What is the Role of Over 100 Excipients in Over the Counter (OTC) Cough Medicines?
by Eccles, R. What is the Role of Over 100 Excipients in Over the Counter (OTC) Cough Medicines?. Lung (2020). https://doi.org/10.1007/s00408-020-00390-x
Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine are more important to the patient than the pharmacology of the active ingredient. Excipients are generally defined as any ingredient in a medicine other than the active ingredient. In most medicines excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine as menthol, glycerol, and sugars, which are declared as active ingredients. This review searched the United Kingdom electronic medicines compendium (emc) and found over 100 excipients in 60 different liquid formulations of over the counter cough medicines. The excipients were divided into functional groups: sweeteners, thickeners, flavors, colors, antimicrobials, and buffers, and the incidence and function of the different excipients is discussed. When considering the efficacy of a cough medicine, clinicians and pharmacists tend to think of the pharmacology of antitussives such as dextromethorphan or expectorants such as guaifenesin, and they rarely consider the role of excipients in the efficacy of the medicine. This review discusses the functions and importance of excipients in cough medicines and provides some new information for clinicians, pharmacists, and all interested in the treatment of cough when considering the composition and efficacy of a cough medicine.
Introduction
Excipients are generally defined as any ingredient in a medicine other than the active ingredient. Their role in most medicines is to act as a stable vehicle for the delivery of the active ingredient in the form of a tablet, capsule, cream, or liquid. In most medicines, the excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine. Cough medicines are unique in that the most common form of the medicine is a viscous sweet syrup [1]. The active ingredients such as the antitussive dextromethorphan or expectorant guaifenesin, etc. could be delivered to the patient as tablets or capsules without any loss of pharmacological activity, but because of the history of cough medicines being formulated from food substances such as honey, a sweet viscous syrup formulation is expected by the patient consumer [2]. Although cough medicines are controlled by medical regulations, they have many similarities to foods and beverages, and most of the excipients now found in cough medicines have been derived from the food and beverage industry. There is a great advantage in using food and beverage additives as excipients in cough medicines as they are generally recognized as safe (GRAS) by regulatory authorities and this makes the registration of new formulations of cough medicines much easier for companies marketing cough medicines. This paper will discuss the role of excipients in cough medicines. The paper will discuss excipients in liquid formulations of cough medicines and will not discuss tablet, lozenge, and capsule formulations. The OTC cough medicines discussed in this article are for the treatment of acute cough associated with acute upper respiratory tract infections, but they may also be used by patients suffering from chronic cough but no information on this use has been found in the literature.
The composition of a cough medicine can be considered as made up of seven functional components as illustrated in Fig. 1. The declared active ingredients are usually pharmacologically active compounds such as dextromethorphan, guaifenesin, etc. but can also include excipients such as menthol, glycerol, and sugars. Sweeteners, thickeners, flavors, colors, antimicrobials, and buffers are excipients and will be discussed below as functional components of a cough medicine. “Other” excipients that did not fit into the functional categories are also discussed.
Fig. 1 Functional components of a cough syrup medicine
- active ingredients
- sweeteners
- thickeners
- flavors
- colors
- antimicrobials
- buffers
Source of Data
The information on cough medicines has been taken from the electronic medicines compendium (emc) [3] which contains freely available information about medicines licensed for use in the United Kingdom and lists over 14,000 documents. The search term cough was used on the database in June 2020 and this generated data on 105 medicines used to treat cough. Medicines in tablet, capsule, or pastille form, multi-ingredient medicines, and medicines only available on prescription were excluded from the list, and this left 60 cough medicines in liquid form. These cough medicines were freely available on general sale or available at pharmacists. The list of excipients in the summary of product characteristics (SmPC) for each of the 60 cough medicines was searched and a list of all excipients and their frequency of occurrence was made. 109 excipients were listed and their properties were mainly determined by reference to the Handbook of Pharmaceutical Excipients or other sources as referenced.
Sweeteners
Sweeteners are common excipients in cough medicines. As discussed above, natural honey was the first cough medicine and is still popular as a cough treatment today. Sweeteners and thickeners mimic the sweetness and viscosity of natural honey and continue the tradition of cough medicines being formulated as sweet viscous syrups. A list of sweeteners and the number of medicines containing each sweetener is shown in Table 1. Natural sugars such as liquid sugar, liquid glucose, and sucrose were the most common sweetener excipients. Natural sugars such as glucose and sucrose were also declared as active ingredients in 10 medicines and it is stated that they “have demulcent properties and will soothe irritated sore throats and possibly block sensory cough receptors within the respiratory tract.”
Table 1 List of sweeteners, with frequency of each sweetener from 60 cough medicines
| Sweeteners | Frequency |
|---|---|
| Liquid glucose | 30 |
| Sucrose | 30 |
| Saccharin sodium | 23 |
| Liquid sugar | 20 |
| Sorbitol | 13 |
| Maltitol liquid (E965) | 6 |
| Acesulfame K | 5 |
| Sodium Cyclamate | 5 |
| Natural sweetness enhancer | 3 |
| Ammonium glcyrrhizate | 2 |
| Partial Inverted Syrup (sucrose, fructose, and glucose) | 1 |
| Sucralose | 1 |
| Xylitol (E967) | 1 |
Artificial sweeteners such as sucralose, acesulfame K, sodium cyclamate, xylitol, and saccharin sodium can provide a low calorie cough medicine or be used to increase the sweetness of a medicine containing natural sugars. Sorbitol is a natural sugar but can also be synthesized from glucose; it provides sweetness with fewer calories than natural sugars such as glucose. Malitol can be synthesized from the natural sugar maltose and has the advantage over Sorbitol in that it is not metabolized by oral bacteria and therefore does not contribute to tooth decay. Malitol can be used as a low calorie sweetener and it has the advantage that it does not crystallize easily and therefore is less likely than natural sugars to cause bottle tops to stick.
Ammonium glychyrrhizate (glycyrrhizin) is a triterpene glycoside found in the roots of licorice plants (glycyrrhiza glabra). The latin name is derived from the Greek word ‘glykos’ meaning sweet and it has been used as a sweetener and medicine for thousands of years in many Asian countries. “Glycyrrhizin has a sweet taste with a characteristic licorice taste sometimes described as “cooling.” The sweetening potency is about 50 times that of sucrose. The sweetness is slow in onset and tends to linger”. Glycyrrhizin does not provide any calories and therefore can be used to greatly enhance the sweetening contributed by natural sugars and provide a licorice taste.
Role of Sweeteners in Cough Medicines
Sweeteners not only improve the taste of cough medicines and make them more pleasant to take but they also reduce the perception of the bitter taste of active antitussives such as dextromethorphan. A review on the role of sweeteners in cough medicines has stated that most cough medicines are formulated as sweet syrups and that the sweet taste provides the major benefit of the medicine and is more important than the pharmacologically active ingredient in the medicines. The review proposed that sweeteners may act as antitussives in two ways, firstly by stimulating salivation and airway secretions that soothe and lubricate the inflamed pharynx and secondly by the generation of endogenous opioids in the brainstem area that controls cough. This proposal was tested in a study that found that the sweet taste of sucrose increased cough reflex thresholds. Although it is stated in the SmPC of 10 medicines that natural sugars can “possibly block sensory cough receptors within the respiratory tract,” no evidence has been found in the literature to support this mode of action.
Thickeners
Nearly all the cough medicines contained a thickening excipient and the list of thickeners and the number of medicines containing each thickener is shown in Table 2.
Table 2 List of thickeners, with frequency of each thickener from 60 cough medicines
| Thickeners | Frequency |
|---|---|
| Glycerol | 48 |
| Propylene glycol | 20 |
| Hydroxyethylcellulose | 14 |
| Carmellose sodium | 6 |
| Arrowroot | 3 |
| Xanthan gum | 3 |
| Acacia (E414) | 2 |
| Maltodextrin | 2 |
| Povidone | 2 |
| Carrageenan | 1 |
The most common thickening agent used in cough syrups was glycerol also known as glycerine and this was found in 48 of the 60 products. Glycerol was also listed as an active ingredient in 17 cough medicines and the SmPC often stated that “Glycerol has demulcent properties and may possibly block sensory cough receptors in the respiratory tract.” No evidence has been found in the literature to support glycerol acting on sensory cough receptors. Glycerol is popular as an excipient in cough medicines because it serves multiple functions; acting as a sweetening agent (0.6 times the sweetness of sucrose), a solvent, lubricant, antimicrobial, humectant, and preservative. The special properties of glycerol as an ingredient of cough medicines have been recently reviewed and the article concludes that “a simple linctus containing glycerol with flavorings such as honey and lemon is a safe and effective treatment for cough in children and adults”. Glycerol is a small molecule with three carbon atoms and its viscous nature is because each of the carbon atoms has a hydroxyl group attached and these hydroxyl groups can bind to other hydroxyl groups by hydrogen binding with water, which makes glycerol very soluble in water, or by hydrogen binding to other glycerol molecules, which causes aggregation of glycerol molecules and means that glycerol does not flow as well as water and is rather viscous.
Propylene glycol was the second most commonly used thickening agent found in 20 of the cough medicines. Propylene glycol has a three carbon chain with two hydroxyl groups and has similar properties to glycerol as a thickening agent. Its solubility in water and viscosity are due to the hydrogen binding of the two hydroxyl groups on the molecule. It has a sweet taste and has useful properties as a solvent, antimicrobial, preservative, humectant, lubricant, and demulcent.
Glycerol and propylene glycol are unusual as a thickening agent as most thickening agents are synthetic long-chain polymer molecules such as hydroxyethylcellulose (Hyetellose, Natrosol), polyvinylpyrrolidone (Povidone), carboxymethylcellulose (Carmellose), and maltodextrin. These synthetic thickening agents are viscous because of the long molecular chains and they are without any taste and are not absorbed or metabolized and therefore safe. In addition to the synthetic thickening agents, a range of natural products are used as thickening agents because they are long-chain sugars or cellulose. Carrageenan is obtained from various red sea weeds. Acacia (Arabic gum) is obtained from trees (Acacia Senegal) in the Sudan region. Arrowroot is a starch substance obtained from the roots of several tropical plants. Xanthan gum is obtained by fermenting carbohydrates with the bacterium Xanthomonas campestris.
The synthetic thickening agents are by far the most commonly used agents in cough medicines and this is because they are easily standardized, and the industrial source is stable. Natural thickening agents are more difficult to standardize and source and they may have a place in medicines that claim to be herbal or natural products.
Role of Thickeners in Cough Medicines
Most cough medicines are formulated as thick viscous syrups and this may be due to consumers considering a thick syrup as having stronger effects than a watery liquid. The viscous formulation may also be historical as viscous honey was one of the first cough medicines, used over 100 of years, and still popular today as an ingredient in cough medicines.
Thickeners may also enhance the sensory impact of a cough medicine by prolonging the residence of the medicine in the mouth and therefore prolonging the duration of any sweet taste of the medicine. Some of the thickeners, such as glycerol, also have demulcent and lubricating properties that will help to soothe an inflamed pharynx .
Thickeners such as glycerol also provide a sweet taste, and others such as carrageenan can support antiviral and antibacterial claims.
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or continue reading here: by Eccles, R. What is the Role of Over 100 Excipients in Over the Counter (OTC) Cough Medicines?. Lung (2020). https://doi.org/10.1007/s00408-020-00390-x