The Development of Risperidone-Loaded Microfibers via Centrifugal Spinning to Enhance the Palatability of a Potential Drug for Autistic Children

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor,

I have reviewed the manuscript, below are given the some queries and suggestions to improve the manuscript.

 

Pediatric Autism Therapy: How authors justify that developed formulation can be good for autism, without any experiment of autism? So title and research article is not completing the objective.

Introduction: Add some recent formulations developed with risperidone to improve the drug physicochemical and pharmacokinetics properties as well as used in autism. Add epidemiology of autism globally and in populated country like India and china.

Risperidone is practically insoluble or only sparingly soluble in water, how did solubility improve by making microfibers with sucrose?

 

Drug loading (DL) of 30 ± 5 μg/mg, an encapsulation efficiency (EE%) of 60 ± 10 %, keep the calculation in same unit for both, either % or μg/mg. In encapsulation standard deviation is too high, why? Why did not calculate the drug content uniformity?

What modification did in preparation of microfibers? How did optimize 95% sugar and 5% drug to develop a good formulation?

Authors change the drug only, rest experiment performed as per ref. 24? What is the novelty in this experiment?

 

Add important FTIR peaks in Figure 4a.

Figure 6: why is four pieces of 20 mg microfibers? Why need to write four? Why did not use microfibers equivalent to one dosage form of risperidone? Why did drug release constant upto 60%, why did not release drug up to 100%? Was drug degraded or processed loss?

Figures. Uniform the graph word font type, size and color to black for all figures.

Lines 338-340: Similarly, the results are also consistent with those obtained from a recent study on the preparation of centrifugal PVP fibers and sucrose fibers used as a solid dispersant system (SDS) for nimesulide delivery. How it can be same supporting results, authors did not use PVP in formulation? Property of API change with changing excipients.

Why did not perform the pharmacodynamics and pharmacokinetics analysis?

Format the manuscript according to journal format.

 

Reduce the plagiarism below 15%, it was found 30%.

Comments on the Quality of English Language

Check manuscript for grammar, typos and sentence errors.

Author Response

We thank the reviewers for their thoughtful and helpful comments. We respond to each point below; their suggestions have undoubtedly improved the paper, for which we are very grateful. The new sections are highlighted in yellow in the revised manuscript.

Reviewer 1

Pediatric Autism Therapy: How authors justify that developed formulation can be good for autism, without any experiment of autism? So title and research article is not completing the objective.

Response: Thank you for your comment. The primary purpose of our study was to improve the palatability of the drug prescribed for children with autism. Medication adherence is often a major challenge in children with autism, as they are typically more sensitive to taste and texture, which makes taking medicines difficult. By focusing on enhancing palatability, our formulation directly addresses this issue and supports better treatment outcomes. However, we do agree that the title may be misleading; therefore, we have modified it in the revised manuscript.

Introduction: Add some recent formulations developed with risperidone to improve the drug physicochemical and pharmacokinetics properties as well as used in autism. Add epidemiology of autism globally and in populated country like India and china.

Response: Thank you very for this suggestion. We have revised the Introduction to include both aspects highlighted by the reviewer. We have added a summary of A recent study on risperidone-loaded medicated gummies for autistic children with ADHD to the Introduction to highlight current formulation advances aimed at improving physicochemical properties and therapeutic applicability in autism. We have also added updated data on the global prevalence of autism spectrum disorder, without specifying a particular Country.

Risperidone is practically insoluble or only sparingly soluble in water, how did solubility improve by making microfibers with sucrose?

 Response: Risperidone is classified as a BCS II drug, i.e., highly permeable and low soluble; therefore, it is considered practically insoluble in water. This has been highlighted in the revised manuscript. The improvement in solubility observed in our study was due to the molecular transformation of the drug from the crystal to the amorphous form, as confirmed by the XRD results. This molecular transformation is common in solid dispersions and is frequently observed in techniques like centrifugal spinning and electrospinning, allowing for enhanced solubility and rapid dissolution, as mentioned in Section 3.6.

 

Drug loading (DL) of 30 ± 5 μg/mg, an encapsulation efficiency (EE%) of 60 ± 10 %, keep the calculation in same unit for both, either % or μg/mg. In encapsulation standard deviation is too high, why? Why did not calculate the drug content uniformity?

Response: Thank you for pointing out the difference in the units. According to the method of calculating the EE and DL, the EE evaluates the process of fabrication, and a high EE indicates an optimum preparation method. The DL is calculated by dividing the actual drug amount by the total fibers used to determine the dose of the drug (i.e., X µg of drug in 1 mg of fibers). The equations used to calculate these parameters were used in several previous studies using centrifugal spinning or electrospinning [https://doi.org/10.1016/j.jddst.2024.105872;    https://doi.org/10.2147/IJN.S460467; https://doi.org/10.2147/IJN.S467469; https://doi.org/10.3390/pharmaceutics15092343].

Regarding the SD of ±10% for the EE, which may appear relatively high. However, this level of variation is expected in centrifugal spinning systems, where drug distribution within the fiber can be influenced by multiple parameters such as drug-to-polymer ratio, drug and polymer mixing, spinning speed, and heat, etc. However, this is considered a limitation of the current system, and has been highlighted in the conclusion section for future formulation improvements.

What modification did in preparation of microfibers? How did optimize 95% sugar and 5% drug to develop a good formulation?

Response: This formulation was optimized in the current study and a previous study within our group [https://doi.org/10.1016/j.jddst.2024.105872]. Having more (10%) or less of the drug (1%) will affect the DL and release behavior of the drug. Also, the overall quality of the fibers (shown under the SEM) can be affected if more drug is added.

Authors change the drug only, rest experiment performed as per ref. 24? What is the novelty in this experiment?

 Response: Thank you for your comment. While the fabrication principle and technique used are similar to Ref. 24, our study is different in its choice of drug, therapeutic target, and formulation, with the specific goal of improving drug acceptability in children with autism.

Add important FTIR peaks in Figure 4a.

Response: Thank you for your helpful comment. The most important peaks have been added and labeled to the FTIR figure (4a) as suggested.

Figure 6: why is four pieces of 20 mg microfibers? Why need to write four? Why did not use microfibers equivalent to one dosage form of risperidone? Why did drug release constant upto 60%, why did not release drug up to 100%? Was drug degraded or processed loss?

Response:  Sorry for the confusion. We rewrote the Figure legend. The aim of the in vitro drug release study was not to reproduce a single clinical dose but to evaluate the release rate of the microfiber formulation. We acknowledge that having a complete release at 60% is not preferable and is considered a limitation in this study; therefore, we included this in the conclusion section. We discussed this release behavior in Section 3.6 and highlighted that further investigation is required. Overall, the ultimate aim of this study is to formulate a bitter taste drug that is low soluble (BCS II) and to compare it with the commercially available drug in proper animal testing. The results of this in vivo study were preliminary but very useful for future consideration. 

Figures. Uniform the graph word font type, size and color to black for all figures.

Response: Thank you for your suggestion. All figure fonts have been revised to ensure uniform type, size, and black color for consistency across the manuscript.

Lines 338-340: Similarly, the results are also consistent with those obtained from a recent study on the preparation of centrifugal PVP fibers and sucrose fibers used as a solid dispersant system (SDS) for nimesulide delivery. How it can be same supporting results, authors did not use PVP in formulation? Property of API change with changing excipients.

Response: Many thanks for the reviewer's observation. The cited study was used to support the result related to the centrifugal spinning process that was used in risperidone microfibers, rather than the composition of the fiber. The sentence has been modified for clarity.

Why did not perform the pharmacodynamics and pharmacokinetics analysis?

Response: Thank you for this valuable comment. The aim of the present study was limited to the formulation development of risperidone-loaded sucrose microfibers and their in vitro evaluation, with the primary objective of enhancing drug palatability and acceptability. Pharmacodynamic and pharmacokinetic analyses were therefore not included, as these would require a complete in vivo study beyond the initial preliminary data. We considered this as a limitation and have clarified it in the revised manuscript in the conclusion section, noting that future studies should focus on in vivo pharmacokinetic and pharmacodynamic evaluation to confirm the clinical relevance of the formulation.

Format the manuscript according to journal format.

Response: Thank you for your comment. The manuscript has been revised to align with the journal’s formatting requirements.

 Reduce the plagiarism below 15%, it was found 30%.

Response: Thank you for your comment. The manuscript has been carefully revised, proofread, and rephrased to reduce similarity, and the plagiarism score is now below 15% in line with the journal’s requirement.

Check manuscript for grammar, typos and sentence errors.

Response: Thank you. The manuscript has been carefully revised and proofread.

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting study addressing a critical challenge in paediatric drug administration, particularly for neurodiverse patients. This is a promising strategy to improve treatment adherence and palatability.

Corrections and comments

• Figure Reference: There is no reference to Figure 1 in the main text.
• Equation 2 contains a spelling error, please correct. In addition, the equation refers only to the fibers and does not account for the entrapped drug, making it inaccurate.
• Disintegration Test: Please specify the dimensions of the square fiber samples used in the disintegration test to ensure reproducibility.
• Page 4, Line 157: The phrase “at a ratio of 1:1 (w/v) mixture” is unclear. Clarify whether this refers to weight of drug to volume of solvent, or another ratio.
• Control Formulation: Was the control a commercially available risperidone oral solution for paediatric use? Please include its composition, especially regarding sweetener content to contextualize the preference results. If sucrose is present in both formulations, it raises the question of whether any sucrose-containing formulation would yield similar acceptability.
• HPLC Validation: Include key validation parameters such as limit of detection (LOD) and limit of quantification (LOQ) to support the reliability of your quantification method.
• Figure 3: Add time stamps to each image to clearly show the progression and allow for better visual comparison.
• Thermal Analysis: Given the potential for thermodynamic incompatibility between sucrose and risperidone, it would be appropriate to include DSC analysis to assess miscibility and stability of the amorphous system.
• “The release has reached a plateau at around 60% during the 360-minute test, confirming the formulation's complete drug release” is contradictory. A release limited to 60% suggests incomplete release or possible overestimation of drug content. Please clarify whether sink conditions were established in the dissolution medium and discuss the implications of incomplete release.
• High Sucrose Concentration has potential dental risks. The use of a high sucrose content raises concerns about dental health, particularly in children. Please discuss this limitation
• Sucrose is known to be hygroscopic, which may affect the overall stability of the fibers . Please include a discussion of this limitation with the formulation and describe how it will be addressed

Author Response

We uploaded the responses to Reviewer 2.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear editor,

I have reviewed the revised manuscript, still have some queries.

Figure 6. Assessment of drug release of the risperidone-loaded microfibers showed an initial 50% burst release within the first 15 minutes, followed by a complete drug release after 360 minutes, error bars are looking almost similar for each time points. How authors can say about complete release, while around 60% is released?

Author Response

We thank the reviewers for their thoughtful and helpful comments. We respond to each point below; their suggestions have undoubtedly improved the paper, for which we are very grateful. The new sections are highlighted in yellow in the revised manuscript.

Reviewer 1

Figure 6. Assessment of drug release of the risperidone-loaded microfibers showed an initial 50% burst release within the first 15 minutes, followed by a complete drug release after 360 minutes, error bars are looking almost similar for each time points. How authors can say about complete release, while around 60% is released?

Response:  Sorry for the confusion. We have replaced ‘complete release’ with ‘maximum release’, similar to the change that we made in the revised manuscript of the first round (R1) throughout the manuscript. We acknowledge that having a maximum release of 60% is not preferable and is considered a limitation in this study; therefore, we included this in the conclusion section. We want to note that we have used non-sink conditions as per this study [https://doi.org/10.1016/j.ejpb.2016.03.021], and this was highlighted in the Methodology section of the revised manuscript. We also have discussed the release behavior in Section 3.6 and highlighted that further investigation is required, as shown below. Finally, we have rechecked the calculations and ensured that the error bars are correct, as shown in the table below. We hope these points are sufficient to clarify any concerns the reviewer may still have. 

“Since the drug was released within 360 minutes, the dissolution rate may be influenced by the components of the microfiber, along with the drug-to-polymer ratio, which may affect the release of the drug [55] as well as the characteristics of the surrounding release medium [56]. Moreover, the amount of drug being loaded in the microfibers has a high impact on the amount of the drug being released from the matrix. When the drug loading is higher, it results in a rapid release, which is then followed by a slower and gradual release phase [57,58]. These results highlight the complex relationship between the components of any formulation and the manner in which the drug is released.

In addition, incomplete drug release can be linked to the low solubility of risperidone in water, as the dissolution medium used was a water-based salt solution -PBS- as mentioned previously, risperidone is classified as a BCS Class II drug, meaning it has low solubility but high permeability, as described [59]. Previous studies indicate that the plain drug release of risperidone in similar conditions does not exceed 30% [60,61], whereas our formulation reached 60% release after 360 minutes. The dissolution study confirmed that sucrose fibers loaded with risperidone effectively showed rapid drug release, which could enhance the palatability and adherence to risperidone medication. Further understanding of the limitations of having a maximum drug release at 60% is required.

 

Time point	Average cumulative release	SD
1	35.04710873	4.3423617
3	38.41349575	4.47549343
5	43.76146322	7.17004306
10	47.4536192	7.7117101
15	50.59501974	8.46364476
30	54.37607849	10.0305575
60	57.28493525	11.1317063
120	59.26009015	11.6799467
180	60.91246215	12.0737324
240	62.21597854	12.7034334
300	63.08001618	12.7443486
360	63.55793703	12.936774

Reviewer 2 Report

Comments and Suggestions for Authors

As the corrections have been implemented I have no further comments 

Author Response

Thank you!