Dr Md Anawar Hossain
Excipients and their uses in medicines
All other materials except active pharmaceutical ingredient in medicines are called pharmaceutical excipients or inactive ingredients (Haywood and Glass, 2011). Excipients are considered as inactive ingredients or inert materials, however, studies over the past years indicated the adverse reactions from them. Appropriate drug delivery system plays a significant role in treatment of diseases.Nowadays, drugs are delivered in many dosage forms including tablets, capsules, oral liquids, topical creams and gels, transdermal patches, injectable products, implants, eye products, nasal products, inhalers and suppositories. The excipients play a significant role in drug delivery system via different ways as below:
1. The excipients or inactive ingredients are mixed with active ingredients to increase the physical properties (size and form of tablets, capsules and other solid forms of medicines),
2. To aid the manufacturing process and formulation development,
3. To protect, support or enhance stability, solubility, permeation, absorption (Ullmann, 2022), or bioavailability or patient acceptability and compatibility (Haywood and Glass, 2011).
4. Therefore, they are considered not just as inert ingredients in a formulation, but as functional ingredients facilitating the therapeutic function of the active ingredients.
5. The excipient controls the drug release so that it does not release too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset (Dave, 2008).
6. Some excipients help the drug to disintegrate into small particles accelerating their flow into blood stream, while other excipients protect the product’s stability giving it maximum effectiveness at time of use (Dave, 2008).
7. Some excipients are used to aid the identification of a drug product.
8. Some excipients are used to make the product taste and look better, especially for children.
9. Excipients are also used as diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives, which are essential components of drug manufacturing process.
Ratio of pharmaceutical excipients and active ingredients
Pharmaceutical excipients are very essential components of a modern drug manufacturing process, although they are considered to be pharmacologically inactive. Their quantity makes up the bulk of the total dosage form in many products (Dave, 2008). Thousands of different excipients are used in manufacturing medicines and, on average, each product contains about 90% excipients (Haywood and Glass, 2011). Reker et al. (2019) characterized the abundance and complexity of inactive ingredients in approved medications. They reported that a majority of medications contain inactive and active ingredients that could cause adverse reactions. Therefore, it is very essential to enhance the safety of medications and their inactive ingredients. We should have pre-analysis of the ingredients contained in medications whether they have any possibility of reactions resulting in harmful by-products and new products.
Patient specific formulation of medications
The amount or ratio of inactive ingredients and active ingredients in pills or capsule should be clearly reported, so that the patients and health care providers can understand the ingredients what they are ingesting in. Some of the patients might be allergic or intolerant to some ingredients. Some excipients might have the potential to alter the pharmacokinetic properties of an active pharmaceutical ingredient by different reactions, such as physicochemical interactions or by modulating metabolic and transport enzymes (Reker et al., 2019). Developing a specific formulation of medications considering a specific sub-population of patients could thereby not only avoid adverse reactions but help to achieve fine-tuned pharmacokinetic and metabolic profiles.
Possible adverse reactions by excipients
The excipients used in medicines should be pharmacologically inactive, non-toxic, and non-reactive with the active ingredients or other excipients. Actually, few excipients fulfil the above ideal characteristics. Some excipients are proved to be not inert, and they have ability to react with other ingredients in the formulation. They also cause adverse and hypersensitivity reactions in patients which can be a mild rash to a potentially life-threatening reaction (Haywood and Glass, 2011). The excipients, either solid powder or solvents, used in the manufacturing of medicines or their by-products/residues may cause multiple toxicities (Haywood and Glass, 2011).Different pharmaceutical manufacturers use different excipients, especially preservatives and colourants to produce the same drug. The Consumer Medicines Information provides a list of excipients, and information on the safety of individual excipients can be found in drug reference guides.
Some patients face an adverse reaction after ingestion of medicines, and they are not sure how they are encountering adverse reactions. The adverse reactions may occur not always from the active ingredient, but also it may result from the similar ingredients if the patient is sensitive to those, or if the patient is taking multiple medicines. The adverse reaction may occur if the quantity of excipients may be high relative to body weight, especially for premature babies. The adverse reaction might result from the excipients contained in their current and past medication history too. Therefore, the patient should identify which factors are causing their individual adverse effects.
Diluents or fillers can significantly affect the physico-chemical properties of the final tablet thus affecting the biopharmaceutical profile. As for example, calcium salts, used as fillers, can interfere with the absorption of tetracycline from the gastrointestinal tract indicating that excipients may not always be inactive or inert material in a drug (Dave, 2008). Therefore, the pharmaceutical manufacturers should carefully select the diluents, binders, lubricants and glidants to avoid the adverse reactions, but maintain the product stability and disintegration capacity for drug release after ingestion.
Use of excipient in preparation of tablet
The international pharmacopoeias contain the list of excipients, and their uses. The same excipient has multiple uses. The manufacturing of tablets can be a complex process. Therefore, the formulation expertise should focus on precaution to produce a product that will be stable during storage, transport and handling. The tablet should be dissolved homogenously and release its active pharmaceutical ingredient as required once ingested.
Dangers to children from excipients use in medicines
Some studies reported that, in some formulations for children, excipients are often used at higher concentrations than the recommended levels in international paediatric guidelines, while inappropriate labelling enhances the potential risks associated with the various excipients (Rouaz et al., 2021). The paediatric safety profiles related to the age and development of excipients often are different from those of adults.
Some toxic excipients are used in formulations for the neonates/newborn children, which include sodium benzoate, propylene glycol, methyl para hydroxybenzoate, propyl, sodium saccharine, benzyl alcohol, benzalkonium chloride, polysorbate 80 and ethanol. European new-borns receive several potentially harmful pharmaceutical excipients: parabens, polysorbate 80, propylene glycol, benzoates, sodium saccharine, sorbitol, ethanol and benzalkonium chloride.
Detailed information about the used excipients is missing in paediatrics. Therefore, it is very essential to conduct new research and develop new guidelines about the use of excipients in medicines for children, which can increase the safety and reduce toxicity of excipients from the adverse effects in paediatric populations. Gallon formulators can formulate safer, more stable and higher quality products.
The pharmaceutical manufacturers should consider the possible adverse effects of the active ingredients and the excipients used in the paediatric population because the excipients that are safe for adults, may not be safe for children.
References
Dave R.H., 2008. Overview of pharmaceutical excipients used in tablets and capsules. Drug Topics Journal, October 24, 2008. Link: https://www.drugtopics.com/view/overview-pharmaceutical-excipients-used-tablets-and-capsules. Accessed on 20/05/2022.
Haywood A., Glass BD., 2011. Pharmaceutical excipients – where do we begin? Aust Prescr 34, 112-114. https://doi.org/10.18773/austprescr.2011.06
Reker D, Blum SM, Steiger C, et al. 2019. “Inactive” ingredients in oral medications. Sci Transl Med. 11(483): eaau6753. doi:10.1126/scitranslmed.aau6753.
Rouaz K., Chiclana-Rodríguez B., Nardi-Ricart A., Suñé-Pou M., Mercadé-Frutos D., Suñé-Negre J.M., Pérez-Lozano P., García-Montoya E., 2021. Excipients in the Paediatric Population: A Review. Pharmaceutics 2021, 13, 387. https://doi.org/10.3390/pharmaceutics13030387.
Ullmann P, 2022. Excipient selection for compounded pharmaceutical capsules: they’re only fillers, right? EDUCATION PRACTICE UPDATE. Link: https://www.medisca.net/pdf/published-articles. Accessed on 20/05/2022.