Excipients in pharmaceutical products

Introduction

Medicines contain active ingredients to treat or cure a disorder. They also contain other ingredients. These are called excipients and are used for a variety of different reasons from improving the taste and texture to helping them dissolve better, work better and last longer as well as making them easier to handle. Excipients are reviewed by healthcare regulatory agencies to ensure they are generally safe for use in human medicine; however, some patients may want to avoid certain excipients for a variety of reasons (1).  

This is true for those living with Inherited Metabolic Disorders (IMDs), with the British Inherited Metabolic Disease Group (BIMDG), highlighting that certain excipients should be used with caution to avoid risks of potentially harmful outcomes including metabolic crises (2). Healthcare professionals are also minded to take greater care in the treatment of paediatric patients, particularly neonates as these groups are not as able to process and eliminate the excipients as easily as adults, meaning they are more at risk of the negative consequences associated with some excipients (3). 

Excipients

There are a wide variety of substances used as excipients. In some cases, these can cause harm, below, we have listed a few IMD specific examples to show their use and potential danger. 

Ethanol & Carnitine Deficiency: This is commonly used to dissolve the active ingredient in medications (4) but can potentially cause issues in individuals living with Carnitine Deficiency. Carnitine is a substance that helps the body turn fat into energy and is made in the liver and kidneys, with this also present in animal products such as red meat (5,6). In people living with Carnitine Deficiency, there is a lack of carnitine in the body with this potentially worsened by ethanol, with a scientific study showing that this substance can further disrupt carnitine’s function in the body (7, 8). 

Aspartame & Phenylketonuria (PKU): This is a sweetener used in some preparations of medicines and when broken down by the body this substance is converted into aspartic acid and phenylalanine (2). Individuals living with PKU should avoid sources containing phenylalanine as this condition means the body cannot properly break down this substance. As a result, phenylalanine builds up in the blood and brain which has the potential to cause brain damage (2,9). Despite these potential risks, it is important to note that if aspartame cannot be avoided in medications for people with PKU, the pharmacy department or medicines information departments are contacted to help doctors minimise the impact (2). 

Lactose & Galactosaemia: Lactose is widely used in tablets and capsules where it acts as a filler or to dilute the medication. It may also be found in dry powder inhalers, freeze dried products, sugar coating solutions and some liquid preparations (10). In the body, lactose is broken down into glucose and galactose. This can be dangerous for individuals living with galactosaemia who cannot process galactose (2). The build-up of this substance can lead to symptoms and complications, including difficulties with feeding and speech, and damage to the liver and kidney (11).  

Due to this potential to do harm, the European Food Safety Authority (EFSA) highlight that the main dietetic principle in the management of galactosaemia is to eliminate all sources of galactose (12). It is important to note that despite these warnings, the amount of lactose present in medications is unlikely to be significant; with this particularly true for adult patients. Additionally, the clinical team responsible for care will work to minimise the time spent on medications including lactose and will work to reduce the amount present (2). 

Sorbitol, Fructose & Hereditary fructose intolerance (HFI): These substances are used as sweeteners in oral medications and sorbitol is used to stabilise an amino acid called peptide in some perinatal medications (13). Patients living with HFI lack the capability to break down fructose meaning this should be avoided. Sorbitol intake should also be avoided as this substance is converted into fructose in the body (2, 14).  

The negative consequences associated with fructose ingestion involve vomiting due to people living with HFI developing a natural defence mechanism against this substance, with this mechanism bypassed when sorbitol is given in the perinatal period leading to serious consequences including kidney and liver failure in addition to acute metabolic crises. Despite these dangers, some medications contain very low amounts of sorbitol and can be given to these patients with careful consideration so long as this is checked and discussed with the specialist IMD team (2).  

Other excipients: This is not an exhaustive list and there are many excipients that may be harmful for people living with an IMD, or the general population. For further details on the excipients in your medication, speak to the healthcare professionals in charge of your care. 

Excipients in paediatric medication

During the development of medicines for paediatric populations, the choice of excipients used requires special safety considerations. This is because the intake of an excipient may result in a different exposure in children than in adults; exposure may also be different in children of different ages.

Exposure to excipients can be more severe in paediatric patients when compared to adults, because paediatric patients are not equally able to process and eliminate the excipients. This means they are more at risk of the negative consequences associated with an excipient (3). Equally, thought must be given to how the substance used may affect developing organ systems (15, 16). This is the case for the excipients discussed in the previous section, however, generally exposure to these and other excipients are regulated to avoid harm with expert guidance offered to further reduce risk (17). 

Benefits of removing excipients

As discussed throughout this statement, excipients are used for a variety of purposes and not all of them can be removed or need to be removed. Without excipients it would not be possible to make drugs into appropriate medicinal products and for others, their removal would reduce the shelf life and make them uneconomic to produce or too expensive for users to purchase. It is, however, important to minimise exposure to excipients when possible and to only use them when there is a clear requirement (18). 

For people living with IMDs, the presence of specific excipients in medications brings the potential for harm (1), particularly in paediatric patients who are at higher risk of the negative consequences associated (3). This means that healthcare professionals may have to adapt the amount of medicine provided to minimise the amount of excipients whilst also reducing time spent receiving the medicine, as well as adjusting diet in some cases (1). 

Reducing or eliminating potentially harmful excipients in medications has the potential to decrease the occurrence of adverse reactions, especially in communities at high risk. Moreover, this approach enables individuals to adhere to their medication regimen for longer, leading to more effective management of their conditions. Additionally, for individuals with IMDs requiring a specialised diet for example PKU, adhering to a specialised diet can be burdensome. By removing excipients that may further restrict this diet, it represents a favourable measure towards enhancing the overall quality of life. 

Final words

As was discussed throughout this statement, there is a balance that must be struck between ensuring the effectiveness of medicines and their safety considerations. It is imperative that our communities are educated about this balance to enable transparency, whilst also increasing trust since this would give healthcare professionals the opportunity to highlight the measures being taken to ensure their safety, despite the risks. 

We understand that there is a need for some excipients, however, we would like to see a future in which non-essential excipients are removed from medications so long as this will not compromise the medication’s effectiveness. This would further ensure the safety of our communities whilst minimising the burden on healthcare professionals to adjust medication doses, regimen schedule and diet to account for the presence of excipients in medication. 

If you are concerned about anything raised in this statement, then get in touch with your doctor, pharmacist or metabolic team who will be able to give you more information about the medication you’re using. 

A black and white headshot of a man with curly hair and a short beard standing in a grassy area with trees visable in the background. The man is wearing a white polo with the top button undone and is smiling slightly whilst squinting at the sun.

Statement by Jonathan Gibson

Hi, I’m Jonathan and I work as the Policy and Public Affairs Officer for Metabolic Support UK.

My background is in genetics and global health and I’ve also worked for the NHS within a busy biomedical science laboratory for over four years undertaking the analysis of samples to ensure you receive the right treatment and diagnosis.

As a creative and compassionate individual, this really is my dream job so I look forward to working closely with the team and our community to tell the stories of IMDs to the world.

References

1) Medicines For Children (2021) Focus on ‘excipients’ in children’s medicines, Medicines For Children. Available at: https://www.medicinesforchildren.org.uk/news/focus-on-excipients-in-childrens-medicines/ (Accessed: 30 November 2023). 

2) BIMDG :: British inherited Metabolic Disease Group (2020) National Formulary for Inherited Metabolic Diseases (IMDs) 2 ND Edition – October 2020, BIMDG :: British inherited Metabolic Disease Group. Available at: https://www.bimdg.org.uk/store/docs/BIMDG_Metabolic_Formulary_Second_Edition_October2020FINAL_582433_25102020.pdf (Accessed: 30 November 2023). 

3) Svinning et al. (2017) ‘O-22 safe excipient exposure in neonates and small children – the seen project’, Archives of Disease in Childhood, 102(10). doi:10.1136/archdischild-2017-esdppp.22. 

4) European Medicines Agency (2018) Information for the package leaflet regarding ethanol used as an excipient in medicinal products for human use, European Medicines Agency. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/information-package-leaflet-regarding-ethanol-used-excipient-medicinal-products-human-use_en.pdf (Accessed: 01 December 2023). 

5) Mount Sinai (2023) Carnitine (L-carnitine), Mount Sinai Health System. Available at: https://www.mountsinai.org/health-library/supplement/carnitine-l-carnitine#:~:text=Carnitine%20is%20a%20substance%20that,all%20the%20carnitine%20it%20needs. (Accessed: 04 December 2023). 

6) National Institutes for Health (2023) Office of dietary supplements – carnitine, NIH Office of Dietary Supplements. Available at: https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/#:~:text=Carnitine%20is%20present%20in%20animal,to%2075%25%20%5B1%5D. (Accessed: 04 December 2023). 

7) Dahash, B. and Sankararaman, S. (2023) Carnitine deficiency, NCBI bookshelf. Available at: https://pubmed.ncbi.nlm.nih.gov/32644467/ (Accessed: 04 December 2023). 

8) Wilson, D.F. and Matschinsky, F.M. (2020) ‘Ethanol metabolism: The good, the bad, and the ugly’, Medical Hypotheses, 140, p. 109638. doi:10.1016/j.mehy.2020.109638. 

9) NHS (2023) Phenylketonuria, NHS choices. Available at: https://www.nhs.uk/conditions/phenylketonuria/ (Accessed: 30 November 2023). 

10) Specialised Pharmacy Services (2022) Prescribing in lactose intolerance and how to identify lactose free medicines, NHS choices. Available at: https://www.sps.nhs.uk/articles/prescribing-in-lactose-intolerance-and-how-to-identify-lactose-free-medicines/#:~:text=Update%20history-,Lactose%20in%20medicines,solutions%20and%20some%20liquid%20preparations. (Accessed: 01 December 2023). 

11) UK National Screening Committee (2021) Galactosaemia, GOV.UK. Available at: https://view-health-screening-recommendations.service.gov.uk/galactosaemia/ (Accessed: 01 December 2023). 

12) European Food Safety Authority (2010) ‘Scientific opinion on lactose thresholds in lactose intolerance and galactosaemia’, EFSA Journal, 8(9), p. 1777. doi:10.2903/j.efsa.2010.1777. 

13) European Medicines Agency (2017) Information for the package leaflet regarding fructose and sorbitol …, European Medicines Agency. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/information-package-leaflet-regarding-fructose-sorbitol-used-excipients-medicinal-products-human-use_en.pdf (Accessed: 01 December 2023). 

14) Hegde, V.S. and Sharman, T. (2023) Hereditary fructose intolerance – statpearls – NCBI bookshelf, National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559102/ (Accessed: 01 December 2023). 

15) European Medicines Agency (2013) Guideline on pharmaceutical development of medicines for paediatric use, European Medicines Agency. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf (Accessed: 01 December 2023). 

16) Svinning et al. (2017) ‘O-22 safe excipient exposure in neonates and small children – the seen project’, Archives of Disease in Childhood, 102(10). doi:10.1136/archdischild-2017-esdppp.22. 

17) Royal College of Paediatrics and Child Health (2020) Position statement 2020-01 choosing an Oral Liquid Medicine for Children, Royal College of Paediatrics and Child Health. Available at: https://nppg.org.uk/wp-content/uploads/2020/12/Position-Statement-Liquid-Choice-V1-November-2020.pdf?UID=12136295720231130212725 (Accessed: 01 December 2023). 

18) Turner, M. and Shah, U. (2015) ‘Why are excipients important to neonates?’, Current Pharmaceutical Design, 21(39), pp. 5680–5687. doi:10.2174/1381612821666150901110341. 

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