Prussian Blue Tablets for Cesium Decorporation: pH-Dependent Performance Under Normogastric and Hypochlorhydric Conditions in an In Vitro Gastrointestinal Model

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the present work, the authors have evaluated the performance of various formulations of Prussian Blue under normal gastric and hypochlorhydric conditions using in vitro model. Overall, the work performed was significant and authors have written manuscript very well covering all aspects. I have few points for author’s consideration for improvement of manuscript.

Abstract:

• I would suggest the authors to define abbreviations at their first appearance. For example, full forms for PB, API, NG are not provided in the abstract. Further, it is also not very clear what does Regimen means. Does it mean normal gastric and hypochlorhydria? Please clarify.

Introduction:

• The authors are aiming to study the static, pH directed non-enzymatic approach using compendial media for understand the behavior of the drug product in normal gastric and hypochlorhydria conditions. In the fifth paragraph of introduction (page 3 of 27), authors have mentioned objectives of present work and again the objectives got repeated on the same page in last paragraph. I suggest the authors remove the duplicacy. Further, the abbreviations such as C0, %Rs are not defined at their first instance in this paragraph. please define and clarify these terminologies for better readability.
• It would be interesting to know if the reference product in this case, Radiogardase® has any specific administration scheme mentioned with respect to normal gastric and hpochlorhydria conditions. It would also be interesting to know if this product is intended to be administered in fasting or in fed condition as per label recommendations. As the authors mentioned that less acid (pH 4) may facilitate more capture as compared to normal condition (pH 1.2), these details will help the reader for better interpretation.

Results and discussion

• Section 2.1: In the second paragraph, authors mentioned various statistical tests used in this case. However, it would be helpful if the authors mention statistical tests at appropriate places at the respective in vitro sections for better readability
• Figure 1: The authors have not indicated the placebo in this diagram. Please clarify. Also the there is some difference in the decorporation for Radiogardase, no difference was seen for compression blend and PB tablet. Please clarify this trend in the context of formulation. Further, this observation is also in conflict with the aspects mentioned by authors in the introduction that less acid may facilitate more decorporation but it is not seen in these results.
• Figure 2: The results are very interesting. The trend of results in stage 2 and stage 3 are different as compared to stage 1. This aspect may require further explanation. Typically the stomach pH condition (normal vs hypochlorhydria) may cause differences but sequent pH conditions are similar in both cases (pH 6.8 and pH 7.2) and thus differences are not expected. However, it seems there is an effect of stage 1 that is getting carried to subsequent stages. However, the trend for Radiogardase remained same in all stages (lower for normal and higher for HC). The authors may explain the differences in behavior of their formulations against Radiogardase for better clarity to the reader.

Discussion

• The authors are suggested to describe about the implication of this interesting work in real world applications. This may be important provide opinion on converting the findings into label recommendations. An ideal formulation may behave independently of the pH conditions (NG vs HC) however, such formulation is not achieved in the present work. the authors are suggested to talk about future perspectives of development of such formulation for better patient compliance and discuss the factors that may govern such behavior.

Materials and methods

• Section 3.1: The authors have tested five different types of formulations, however the rationale for testing these types is not clear. Further, details about the PB tablets (LPAP20221DE3) is also required to be elaborated (although reference 43 is given). Brief description about this formulation in comparison with Radiogardase will be beneficial.
• Section 3.4: The authors have used pH 4 acetate buffer for mimicking the hypochlorhydria condition. However, under the actual acid reducing agents administration in fasting condition, the stomach pH is elevated to pH 4 but acetate buffer species is not present. It may be better to consider pH 4 with gastric media contents (pH 1.2). kindly provide authors opinion on this aspect.

Author Response

We attach our comments in a file.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The completed manuscript is a continuation of the authors' previous work, in which they formulated tablets containing Prussian blue. In this manuscript, they compared the tablet formulation with the efficacy of Radiogardase® capsules and concluded that it could be an alternative.
The structure of the manuscript is logical, but in my opinion, it needs to be supplemented before publication.
The authors describe how they prepare the powder mixture before pressing, but they do not specify the batch size. Without this information, the data provided is meaningless.
- How were they able to extract 105 mg from a 700 mg tablet for measurement?
- The word "pellet" appears twice on page 18, which has not been mentioned before. What material are these pellets made of, what size are they, and what exactly did the authors use them for?
- Some parameters are missing in the case of ICP-OES measurement. Do the authors have any information on the values of the coolant flow, light tube, optic flush, optic temperature, Osc. exhaust, and Osc. impedance?
- In my opinion, a photo taken during the measurement, perhaps of the samples being tested, would make the manuscript more interesting.

Author Response

We attach our comments in a file.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I would like to thank the authors for making the necessary changes in the manuscript. The readability of the manuscript has been increased significantly.

Reviewer 2 Report

Comments and Suggestions for Authors

I accept the answers. I found them to be correct. I have no further questions regarding the manuscript.