Authors
S. HUIJGHEBAERT (1), P. DE BRUYNE (2), K. ALLEGAERT (3), M. VAN WINCKEL (4) / [1] Independent researcher, , Belgium, Pharmacist PhD, [2] Ghent University, Ghent, Belgium, Clinical Pharmacologist, Paediatrics, [3] KU Leuven, Leuven, Belgium, Department of Development and Regeneration , [4] Ghent University, Ghent, Belgium, Paediatric Gastroenterology
Introduction
In deciding whether a product falls under EU drug regulations (EMA reviewed and approved) or EU medical device (MD) regulations (a national competence requiring CE certification only), the EU Directive states that particular account shall be taken of the principal mode of action of the product; in MDs, pharmacological actions are ancillary to the primary MD function. Hence ‘medicine’ products are increasingly launched in the EU as medical devices (MDs), claiming effective treatment primarily through a barrier function, while making multiple pharmacological claims.
Aim
To analyse the evidence for barrier and/or pharmacological actions of barrier-claiming MDs, by analysing package inserts, published evidence and promotional claims of 3 MDs and their ingredients: gelatin tannate (GT, Tasectan®,Gelenterum®) for diarrhea; hyaluronic acid/chondroitinsulphate/poloxamer 407 HACSPol (Ziverel®,Esoxx®) for GORD; glycerin/trypsine (GlyTS) oral mouth spray (Viruprotect®,Coldzyme®) for common cold.
Methods
Extensive literature search on pubmed and internet in general (extensive reference list available).
Results
None of the studies claiming barrier function were unambiguously conclusive: the claimed film effect was never observed/visualized. For all 3 MDs, mapping the experimental design illustrated that the claimed barrier was at the wrong side (contradicting pathophysiology): oral GT (=in gut lumen) was claimed to function as barrier against LPS toxins administered intraperitoneally (=serosal); HACDSPol reduced the protein extravasation from inflamed oesophageal wall to lumen (Evans blue used, instead of testing a bioadhesive barrier against luminal acid/pepsin diffusion/aggression as proven for alginates). It is recognized that Pol407 and modified HA/Pol407 composites can form (film)barriers by thermogelling (e.g. FDA-approved LeGoo® for endovascular occlusion on cardiac surgery and Seprafilm® against surgical adhesions, yet excluding GI-sutures); however, for thermogelling about 10-fold higher concentrations Pol 407 are needed; they are stable MDs requiring single application only; submucosal HACSPol(80%)-injected oesophageal cushions disappeared in 20 min. GlyTS, spayed in the throat, was claimed to form a barrier against rhinoviruses: however, rhinoviruses cause infection via nasal and not oral cavity, while glycerol is a good solvent mixing with water; 1-day prophylactic treatment with GlyTS could not prevent rhinovirus infection following nasal viral challenge. The assessed effects were always explainable by pharmacological actions of single ingredients, or physicochemical effects specific to the test model: 1) In GT models, effects were observed at caustic 37% HCl (tanning action; no significance at 3.7% - 10% HCl) or pH was close to the isoelectric point (iP) of G (pH 4.7) keeping GT precipitated, which however cannot guarantee barrier function at the pH range of human gut and its secretions: GT hydrolyses above and below iP. Tannins are moreover hydrolysable and bacterially degraded, gelatine digested. Tannins have been found to exert many bio/pharmacological actions at (very) low concentrations (tannate-specific; range 0.1- 100 µg/mL; 0.1-1% of GT dose in the models): all but one model (using aberrantly high toxic TA doses) failed to validate the claimed barrier effect by including relevant TA controls. TA also precipitates dextran in presence of protein at iP 5 (= pH in mice gut), invalidating the GT dextran sulphate–induced colitis model. 2) For HACSPol, pharmacological actions of HA (fragments) can be mediated by binding to HA-binding receptors, abundantly present in the human oesophagus; they include angiogenic, immunostimulatory and anti-inflammatory actions (0.2% topical solutions heal buccal ulcers (= 6x less)). The effect may also be poloxamer-mediated alone, as Pols have been shown to reduce leakage by counteracting cell integrity deterioration, or simply to inhibit influx of Evans blue. 3) TS acts as signalling molecule on PAR in many complex processes of the body (including viral infection). For all MDs, pharmacological claims were made either in patent, developer-associated publications, leaflet or promotion, to support action and efficacy: a recent review listed HACSPol under ‘Drugs’ for GORD (Savarino 2017).
Conclusions
Evidence provided for barrier effect of MDs is non-conclusive. The barrier claim lacks either a scientific rationale (wrong barrier side), or is not tested in a validated model applicable in humans. As MDs escape claim control of medicinal drugs, vague barrier claims allow them making largely pharmacological and non-proven efficacy claims. Hence, CE marking of such MDs does not represent medicinal quality.
