On the potentization of nothing, equal contents for all, and double-blind studies

Before medicinal products can be brought to market, they must today successfully undergo a licensing procedure which involves tests to prove that they are effective and safe. However, there are also products that are allowed to be sold with medicinal claims, although they have not had their efficacy proven in this way: homeopathic medicines. The methodology behind these preparations was developed by German doctor Samuel Hahnemann at the end of the 18th century. According to this methodology, like heals like; in other words, an illness can be treated with substances that, in a healthy person, would provoke the symptoms witnessed in the patient (the word "homeopathy" comes from the Greek "homoios" (like) and "patheia" (suffering)).

Since many of the substances used are detrimental to health in their pure form, they are diluted according to certain principles. Here, the homeopathic doctrine is based on the astonishing assumption that the potency of a substance increases with dilution ("potentization"). Higher potencies are therefore considered to be more powerful remedies – even though they contain very little or even none of the original "active ingredient". All the explanations contrived thus far contradict the known laws of physics and chemistry [1], and even 200 years later, there is still no scientifically tenable proof that homeopathic medicines produce any specific effect beyond that of placebo [2, 3].

Despite this, in 2018 homeopathic products achieved sales worth roughly 670 million euros in Germany, another year on year increase. Adherents of Hahnemann have suffered a few setbacks lately, however: the French government is following the example of Australia, Russia and the UK and will end state reimbursements for homeopathic medicines by the end of 2021. In the U.S., over-the-counter homeopathics must bear a label stating that there is no scientific proof of their effectiveness and that the claimed effects are based on theories from the 18th century [4]. At the same time, taking substances which are supposedly "holistic" or "gentle" is not always harmless if it means that patients do not seek prompt and suitable treatment for serious illnesses. There are even suspicions of direct adverse effects on health and even fatalities, for example in the case of toddlers given teething tablets containing Belladonna (deadly nightshade) 12c. According to the manufacturer, tablets sold in the U.S. that are theoretically based on a 1 : 1,000,000,000,000 (!) dilution of the basic substance should contain only 0.0000000000002 mg (0.2 femtograms) of potentially toxic belladonna alkaloids. However, random samples by the FDA found individual tablets containing a million times this dosage [5].

Although these samples did not contain any acutely toxic quantities, they do flag up a universal problem in pharmaceutical technology: how to distribute very small quantities of active ingredients homogenously in solid dosage forms such as powder, capsules, and tablets. Medicinal products frequently contain only a few micrograms of highly active substances such as hormones, equating to a relative percentage of 0.03% to 0.1%. In these cases, unfavorable grain size distribution or the effects of segregation can rapidly result in very wide variation in contents from one tablet or capsule to another. If the active ingredient can be dosed as a homogenous solution, this problem is eradicated. However, many active ingredients do not remain stable when stored in an aqueous solution. There are two answers to this, and Harro Höfliger has equipment that can help with both.

For a long time now, it has been possible to fill hard capsules with liquid or semi-solid, non-aqueous preparations. With the dosing pumps of our Modu-C capsule filling machines, this can be done very precisely and over a broad viscosity range. (The fact that, unlike in tablet presses, there is no dust, is a welcome side effect, especially when highly active substances are involved!) What's more, today there are dosing systems that can dose extremely tiny quantities of liquid with very high precision, and function like the familiar inkjet printer. It therefore makes sense to add a solution of the active ingredient to a suitable neutral carrier, then to remove the superfluous solvent. The printing of water-soluble polymer films (orally disintegrating films, ODF) is a particularly elegant method, and the dosing quantity can even be verified in-line using suitable analytical techniques [6]. As a manufacturer of web processing machines that are suitable for this task, Harro Höfliger is involved in several projects of this kind.

However, even if an "allopathic" medicine contains verifiable and therapeutically plausible quantities of the active ingredient, the possibility of it triggering a placebo effect in the patient, as mentioned at the beginning of this article, cannot be excluded. This must be quantified in so-called randomized, double-blind trials, whenever the administration of a placebo can be ethically justified. Since neither the patient nor the doctor performing the trial is allowed to know whether the administered medicine contains the active ingredient under test, a reference treatment or a placebo, the dosage form must not give any indication of difference on any sensory level.

A rather sophisticated method for peroral forms such as tablets or capsules which generally does not alter the products' characteristics involves "hiding" it in hard capsules and adding additional powder ("backfill") to ensure acoustic "blinding". For additional peace of mind, special capsules ("DBcaps") that are difficult to open can be used, or the capsules can be banded, i.e. given a tamper-proof seal. Here, too, Harro Höfliger can help, because our line of Modu-C capsule fillers can not only handle the rather unusual empty capsules, it also offers various modules for non-destructive feed and precise separation of the diverse test medications.

[1]          Martin Lambeck: Irrt die Physik? C.H. Beck, Munich (2003).

[2]          NHMRC Information Paper: Evidence on the effectiveness of homeopathy for treating health conditions, National Health and Medical Research, March 2015 https://www.nhmrc.gov.au/sites/default/files/images/nhmrc-information-paper-effectiveness-of-homeopathy.pdf.

[3]          Homeopathic products and practices: Assessing the evidence and ensuring consistency in regulating medical claims in the EU, EASAC European Academies' Science Advisory Council, September 18, 2017 https://issuu.com/easaceurope/docs/easac_homepathy_statement_web_final.

[4]          Enforcement Policy Statement on Marketing Claims for OTC Homeopathic Drugs Federal Register  Vol. 81, No. 239 (December 13, 2016) 90122-23.

[5]          https://www.fda.gov/drugs/information-drug-class/laboratory-analysis-homeopathic-teething-tablets  (last accessed: 01.08.2019).

[6]          Vakili, Hossein: Application of analytical techniques in quality control of printed pharmaceutical dosage forms. Åbo Akademi University (2018).

By Dr. Karlheinz Seyfang