In preparation for this weeks practical session, we would like you to think about the use of flavourings in oral liquid medicines. Are the flavouring only used to make the medicine taste nice or is there more to it than that? Do some flavouring have a therapeutic use and do some flavourings mask the taste of certain medicines better than others? Are there any incompatibilities between certain flavours and the active product ingredient?
These are a few of the questions that could be asked about flavourings so have a think, see what information you can find and share your thoughts with the group.
Oral solutions and syrups are a very useful formulation choice, as it allows dosing of certain medication for people who have issues taking tablets or just prefer the oral solution, key examples of target groups are children or the elderly. An issue that does arise with this however is unpleasant taste; many drugs have metallic or bitter tastes, obviously not desirable. This can make dosing medication quite difficult, especially in patients who might not understand the benefit of the medication e.g. children. This is where flavourings come in; by adding a flavour it can often mask at least some of the taste making it much more palatable. Key examples of flavourings include Strawberry Flavour 500018E (used in calpol). However flavourings do not solve everything and the bitter taste can prevail, so sugar or sugar substitutes e.g. sorbitol are added to sweeten the syrup. In America, some pharmacies e.g. walgreen’s have a service when you can pick your flavour from mango to bubble gum!! Sometimes the flavouring is added simply to mask the smell, a good example of this was the mouthwash we made in labs (Sodium Chloride Mouthwash BP) the peppermint added masked the smell and made it more appealing, however did not do much for the taste. By changing the scent, it will still help the compliance of some patients. The brain receives some additional impulses from the olfactory receptors in the nose which coordinate with the gustatory stimuli to produce the mingled sensation that is recognised as the flavour of a substance. Some flavourings may have a mild therapeutic effect e.g. ginger in a laxative mixture and it has a carminative effect. Flavours are tailored to the taste of the medicine, see below.
ReplyDeleteSalt- Butterscotch/maple
Bitter- Cherry, mint, liquorice
Sweet- Fruit, berry, vanilla
Acid- Citrus
As some match better, there are some incompatibilities; e.g. lemon oil in an aqueous solution, they will not be miscible and therefore presents the issue of non-uniform mixture. Flavourings are undoubtedly very useful for oral preparations and they certainly helped me taking medicine as a child.
A good source I found, where the complementary masking flavour list is from:
A. V. SHARMA & P. V. SHARMA. (1988). FLAVOURING AGENTS IN PHARMACEUTICAL FORMULATIONS . Ancient Science of Life. 8 (1), 38-40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331350/pdf/ASL-8-38.pdf
Also used was this book:
Troy, Beringer (2006). Remington: The Science and Practice of Pharmacy. 21st ed. Philadelphia: Lippincott Williams & Wilkins. 1060-1069.
From extemporaneously dispensed medicines to those prepared at an industrial level, the addition of flavourings is a key part of the manufacturing process. Certain pharmaceutical ingredients have been noted to have unpleasant tastes, such as captopril, clarithromycin and prednisolone. The most common use of flavourings is to mask these tastes, and improve patient compliance of oral solutions. In certain patient groups the taste caused by a pharmaceutical ingredient can trigger nausea. As oral solutions may be the only reasonable formulation for children and patients with dysphagia, it is important that the process of taking these medicines is not marred by poor taste. Therefore it is essential to create a more palatable medicine by tailoring flavours to the taste being masked (Marriott, 2010).
ReplyDeleteThe following are recommended:
• Mint for bitter tasting medicines
• Butterscotch for salty tastes
• Vanilla for sweet tastes
• Citrus for sour tastes
Whilst natural flavourings focus on improving taste, synthetic flavourings have also been developed that possess other functions. These include improvement of shelf life, stability, solubility, purity, fluidity and humectant properties. A key example of this is glycerol, commonly used as a vehicle in a variety of oral solutions such as simple linctus BP. In addition to its sweet taste, glycerol also acts as a humectant and lubricant. Medicinal properties of the flavouring have also been noted, namely its use in reduction of intraocular pressure in severe cases of glaucoma (Jones, 2016). Peppermint water BP is commonly used to add flavour to extemporaneous products, but it has also been shown to alleviate dyspepsia and stomach cramps.
With preference for natural flavourings in the UK, this can also cause issues when mixing them with active pharmaceutical ingredients. For example some flavourings added in the hope of achieving a citrus flavour may contain grapefruit juice. As grapefruit juice inhibits CYP3A4, this is clearly an issue when incorporated with medicines that are usually inactivated by the enzyme e.g. statins. There is also the issue of oil-based flavourings, as these will not incorporate well or be uniformly distributed in the solution. Often these are dissolved into a small amount of alcohol to attempt to reduce this. There has also been speculation regarding the effect of liquorice flavouring reducing the action of blood pressure medication, and increasing the risk of digoxin toxicity (Hesham et al, 2012). A disadvantage of syrups being used as flavourings, particularly in children and diabetic patients, is the high sugar content and cariogenic nature. To combat this artificial sweeteners such as sorbitol are often added, though it remains difficult to mimic the taste of products using sucrose. However sorbitol also has a therapeutic use as a laxative, therefore adverse effects such as diarrhoea may be present when sorbitol is used as a flavouring (Crowley, 2005). In spite of this the addition of flavourings is an essential consideration for patient compliance, with the added bonus of some being able to alter properties of the formulation.
References:
DeleteCrowley, M. (2005). Solutions, Emulsions, Suspensions and Extracts. In: Troy, D. (Ed). Remington: The Science and Practice of Pharmacy, 21st edition. Lippincott Williams and Wilkins, Maryland. P. 754. (Use of sorbitol as a flavouring and its properties as a laxative).
Hesham, O., Komarova, I., et al. (2012). Licorice abuse: time to send a warning message. Therapeutic Advances in Endocrinology and Metabolism, 3: 125-138. (Described the potential interactions between flavourings and medicinal products, and the incompatibilities of them).
Jones, D. (2016). FASTtrack: Pharmaceutics – Dosage Form and Design, 2nd edition. Pharmaceutical Press, London. pp. 1-5. (Details of other functions of flavourings, and how this is useful when compounding medicines).
Marriot, J., Wilson, K. (2010). Pharmaceutical Compounding and Dispensing, 2nd edition. Pharmaceutical Press, London. pp. 89-91. (Information regarding the use of flavourings for specific tastes and improving palatability).
I think your explanation about the use of Grapefruit juice as a flavouring/excipient was very interesting. I previously did not know that this could be used, and learning about the effects of grapefruit juice in drug metabolism can cause concerns and issues with the medicines and may cause incompatibility. That was really useful and when i was writing a blog about flavouring i did not find this information.
DeleteThere is also evidence of peppermint, menthol and rose water having an inhibitory effect on calcium channels, which may interact with calcium channel blocking drugs as a result (Hawthorn et al, 1988). Whilst it may not be as clinically significant as drug-drug interactions, it raises the question as to why less emphasis is placed on interactions between drugs and flavourings.
DeleteReference:
Hawthorn, M., Ferrante, J., Luchowski, E., Rutledge, A., Wei, X., Triggle, DJ. (1988). The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Alimentary Pharmacology and Therapeutics, 2: 101-118.
you've made a very interesting point about this, I didn't realise that flavourings could have this effect and so reading through the reference its clear that their needs to be more evidence and research in to this.
DeleteFlavourings are an essential part of formulating medicines. If a medicine is going to be successful it has to have an acceptable taste. The taste may need to be tailored for the type of patient that will be using the medication, for example children may prefer sweet flavourings and elderly patients may prefer more bitter flavours.
ReplyDeleteIngredients within the drug may result in a foul tasting product, these may be the active ingredients or just the excipients, which would limit it’s attractiveness. Just like in the cosmetic industry, if a product is unpleasant to use people will use alternative products.
The use of flavourings in medicinal products may promote their therapeutic effect as a better tasting product, such as lemsip, will ensure that the entire dose is taken compared to a foul tasting product. In cough medicines menthol is used as a flavouring agent even though it is effective as a mild local anaesthetic (Chung et all, 2009).
Different flavourings mask certain tastes better than others, for example sweet flavours are masked well with fruit, vanilla or acacia syrup. Bitter tastes are masked better with cocoa, eridictyon, walnut or liquorice. Sour tastes are masked well using fruit, cherry syrup and citrus; and salty tastes are masked best using cinnamon, orange, liquorice syrup and butterscotch.
Some flavourings are incompatible with certain drugs, for example lemon syrup contains citric acid which causes salicylic acid to precipitate out of the solution if added so a sodium salicylate syrup. Therefore it is wise to choose flavourings carefully when formulating medication.
References:
Chung, K. Widdicombe, J (2009). Pharmacology and Therapeutics of Cough. London: Springer. p252 (Therapeutic flavourings.)
The Pharmaceutics and Compounding Laboratory. (2017). Aesthetic Considerations of Oral Liquid Dosage Forms. Available: http://pharmlabs.unc.edu/labs/aesthetic/palatability.htm. Last accessed 09/03/2017. (Explains flavours used to mask tastes.)
Flavourings can be added to a number of orally taken medicines, for a variety of reasons. Primarily, it is to mask the taste of the medicine, which otherwise could be foul tasting. Secondly, it makes the medicine more appealing, and this can help greatly in improving patient compliance, with there being a significant impact on children. Some classes of medicines that have flavourings added to them include antibiotics, antihistamines, barbiturates, decongestants and electrolyte solutions (Sharma and Sharma, 1988).
ReplyDeleteFlavours that can be used include maple and butterscotch for salty flavours, cherry for bitterness, vanilla or fruit flavours for sweetness and citrus tones for sourness. Flavourings used could either be natural or synthetic. The addition of flavours to medicinal products run a risk of triggering a sensitivity or allergic reaction in patients, therefore any patients who suffer any allergies could be at a higher risk. In all preparations, vigorous testing must be conducted to ensure that the flavours that are added primarily do not compromise the integrity, stability or shelf life of the product.
Some considerations should be made, for example, the concentration of sweetener in a medicine may not be suitable for those with diabetes. Some formulations may produce a laxative effect; polyols such as sorbitol and mannitol (European Medicines Agency, 2013).
Tablets can also have flavourings added to them to make them more tolerable. The flavours can be added to the coating if to be swallowed or within the tablet if it is in a chewable form. Anti-convulsants, vitamins and antihistamines are examples of drugs that can be formulated in such a way that incorporates a flavour. This is particularly useful in paediatric patients to increase compliance (European Medicines Agency, 2006).
References:
A.V. Sharma and P.V. Sharma (1988) Flavouring agents in pharmaceutical formulations. Ancient science of life. Vol. III. Pages 38-40
European Medicines Agency (2006) 2.1.5 Chewable tablets. Reflection paper: Formulations of choice for the Paediatric population. Page 10
European Medicines Agency (2013) 9.3 Flavours. Guideline on pharmaceutical development of medicines for paediatric use. Page 18
The flavours used in the medicines may have different functions. I believe that the most important use of flavouring in medicines is for compliance and adherence. Flavourings are used in oral suspensions and solutions which are good vehicles for medicines, than using other formulations such as injections and oral tablets/capsules that have poor compliance due to their tastes. My experience of taking tablets has been unpleasant due to the iron tastes, and this is the main issue for compliance in patient’s drug therapy.
ReplyDeleteThe committee for medicinal products for human use suggested that the qualitative and quantitative composition of any components of the flavouring agent that are known to have a recognised action or effect should be provided, in terms of it risk in patients, as it would suggest that the use of flavouring in certain preparations should be cautioned as it can alter the activity of medicines. Safety concerns should be discussed, along with including the risk of allergies (Committee for Medicinal Products for Human Use (CHMP), 2013).
A flavor, as used in the pharmaceutical industry for inactive ingredients, refers to natural or artificial tastes, which may include fragrances and colors of the flavoring. Flavors are used for orally consumed products such as syrups, chewable tablets, suspensions, or gums that impart beneficial therapeutic effect, as well (Committee for Medicinal Products for Human Use (CHMP), 2013).
Adverse reactions to flavourings are rare, since these chemical compounds are employed in minute concentrations in medications (Balbani, et al., 2006). The flavouring used in preparations is to mask the unpleasant tastes in the formulations.
• a bitter product - mint, cherry or anise may be used
• a salty product - peach, apricot or liquorice may be used
• a sour product - raspberry or liquorice may be used
• an excessively sweet product - vanilla may be used
References
Committee for Medicinal Products for Human Use (CHMP). (2013). Guideline on pharmaceutical development of medicines for paediatric use. [online] Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf [Accessed 10 Mar. 2017].
Balbani, A., Stelzer, L. and Montovani, J. (2006). Pharmaceutical excipients and the information on drug labels. [online] Available at: http://www.scielo.br/scielo.php?pid=S0034-72992006000300018&script=sci_arttext&tlng=en [Accessed 10. Mar. 2017]
Flavours are widely used within oral solutions and formulations. Oral solutions are a popular form of medicine used specially by those who cannot take or have difficulty taking solid oral medications such as tablets. Because of this it is important to make sure the medication is pleasant and attractive. This is achieved by adding flavourings to enhance, mask or improve the taste of the medication so that it is easily consumed. Flavours can be natural or artificial and may include colours or fragrances. They are widely used in syrups, suspensions, chewable tablets or gums. In 2013 new regulations were put into place across Europe which states all flavours used in food, drinks and medicines sold in the UK must be scientifically assessed for safety and must contain information labels that show the consumers what flavourings are in the products (action on additives, 2016). Even though adding minor additives such as flavourings into medications does not seem like it could cause significant change or alterations to the medication itself, it can in fact alter the function of the medication and cause conflicts. An example of this is using grapefruit based flavourings. Grapefruit may be used as an ingredient in the formation of citrus flavour however grapefruit is known to inhibit the function of the enzyme CYP3A4, this can be an issue when taking medications such as statins. Due to issues such as these it is important to follow regulations put into place and monitor medications closely.
ReplyDeleteFlavourings can be used to improve compliance and adherence within patients and can play a vital role in enhancing paediatric adherence to drug therapy. Children’s taste buds are more sensitive to bitter taste than adults, this can reduce compliance and the willingness to take medication. Sugars, salt, acids are seen to reduce bitterness of pharmaceuticals better than other flavours. Palatability is an important factor in patient tolerability, if a medicine tastes nice then they are more likely to take it properly (correct dose, time, frequency) which in turn will increase the pharmacological effect and lead to a better therapeutic outcome. Flavourings should only be used if they are shown to have a recognisable action/ effect and safety concerns such as allergies to certain components should be discussed with the patient before providing them with a favoured medication.
Medicines are mostly known to have a bitterness. This bitter taste can be reduced by balancing it with complementary tastes: sweet (berry, vanilla), salty (butterscotch), sour (cherry, mint). After masking the bitterness using these flavours, other additives and flavouring agents such as mint, grape, orange can be selected to enhance its taste, based on their compatibility with the medications active ingredients.
References:
Action on additives. (2016). Flavourings . Available: http://www.actiononadditives.org/flavourings. Last accessed 15th March 2017.
Senopsys. (2016). Flavor Masking of Drug Products. Available: http://www.senopsys.com/flavor-masking-services-for-palatable-drug-products/?gclid=CMeckMO2wNMCFUK4GwodETIH8g. Last accessed 15th March 2017.
Committee for Medicinal Products for Human Use, Paediatric Committee . (2013). Guideline on pharmaceutical development of medicines for paediatric use. Available: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf. Last accessed 15th March 2017.