Novel Crosslinked HA Hydrogel Films for the Immediate Release of Active Ingredients
Round 1
Reviewer 1 Report
The manuscript “Studies on novel HA hydrogel films loaded with active ingredients for immediate release on the skin” seems interesting. The overall design looks good. However, I recommend considering the following points to improve the quality of the research.
Comments and suggestions for authors
1) Why the authors stated the title as novel HA hydrogel films, is it due to the crosslinker (PT) or the formulations? Authors should clarify it in the introduction or discussion part?
2) Introduction: Please discuss the crosslinker PT in the introduction. What is its significance and rationale for formatting the hydrogels on the basis of topical/transdermal drug delivery?
3) Introduction, line 24: The first word that appeared should be defined with an abbreviation. In line 34, HA should be abbreviated. Thus, write the abbreviation of HA at the first appeared word and then mention HA all over the manuscript. Please check the manuscript and make it consistent.
4) Introduction: After paragraph (line 89), could you please discuss the importance/rationale of drug-loaded hydrogel films for transdermal drug delivery based on different references? This part is lacking in the introduction. Suggest making separate a paragraph.
5) In line 90: Could you please elaborate or discuss more on the aim of the study?
6) Result and discussions: Authors have discussed well for the obtained result. However, could you please discuss the main finding based on the reported references (topical/transdermal drug delivery), like the release study or others? I hope this will highlight the significance of the study and improve the manuscript.
Author Response
We would like to thank the reviewer for the comments. Please see our responses below in blue colour:
The manuscript “Studies on novel HA hydrogel films loaded with active ingredients for immediate release on the skin” seems interesting. The overall design looks good. However, I recommend considering the following points to improve the quality of the research.
Comments and suggestions for authors
1) Why the authors stated the title as novel HA hydrogel films, is it due to the crosslinker (PT) or the formulations? Authors should clarify it in the introduction or discussion part?
The novelty of these HA hydrogel films was reported in our previous paper where we presented the novel method of preparation of HA crosslinked films, using PETRA as the crosslinking agent under high temperature (oven) and high pH. We have now added this clarification in the final paragraph of the Introduction (please see highlighted part).
Also, we decided to rephrase our title to: “Novel crosslinked HA hydrogel films for the immediate release of active ingredients”
2) Introduction: Please discuss the crosslinker PT in the introduction. What is its significance and rationale for formatting the hydrogels on the basis of topical/transdermal drug delivery?
Please find a paragraph in the Introduction (lines 68-73 of the revised manuscript) with additional information about PT.
3) Introduction, line 24: The first word that appeared should be defined with an abbreviation. In line 34, HA should be abbreviated. Thus, write the abbreviation of HA at the first appeared word and then mention HA all over the manuscript. Please check the manuscript and make it consistent.
Thank you, done.
4) Introduction: After paragraph (line 89), could you please discuss the importance/rationale of drug-loaded hydrogel films for transdermal drug delivery based on different references? This part is lacking in the introduction. Suggest making separate a paragraph.
Few additional justifications have been added for each of the chosen active ingredients. Please see highlighted parts in yellow.
5) In line 90: Could you please elaborate or discuss more on the aim of the study?
Please see revised paragraph with the aim and objectives of the study (final paragraph in the Introduction)
6) Result and discussions: Authors have discussed well for the obtained result. However, could you please discuss the main finding based on the reported references (topical/transdermal drug delivery), like the release study or others? I hope this will highlight the significance of the study and improve the manuscript.
A paragraph has been added at the end of the Results and Discussion to highlight the significance and applicability of these films.
Reviewer 2 Report
In this manuscript, the author investigated the novel HA hydrogel films loaded with active ingredients for immediate release on the skin, the (95-100) % release of the actives achieved from the HA hydrogel films within 10 min, revealed that the films are an efficient topical delivery system of these actives. There some issued need to be addressed, therefore a major revision of this review is recommended.
(1) The whole manuscript was in a bad organization, the structure characterization such as FTIR should present firstly, the release profile (Figure 1) should present before the release data (Table 3)
(2) The figure of DSC curves and FTIR spectra are too vague, which should be redrawn.
(3) How does the HA crosslinked with PT? Through intermolecular interaction or chemical covalent? In the FTIR spectra discussion, the author should demonstrated the successful crosslinking.
(4) In the section of release kinetics, the fitted plots and kinetic parameter of four models originated from release data should be provided, and corresponding reference (Gels 2022, 8, 649) should be cited.
(5) Why does this system can realize zero order release, the mechanism should be explained.
(6) The references format should be revised according to the journal’s requirement.
Author Response
We would like to thank the reviewer for their comments. Please find our responses below in blue colour.
In this manuscript, the author investigated the novel HA hydrogel films loaded with active ingredients for immediate release on the skin, the (95-100) % release of the actives achieved from the HA hydrogel films within 10 min, revealed that the films are an efficient topical delivery system of these actives. There some issued need to be addressed, therefore a major revision of this review is recommended.
- The whole manuscript was in a bad organization, the structure characterization such as FTIR should present firstly, the release profile (Figure 1) should present before the release data (Table 3)
We have now moved Figure 1 before Table 3. We have kept the FTIR results in the same order before they tally together with the DSC and SEM tests, and correlate with the aforementioned release results.
- The figure of DSC curves and FTIR spectra are too vague, which should be redrawn.
We have now redrawn all DSC curves and FTIR spectra.
- How does the HA crosslinked with PT? Through intermolecular interaction or chemical covalent? In the FTIR spectra discussion, the author should demonstrated the successful crosslinking.
It is a chemical covalent bond. Please find this added clarification to our manuscript (lines 442-445)
- In the section of release kinetics, the fitted plots and kinetic parameter of four models originated from release data should be provided, and corresponding reference (Gels 2022, 8, 649) should be cited.
We have now added all the release plots as requested. We could not locate the relevance of the proposed reference though.
- Why does this system can realize zero order release, the mechanism should be explained.
An explanation has been added (lines 390-393)
- The references format should be revised according to the journal’s requirement.
Done
Round 2
Reviewer 1 Report
The authors have edited the manuscript as per my suggestions, and now the manuscript looks better. Thus, I recommend for publication.
Author Response
We would like to thank the Reviewer for their feedback.
Reviewer 2 Report
Though major revision was made by the author, there are still some issues need to be addressed. Therefore, a major revision of this review is recommended.
(1) How does the HA crosslinked with PT? The author explained as “Hyaluronic acid polymer was successfully crosslinked with PT with the ester bond (C-O-C) between the hydroxyl group of the HA and the carbonyl carbon of the crosslinker PT. This reaction was illustrated in detail in our first paper [12].” However, the hydroxyl group of the HA can not directly react with carbonyl of the crosslinker PT. In addition, what is the peak for the cross-linked covalent bond in the FTIR? Thus, reasonable explanation and corresponding references should be provided.
(2) Why does this system can realize zero order release? The author explained as “This could be explained by the constant thickness of the swollen hydrogel film during the diffusion of the active’s molecules”, which is unreasonable, because the diffusion distance of the active’s molecules is not constant. Thus, reasonable explanation and corresponding references should be provided.
(3) The format of Figure 2 should revised, as the caption was overlapped by the figure.
(4) In Table 5, only the correlation coefficient was provided, for the release kinetics, the kinetic constant (k) is the most important, therefore the kinetic constant (k) for different kinetic model should be provided.
Author Response
(1) How does the HA crosslinked with PT? The author explained as “Hyaluronic acid polymer was successfully crosslinked with PT with the ester bond (C-O-C) between the hydroxyl group of the HA and the carbonyl carbon of the crosslinker PT. This reaction was illustrated in detail in our first paper [12].” However, the hydroxyl group of the HA can not directly react with carbonyl of the crosslinker PT. In addition, what is the peak for the cross-linked covalent bond in the FTIR? Thus, reasonable explanation and corresponding references should be provided.
Thank you for this comment. We have now added the following explanation, please see lines 491-501 of revised manuscript highlighted in green colour:
“Initially the free radicals of PT are activated under alkaline conditions to generate nucleophiles which activate radical polymerization. The generated PT radicals abstract hydrogen atoms from HA to generate HA radicals which then bind with PT radicals to form crosslinks [12]. This reaction was illustrated in detail in our first paper [12]. Figure (3, A) shows that the stretching peak at around 1738 cm¯¹ in pure PT was reduced in intensity in the crosslinked blank hydrogel film, indicative of the reaction of the carbonyl group of PT with the hydroxyl group of HA, while the stretching peak around 1100-1300 cm¯¹ corresponding to (C-O-C) is the new bond (crosslink) between HA and PT.”
(2) Why does this system can realize zero order release? The author explained as “This could be explained by the constant thickness of the swollen hydrogel film during the diffusion of the active’s molecules”, which is unreasonable, because the diffusion distance of the active’s molecules is not constant. Thus, reasonable explanation and corresponding references should be provided.
Thank you for this follow-up comment. After a careful look at our release graphs (Figure 2) and Table 5, it became apparent that there were errors on the R2 values on Table 5. We have corrected the R2 values on Table 5 to correspond to those on the graphs, and we indicate in bold the highest R2 for each film. It is now obvious that the Korsmeyer–Peppas model describes best the release kinetics from all films. We have therefore revised our discussion accordingly and we have also added reference [43] (Gels 8; 649) which explains nicely the immediate release kinetics from aerogels and which also tallies with our results where the immediate release of our model actives was predominantly explained by the Korsmeyer–Peppas equation.
Please see lines 408-421 highlighted in green colour on the revised manuscript.
(3) The format of Figure 2 should revised, as the caption was overlapped by the figure.
We have now fixed this.
(4) In Table 5, only the correlation coefficient was provided, for the release kinetics, the kinetic constant (k) is the most important, therefore the kinetic constant (k) for different kinetic model should be provided.
We have now added all the release kinetic constant (k) values on Table 5.
Round 3
Reviewer 2 Report
Figure 3,4,5,6 were missing, which should be revised
Author Response
Apologies for this, several icons seem to have disappeared from this submitted version. Please find attached a rectified version.
