Phospholipid-Based Delivery System Optimizes the Solubility and Systemic Exposure of Palmitoylethanolamide and Supports Clinical Benefits in Chronic Neuropathic Low Back Pain

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the present study, the authors evaluated a phospholipid-based delivery system (Phytosome™) formulation of PEA with respect to its solubility, systemic exposure, and clinical efficacy in patients with chronic neuropathic low back pain. This phospholipid delivery system has previously been successfully applied to a variety of natural bioactive compounds, including quercetin, berberine, curcumin, boswellic acids, lemon balm extracts, and coenzyme Q10. Owing to its amphipathic structure, the system improves wetting and limits self-aggregation, thereby enhancing solubility, optimizing intestinal absorption, and supporting formulation stability. However, the following issues remain to be addressed.

1. The article mentions that both clinical trials were of an “exploratory” nature, with relatively small sample sizes (12 healthy volunteers and 120 patients, respectively). It is recommended that the “Limitations” section further explain the rationale for this exploratory design and clarify directions for future research, such as whether larger-scale, multicenter randomized controlled trials are planned, in order to strengthen the scientific continuity of the study.
2. Although the article refers to PEA acting via multiple targets such as PPAR-α and TRPV1, no neuroinflammatory or pain-related biomarkers were included in the clinical trials. At minimum, the Discussion should provide an explanation for why these biomarkers were not assessed.
3. Some figures and tables (e.g., Table 2, Figure 1) lack clear legends and unit descriptions, particularly regarding the calculation of the actual PEA content in PEA-PL.

4. There is inconsistency in the use of certain terms and abbreviations, such as “PEA-PL” sometimes written as “PEA- PL”, and “DN4” versus “DN-4” in figures and tables. It is recommended to standardize terminology, abbreviations, and numerical formatting throughout the manuscript, ensuring consistency between figure/table titles, legends, and the main text, to enhance the professionalism of the manuscript.

Author Response

Please find attached our responses to Reviewer 1 comments.

Many thanks and kind regards,

Prof. Amjad Khan

(On behalf of all the authors)

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Phospholipid-Based Delivery System Enhances the Solubility and Systemic Exposure of Palmitoylethanolamide (PEA) and Supports Clinical Benefits in Chronic Neuropathic Low Back Pain” is a clinical study that demonstrates efficacy of a trademark phospholipid-delivery system, Phytosome™ in enhancing the bioavailability and subsequent enhancement of efficacy of Palmitoylethanolamide (PEA) against chronic neuropathic low back pain (CNLBP). The study essentially focusses on demonstration of enhancement of PEA plasma concentration by Phytosome™ delivery system.

The study has been well designed into two distinct stages. The first stage, highlights the potential of Cronilief™ in increasing the bioavailability of PEA in the plasma of clinical subjects. In the second stage, the Cronilief™ is explored for clinical against CNLBP. The second phase study is further determined by primary outcomes and secondary outcomes. The outcomes of both the primary and secondary parameters have been well documented, and have demonstrated satisfactory results.

However, before coming to any conclusion, there are few queries and suggestion that the authors are requested to respond to:

1. The manuscript clearly mentions two trademark products, Phytosome™ and Cronilief™, but neither of them have been highlighted in the title of the manuscript, although, they are at the center of the objective of the study. Kindly justify the selection of title of the manuscript. The title also has abbreviation PEA that may be removed anyway.
2. The experimental designs have been well streamlined; however, we could not understand the lack of Phytosome™ as placebo themselves, in the second phase of clinical efficacy of CNLBP?
3. The detailed protocol for HPLC quantification of PEA in Cronilief™ is missing.
4. In table 2 the ± SD values of the mean values of plasma PEA concentrations are missing. Table 1 also lacks ± SD values.
5. In figure 1, color legends may be added for PEA, PEA-PL (300mg), and PEA-PL (600mg) to enhance the readability of the figure.
6. While comparison between the plasma concentration level of PEA-PL and PEA was performed in Spain, the clinical trials on clinical efficacy study in chronic neuropathic low back pain was performed in Pakistan. What was the reasoning behind performing clinical trials in two distinct ethnic groups? How reliable could the correlations between the two could be?
7. There is lack of clarity with regards to the formulation of PEA-PL. In the objective of the study, the authors stated use of Phytosome™, a PL-based delivery system that has been previously reported to enhance the bioavailability of various phytochemicals. Whereas, in the methodology, Cronilief™ was prepared, apparently using Phytosome™ and PEA. Kindly, rephrase the methodology part for enhanced clarity for the readers.
8. The discussion may include some similar products of drug-delivery systems that have been previously been reported with regards to PEA, and how the current system has an edge over the existing systems of drug-delivery?
9. The conclusion, likewise, does not mention anything about either of the trademark products.

 

Author Response

Please find attached our responses to Reviewer 2 comments.

Many thanks and kind regards,

Prof. Amjad Khan

(On behalf of all the authors)

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript has been significantly improvised as suggested. The queries have also been answered satisfactorily.