut protein may occur in children through the application of creams containing arachis (peanut) oil to inflamed skin (e.g. emollients such as zinc cream or zinc and castor oil ointment for nappy rash, eczema, dry skin or inflammatory cutaneous conditions).3,14 Once skin sensitisation has occurred, subsequent contact with the sensitising chemical can cause allergic contact dermatitis.

Problems due to food intolerance

Patients may have food intolerances that produce unwanted effects on exposure to the causative substances, including when these are excipients. Examples include patients intolerant of lactose or colourings.3 In adults with lactose intolerance, ingestion of lactose may cause gastrointestinal symptoms.6 Typically, the dose of lactose in medicines is below 2 g per day and is unlikely to cause symptoms except in patients with severe intolerance.6 However, many of the products used for common gastrointestinal conditions (e.g. dyspepsia, inflammatory bowel disease, irritable bowel syndrome) contain lactose as an excipient; in patients with lactose intolerance (who may be taking more than one such medication), their use may be of clinical significance.15 A recent study identified the amount of lactose in medications used for gastrointestinal disorders in the UK (e.g. antispasmodics, antacids, drugs for inflammatory bowel disease) and lactose-free alternatives that may be helpful for some patients.15

Drug interactions

Excipients that accelerate transit through the small intestine (e.g. polyethylene glycol, sodium acid pyrophosphate, mannitol) reduce gastrointestinal absorption of medicines primarily absorbed at this site (e.g. ranitidine, cimetidine).16

The bioavailability of a drug may be reduced when it forms a poorly soluble, non-absorbable complex with an excipient (e.g. tetracycline with calcium phosphate; amfetamine with sodium carboxymethyl-cellulose; or phenobarbital with polyethylene glycol 4000).1,17

In November 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) issued warnings relating to excipients in a new formulation of tigecycline (▼Tygacil), an intravenous antibacterial licensed for complicated intra-abdominal or skin and soft-tissue infection.18 These excipients make the antibacterial incompatible with amphotericin B, amphotericin B lipid complex or diazepam; as a consequence, these medicines should not be given simultaneously with the new tigecycline formulation through the same Y-site infusion system.18

Particular problems in children

Infants and other children may not be able to metabolise or eliminate an ingredient in a medicinal product in the same way as adults.19 Many colouring agents have been associated with hyperactivity and other unwanted effects in children.1921 Benzyl alcohol has been associated with a fatal toxic syndrome in preterm neonates, and therefore parenteral preparations containing this preservative should not be used in neonates.3

In a study, 38 premature babies, who were less than 30 weeks' gestation and weighed under 1,500 g at birth, were found to be exposed to over 20 different excipients during their stay in a neonatal unit.22 These included ethanol (in iron and furosemide) and propylene glycol (in dexamethasone), each of which has been associated with neurotoxicity. The babies' exposure to ethanol in these medicines was around 0.2–1.8 mL per week, which is equivalent to 1–7 units of alcohol per week (corrected for weight). Also, all of the infants given dexamethasone exceeded the World Health Organization's acceptable daily intake limit of 25 mg/kg body weight of propylene glycol at some stage during their hospital stay. Infants also had high intakes of sorbitol (in dexamethasone and iron), of around 0.1–3.5 g/kg per week; many of the babies exceeded their weight-adjusted equivalent of the maximum adult intake of sorbitol.

Other problems

Aspartame, a source of the amino acid phenylalanine, is used as a sweetener in some medicines.3 This matters for people with phenylketonuria, a condition in which the ability to metabolise phenylalanine is compromised, such that dietary intake of phenylalanine needs to be restricted to a small amount sufficient for tissue building and repair.3

Alcohol as an excipient can cause problems for patients with chronic alcohol dependence being treated for this with disulfiram, a drug intended to cause a reaction (which can be severe) when alcohol is also taken. So such patients should be warned of this risk.3 Medicinal products containing alcohol (or gelatin derived from animal products) may be unacceptable to some patients on religious grounds. Propylene glycol can cause adverse effects if its elimination is impaired, for example, by renal failure; also it may interact with disulfiram and metronidazole.3 Excipients including alcohol and polyethylene glycol have been implicated in extravasation injury, which may follow leakage of drugs or intravenous fluids from the veins, or inadvertent administration into the subcutaneous or subdermal tissue; if not dealt with promptly, this problem can lead to tissue necrosis.3

How are excipients regulated?

The European Medicines Evaluation Agency Committee for Medicinal Products for Human Use (CHMP) has published a guideline on the information companies need to provide on excipients when applying for marketing authorisation of a medicinal product.2 Documentation of the chemistry of any new excipient is required, including data on manufacturing, quality, stability, purity, microbiological tests and toxicology.2,23 The presence of each excipient must be justified in both qualitative (function) and quantitative (optimal amount) terms.23 The medicine should contain the smallest amount of the excipient capable of achieving the desired function.23 Colourings must satisfy the requirements of European Union (EU) directives on colours for use in foodstuffs, including specific purity criteria.2 Flavourings should normally comply with EU directives on flavouring substances used in or on foodstuffs.2

Safety studies

Before a product is marketed, the compatibility of its excipients with active substances and other excipients should be established.23 In principle, the same pivotal studies as for a new active substance should be carried out for a new excipient.23 In particular, safety studies with the final product should be done for formulations that substantially alter the pharmacokinetics or pharmacodynamics of the active substance.23 Tolerance must be determined at those body sites that come into contact with medicinal products; for substances applied to the skin, the sensitising potential must also be investigated.23

After a medicinal product is placed on the market, new information about its unwanted effects under normal conditions of use needs to be collected, collated and evaluated through pharmacovigilance systems. These systems are a legal obligation under European pharmaceutical legislation, and this covers active substances and excipients.23 Pharmacovigilance could lead, for example, to withdrawal of a product from the market if safety concerns arise after launch. A risk management system, which includes routine pharmacovigilance activities and, in most cases, a risk management plan, is required for any new marketing authorisation.23 The risk management plan may contain a list of studies to further characterise known or potential risks, as well as a plan for risk minimisation activities (e.g. pregnancy prevention programmes and birth registries where there is a possibility of mutagenicity).

Labelling

The SPC of any medicinal product is required to contain a list of excipients.23 In addition, the particulars must appear on the outer packaging of medicinal products or, where there is no outer packaging, on the immediate packaging; this includes a list of excipients known to have a recognised action or effect (or, if the product is injectable, topical or an eye preparation, all excipients).23

The European Commission has published a list of excipients and the wording required for each of these in the packaging inserts for patients.10 For example, a topical preparation that contains formaldehyde needs to carry the warning “May cause local skin reactions (e.g. contact dermatitis)”, and in an oral preparation should carry the warning “May cause stomach upset and diarrhoea”.10

What are the practical implications?

Before the patient receives a medicinal product

Patients with certain conditions may need formulations of medicinal products that do not contain particular excipients (e.g. sugar-free products for people with diabetes or lactose intolerance; alcohol-free formulations for people also taking disulfiram); this requires consideration of excipients prior to writing a prescription.

A vaccine is contraindicated in people who have had an anaphylactic reaction to one of its excipients (e.g. neomycin).24 Anyone with a confirmed anaphylactic reaction to egg should not receive influenza or yellow fever vaccines.24 Where there is doubt about whether or not a person can receive a vaccine, advice should be sought from an appropriate consultant paediatrician or physician, the immunisation co-ordinator or a consultant in health protection.24

If an unwanted effect occurs

If a patient experiences an adverse reaction or unwanted effect thought to be due to a prescribed medicinal product, it is important for clinicians to consider not only the active ingredient, but also any excipients present, as the potential cause of the problem.

Where to find out more

The British National Formulary (BNF)

The BNF provides information on the inclusion of some important excipients, where appropriate, in the individual product monographs.3 For example, it notes as ‘sugar-free’ those oral liquid medicines that do not contain fructose, glucose, or sucrose or that do contain other sweetening agents such as hydrogenated glucose syrup, mannitol, maltitol, sorbitol, or xylitol. It also notes the presence of aspartame, tartrazine, arachis (peanut) oil or sesame oil in medicines; propylene glycol in oral or parenteral medicines; and other selected excipients in skin preparations, vaccines, eye drops and injections. Pressurised metered aerosols containing CFCs are also identified.

Pharmacopoeias

Most medicinal products in the EU contain established, standard excipients, and these are described in the European or the national pharmacopoeias.23

Product information

SPCs and patient information leaflets list excipients in the formulation of a medicine, and may state any adverse effects due to the excipient; many SPCs are available via the electronic Medicines Compendium (eMC; www.emc.medicines.org.uk).25 Further information should also be available from the company that holds the relevant marketing authorisation.

Other resources

Guides to the uses, properties and safety of excipients include Aulton's Pharmaceutics: The Design and Manufacture of Medicines17 and the Handbook of Pharmaceutical Excipients.26

Conclusion

In addition to their active drugs, medicinal products contain ingredients known as excipients that are essential for manufacturing the products; maintaining their physical form, quality and stability; and drug delivery. However, these substances may have unwanted effects, such as allergic reactions, skin sensitisation, and interactions with other drugs. The quantity of the excipients may be especially high relative to body weight when used in very small patients (e.g. premature babies); this can lead to individuals being exposed to excessive doses of the excipient.

Clinicians need to be mindful that medicinal products contain excipients, and these should not be assumed to be inert substances. It is sensible to consider the excipients prior to the patient receiving a medicinal product (e.g. a vaccine or prescribed medication) and this must be done if an unwanted effect occurs.

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    [R=randomised controlled trial; M=meta-analysis]

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