Development and Characterization of Bigels for the Topical Delivery of Curcumin

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,
In my opinion, the introduction requires more detailed discussion on the stability of curcumin, particularly regarding pH. For instance, in the paper DOI: 10.1021/acs.jafc.6b04815, there is an interesting study on its application (I am not the author). Please also add information about the impact of temperature. I believe that the stability of curcumin is crucial for understanding the context of your research.
Regarding bigels, I suggest including more information about their stability and rheological properties, which depend on the ratio of hydrogel to organogel. I would also consider expanding on the potential applications of bigels, as the topic is, in my opinion, highly promising. Additionally, it may be worthwhile to briefly mention transdermal delivery, as relevant studies are available in the literature.
From the point where castor oil is introduced, the introduction lacks fluidity and a connecting sentence. The oil appears without proper contextualization. Moreover, why were these specific components selected? Can we describe more compounds and explain a wider context?
I also find the objective of the study insufficiently highlighted in the introduction. While you mention novelty, a clear research aim is missing.

Regarding bigels and rheology, there aren't indeed some relevant publications available, but I find this: https://pubmed.ncbi.nlm.nih.gov/39058356/. Although not directly related to your topic, this could serve as a useful point of reference.

In the Materials and Methods section — why was supermarket oil chosen? I do not understand this approach and would appreciate clarification. Similarly for xanthan gum — why were raw materials of such quality used? I find this choice puzzling. Curcumin had a purity of 65%; what were the impurities, and could they have influenced detection? Was the curcumin content recalculated in terms of the actual amount loaded into the gel?

The formulation section (2.2) has been described appropriately.

In section 2.6, was any precision, linearity, or repeatability of the method assessed?

The statistical analysis lacks information on which data were analyzed, which tests were used, and what level of statistical significance was considered.

In the discussion of results, please provide more specifics, especially when comparing your findings with those of other authors. A good practice is to clearly state what results others obtained, whereas in some places your references are overly general. In tables and figures, please include information about statistical significance — this can be added in the captions. Simply stating statistical significance is not very informative if I cannot verify it.

In section 3.5 — could the type of fatty acids (saturated vs. unsaturated) influence the formation of the bigel?
Please consider arranging some figures side by side to make the manuscript more concise and visually coherent, especially in the sections involving DSC analysis.
Why were only three replicates performed for the release study, when in my opinion the standard is six? Which model best fit the release data, and why? Your explanations need correlations with literature data. Please elaborate on this, as the classic suggestion is the Higuchi model, yet you report a better fit with Korsmeyer–Peppas, and in some formulations even first-order kinetics. Why ?

I also miss a clear indication of what the best or optimal system from your samples, as well as a broader attempt at discussion — even if available data are limited. 
In my view, the conclusions are too long and do not indicate the optimal formulation. There is also a lack of perspective for future work or potential applications.

I suggest revising the manuscript, as the topic is interesting and many elements have been carried out very thoroughly. However, some aspects raise questions that should be addressed, but in my opinion manuscript has potential.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presented by Juan Luis Perez-Salas et al., deals with the preparation and characterization of some bigels for the topical delivery of curcumin.

The manuscript is scientifically correct and contains sufficient analyses necessary to characterize the obtained bigels. They use mathematical models for release study of curcumin from bigels. They found that the permeation of curcumin increase with increasing organogel content.

I have some comments:

2.1. Materials

Comment 1

Please include information about curcumin.

2.2. Bigel formulation

Comment 2

Please include information about curcumin concentration in bigels compositions.

Comment 3

Please include information about preparation method of curcumin loaded bigels.

3.8. Differential scanning calorimetry

Comment 4

For the DSC thermograms (figure 5 and figure 6) please include information for Tpeak, Tonsed and Entalpy.

Conclusions

Comment 5

Comparing the results obtained with those published in the literature is necessary to highlight the performance of the studied bigels.

 

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

This study aims to develop bigels for the topical delivery of curcumin. It is generally well-written. Curcumin has been loaded in bigels in previous studies, but there is lack of publications on topical delivery. Hence, the topic is relevant and unique. However, several issues must be addressed. Please address the comments below:

Introduction/Discussion - Briefly state methods to improve the solubility and delivery of curcumin and why these strategies are insufficient or impractical for the proposed application. Add references: https://doi.org/10.3390/life13010207

Introduction/Discussion - Add more rationale for selecting castor oil and coconut oil. Are these the standard materials for making bigels? If not, what are their advantages compared to other alternatives warranting their prioritization?

Materials - Please specify the type of coconut oil and castor oil used. Include fatty acid profile of the specific products used if available. If not, try to perform characterization or cite studies that have used the same products.

Methods - The temperatures for rheological measurements (25°C, 37°C, and 45°C) are defined as room temperature, human body temperature, and stress temperature condition, respectively. State the rationale for selecting 45°C as a "stress temperature condition"

For all figures and tables, define all the abbreviations used in the caption.

The icons for Figures 1, 2, and 3 are a bit difficult to distinguish. Can the figure be revised to use color coding instead or in addition?

Figure 3 looks compressed. Please follow the scale of Figures 1 and 2.

Mechanism of release - Authors report that the release of curcumin is not only controlled by diffusion, but also by other phenomena. Briefly state and discuss these other phenomena.

Extrapolation of clinical benefit - The recommendation for use in psoriasis or eczema simply due to greater permeation capacity is premature. Please remove this claim.

Future directions - Discuss future directions, such as further in vivo studies and the potential for using the produced bigels for advanced manufacturing techniques, such as 3D printing. Add references: https://doi.org/10.3390/gels10010008

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,
You have reliably addressed my comments. Information regarding curcumin stability has been added, and the influence of the oil component on bigel structure has been discussed. The application of bigels could have been described slightly more extensively, indicating specific active pharmaceutical ingredients (APIs) that were or are being utilized. This aspect could have been discussed somewhat better.

Regarding the use of castor oil – please consider oleic acid in the future (as a potential carrier). Based on my experience, it offers good compatibility and enhances transdermal delivery efficiency.

I also appreciate that you have provided a broader and more detailed description of the rheological properties.

I find the use of supermarket oils somewhat careless, and this constitutes my main criticism of the study, primarily due to concerns regarding stability, storage conditions, and the lack of standardization inherent to food-grade products.

Furthermore, I remain concerned about the 65% purity of curcumin. Considering that raw materials with a purity of 98% are readily available on the market, nothing has been mentioned about verifying or checking the purity of your raw material. Your explanations do not convince me. Please bear in mind that the absorption maximum of impurities could overlap with that of curcumin. A calibration curve without HPLC is somewhat insufficient in my opinion.

I understand your explanations regarding the use of a standard method; however, you could calculate detection limits and other parameters from the calibration curve, so I do not fully comprehend their absence.

Comments regarding section 3.5 have been appropriately addressed. I am also wondering whether further studies are necessary (as you suggested), because, in my opinion, existing knowledge is sufficient for drawing certain conclusions. Nevertheless, the literature review and references provided are accurate.

Your discussion regarding release profiles also does not fully convince me. However, you present rational conclusions, and your literature references are correct. I am willing to accept this argumentation.

I must acknowledge that most of the revisions are of a very high standard, and overall, I am satisfied. Nevertheless, my primary concern remains with the curcumin issue, and I request further clarification in this regard. After receiving such explanations, I believe I will be ready to accept the article for publication.

Congratulations on your valuable research direction.

Kind regards,

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

All issues have been addressed.

Author Response

All issues have been addressed.

R= Thank you very much for the comments, suggestions and the review

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,
I recommend your paper for publication; however, please avoid using commercially (food market) available raw materials. Additionally, I would like to point out that microorganisms are typically incubated at 37°C, which closely resembles human skin temperature. So you should rather tested your samples in 37°C.
Moreover, I noticed that my previous suggestion regarding curcumin has posed significant challenges for you, as you lack certainty regarding what was actually measured. Without purity assessments and High-Performance Liquid Chromatography (HPLC), accurate quantification is not feasible. Furthermore, establishing an appropriate HPLC method itself can be challenging
I acknowledge your efforts in addressing my comments, although it appears there were difficulties in fully resolving these analytical issues. For future UV/VIS analyses, please ensure the purity of compounds is sufficiently high to guarantee accuracy. Nevertheless, I can accept the possibility that what you incorporated into your formulation was effectively released.
Overall, you have satisfactorily responded to my comments. The study is interesting and worthy of publication.
With regards,