Comment on: “Differences in In Vitro Properties of Pancreatin Preparations for Pancreatic Exocrine Insufficiency as Marketed in Russia and CIS”

Referring to the publication by Maev et al. [1], it can be agreed with the authors that particle size, label claim-compliant lipase activity, high batch-to-batch conformity, gastric resistance and quick enzyme release in the intestine are relevant parameters for successful treatment of pancreatic exocrine insufficiency with pancreatic enzyme-replacement therapy (PERT). However, the authors’ claim that the particle size of PERT should be smaller than 2 mm appears debatable, and it should be emphasized that particle size distribution (PSD) is also relevant.

After measuring particle sizes, the authors concluded that only Kreon and not other PERTs available in Russia or CIS (Commonwealth of Independent States: Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, Uzbekistan) fulfilled the criterion of a suitable particle size of 2 mm. Ermytal, Pangrol and Panzytrat displayed a significantly larger particle size than Kreon when using the selected parameter Feret max X₅₀. Unfortunately, the authors provided no data regarding the PSD or X₁₀ and X₉₀. For Ermytal, Pangrol and Panzytrat, the PSD was small because of the production process (sieved microtablets). This is not necessarily true for pellet-based products such as Kreon. Thus, evidence is lacking that the average diameter is not caused by the combination of two particle fractions with diameters either too big or too small to empty simultaneously with the meal. For a complete evaluation, data regarding the length/width ratio of the cylinder-shaped pellets would also be needed (Feret min X₅₀ data missing). The authors pointed out that the critical dimension of the particle is the length of the cylinder, but it has been shown that particles of that shape can leave the pylorus lengthwise [2]. Given that, for Kreon, the Feret max is already quite small, it is possible that quite a high number of particles have a width small enough to leave the pylorus before the chyme, especially as even 2 mm enteric-coated pancreatin microspheres have been shown to do so [3].

Even if all Kreon particles showed a very narrow PSD and a rather round shape, it is questionable whether the particle size difference of 1 mm compared with Ermytal, Pangrol and Panzytrat in any way affects the efficiency of the PERT. It is true that the European guideline [4] recommends particles smaller than 2 mm, but it has only recently been demonstrated that there is no scientifically sound evidence for this cut-off value, which needs serious re-evaluation [5].

This criticism includes the fact that the cited guideline has failed to provide clinical evidence for the claimed advantage of smaller-sized particles. Instead, that document cited a study that, rather than reporting a trial comparing different pellet sizes for gastric emptying and efficacy, provided evidence for 2 mm particles emptying faster (not slower) than a pancake meal from the stomach of patients with chronic pancreatitis [3].

Finally, Maev et al. [1] themselves conceded that there was no evidence to suggest an impact on clinical outcome of particle size differences in the discussed range. So, we agree with the author that studies with direct comparisons are lacking.