Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The Role of Alcohol in Pharmaceutical Products ***

Dr. Iris Krugmann (Abschlußjahr: 2015)

Summary
Language: English
Ethanol has traditionally a variety of applications, and remains pharmaceutically relevant. It is a universal solvent for both hydrophilic and lipophilic substances. At the same time it replaces preservative and stabilizer additives. Additionally, as prescribed by various pharmacopoeias and described by many HMPC monographs, ethanol is used in the production of herbal extracts and in homoeopathy in the production of liquid potencies. Because of its widespread use as a recreational substance in nearly every culture and its well-known toxic potential, in recent years experts and consumers have discussed the safe use of ethanol-containing medicinal products, especially for children. One side of the debate is based on scientific evidence, whereas the other is very often emotional, based on observations with excessive uptake. For a relevant and science-based assessment one needs to distinguish between the necessity of ethanol in medicinal products and risks caused by the abuse of alcoholic beverages or intoxication in children caused as worst case consideration e.g. binge drinking.
There should be a continuation in the support of the efforts of European authorities to reduce or remove ethanol content, especially in pediatric medicines, where possible.
Although there are no data regarding new risks, the European authorities assert that safety limits are required, if ethanol is necessary. According to “Reflection Paper on Ethanol content in herbal medicinal products and traditional herbal medicinal products used in children” (EMEA/HMPC/85114/2008), optional medical prescription drugs intended for pediatric population must have an ethanol concentration below 5% and after intake of a single dose of ethanol containing medicinal products, the resultant blood alcohol concentration should not be higher than 0.125 g/L (= 0.125‰) based on the impairment of psychomotor skills. The major acute toxic effect of ethanol is neuronal dysfunction with blood alcohol concentration of approximately 1 g/L, but has been reported with concentrations as low as 0.2 g/L. Thus in the United States the safety threshold has been established at 0.250 g/L after a single recommended dose, which is higher than the conservative European limit.
At the same time there is the requirement for strengthened warnings for ethanol on the packaging and in the package leaflet, as made clear by the revision of the Excipients-Guideline. In Germany, the “Arzneimittelwarnhinweisverordnung” (AMWarnV) is still valid, which has less strict formulations than the Excipients-Guideline. However, it is possible that this German regulation will be adjusted in the longer term to match the stringent European standard. This would entail adjustments in the texts of packaging leaflets and folding boxes. Additional information and warnings must be added, which would certainly result in marketing disadvantages for all ethanol-containing products.
There is no question that the intake of considerable amounts of ethanol by children is toxic and can cause permanent damages, but the quantity/dose is the decisive factor and should always be considered.
In the literature there are many cases of ethanol intoxication but these were not caused by the alcohol from medicinal drugs, but by abuse of alcoholic beverages.
Herbal medicinal products are usually dosed in drops or millilitres, homoeopathic medicines are usually dosed in drops. The blood alcohol concentration reached after the maximum single dose of a herbal medicinal product usually remains well below the respective safety thresholds (0.125‰ for the EMA and 0.250‰ for the FDA).
20 drops of a 45% (V/V) herbal medicine, which corresponds to 0.40 g alcohol administered to a child of 5 kg, results in a maximum blood alcohol concentration of 0.08‰.
The resultant blood alcohol concentration is comparable to that reached after ingesting certain foodstuffs, for example apple juice. Apple juice usually contains 0.4% (V/V) ethanol. This results in an uptake of 320 μg ethanol with 100 ml juice and to a maximum blood alcohol content of 0.055‰ in a one-year-old child.
Furthermore, in study data from several non-interventional studies with different ethanol containing herbal medicinal products in more than 50,000 children, no alcohol-related side effects were found. Additionally, an open clinical study has shown that after oral administration of a single dose of a fixed combination of thyme herb and primrose root as a fluid extract containing 4.9% (V/V) ethanol, the blood ethanol concentrations in children (1-4y: n=12, 5-12y: n=4) remained below the safety threshold (0.125‰).
Ethanol only needs to be avoided completely by high risk patients ('dry alcoholics', people with liver disease, brain injury or epilepsy). Furthermore, the use of medicinal drugs containing relevant amounts of ethanol is not recommended in pregnant or breastfeeding women and in patients taking interacting drugs. For these reasons all pharmaceutical preparations bear dose graded warnings on the packaging and in the package leaflet. Although these data illustrate the safe use of ethanol-containing medicines at recommended dosage, companies are trying to meet the demands of authorities and consumers to waive ethanol in pharmaceutical products, for example, by switching to other solvents. However, this can lead to other toxicity questions and altered efficacy. So far there is no equivalent substitute in most cases. The production of dry extracts instead of fluid extracts and the removal of ethanol from finished products must meet very stringent requirements (under certain circumstances new preclinical and clinical data) and requires major investments in terms of time and costs.
Thus it is technologically difficult to refrain from ethanol. Ethanol is a well-known and commonly used excellent solvent, preservative and extraction agent with known toxicology. It is a natural metabolite and natural ingredient in many foodstuffs.
Therefore one can conclude that to date the risk is low and the benefit predominant.
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