Formulation Strategies of Nanosuspensions for Various Administration Routes
Round 1
Reviewer 1 Report
A review paper is already available online with more comprehensive information on nanosuspensions.
Author Response
Reviewer comment: A review paper is already available online with more comprehensive information on nanosuspensions.
We thank the referee for the comments.
Numerous reviews and research studies have been conducted since nanosuspensions began to be investigated in the 1990s.
Especially with commercial success, nanosuspensions have been developed and continue to be developed for many low-soluble active substances.
As nanosuspensions are suitable for many different routes of administration and can be developed with different drug forms, a wide range of literature data can be reached. In addition, studies on nanosuspensions are expanding day by day.
In this review, it is thought that the emergence of new reviews with the perspectives of research groups focusing on current, different issues, especially working with nanosuspensions, maybe a need and approaches that will contribute to the literature.
We also focused on the conversion of nanosuspensions into dosage forms and related examples. Nanosuspensions with different pharmacological activities and different routes of administration have been tried to be given. Very up-to-date studies were used for each route of administration and drug form. As researchers who have produced many research articles on this subject, our article has been compiled with a different perspective and detailed information has been presented.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The manuscript entitled Formulation Strategies of Nanosuspensions for Various Administration Routes is focused on nanosuspensions as drug delivery systems, the preparation methods and intended routes of administration.
The authors should explain what is the novelty and originality of their work, how their manuscript differentiates from the following article: https://doi.org/10.1016/j.ejps.2023.106425. The structure of the suggested manuscript is quite similar to that of the published one.
Also, the paper is very difficult to read, the quality of English language is very low and needs a serious revision, by native speaker preferably.
With regard to this, I cannot recommend the manuscript for publication.
Author Response
Reviewer comment: The manuscript entitled Formulation Strategies of Nanosuspensions for Various Administration Routes is focused on nanosuspensions as drug delivery systems, the preparation methods and intended routes of administration.
The authors should explain what is the novelty and originality of their work, how their manuscript differentiates from the following article: https://doi.org/10.1016/j.ejps.2023.106425. The structure of the suggested manuscript is quite similar to that of the published one.
Also, the paper is very difficult to read, the quality of English language is very low and needs a serious revision, by native speaker preferably.
With regard to this, I cannot recommend the manuscript for publication.
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We’d like to thank reviewer for the valuable comments.
The article mentioned by the reviewer (https://doi.org/10.1016/j.ejps.2023.106425) focused on the use of nanosuspensions, especially in natural products.
Studies on nanosuspensions of natural products such as baicalin, curcumin, quercetin, silybin, and resveratrol have been reviewed.
Detailed research on the preparation of nanosuspensions and the selection of stabilizers, especially with the preparation of intravenous nanosuspensions, is presented.
In our review, the preparation of nanosuspensions according to different drug forms was discussed with general preparation methods. The drug forms of nanosuspensions with different pharmacological activities and different routes of administration are discussed. Characterizations of nanosuspensions and obtained in vitro/in vivo outputs are given specific to different routes of administration and drug forms.
There are quite a few differences between the articles on the mentioned topics.
The English of the manuscript has been improved by the help of native speaker. Please find enclosed file.
Author Response File: Author Response.pdf
Reviewer 3 Report
The work is devoted to formulation strategies of nanosuspensions for various administration routes. Nanosuspensions provide the enhanced solubility and dissolution of low water-soluble drugs by means of their small particle sizes and large surface areas. In addition, they can alter the pharmacokinetics of the drug and thus improves the efficacy and safety of the drug. These advantages of NSs can be used to enhance the bioavailability of poorly soluble drugs in oral, dermal, parenteral, pulmonary, ocular, or nasal routes for systemic or local effects. This review focused to discuss the effect of the formulation and process parameters on the properties of the NSs and to highlight the recent advances, novel strategies, and practical considerations for the application of NSs to various administration routes. The article looks like a Review article and may be published after minor revision.
Notes:
1. The quality of the Figure 1 should be increased for clarity. The interval between letters should be increased.
2. What are the most commonly used stabilizers for different types of administration? Some discussion should be added.
3. Why are not for all studied nanosuspensions indicated PDIs in the tables 5-7, 9, 11? Does the monodispersity (PDI value) of the nanosuspensions play the crucial role at the administration?
Author Response
Reviewer comment: The work is devoted to formulation strategies of nanosuspensions for various administration routes. Nanosuspensions provide the enhanced solubility and dissolution of low water-soluble drugs by means of their small particle sizes and large surface areas. In addition, they can alter the pharmacokinetics of the drug and thus improves the efficacy and safety of the drug. These advantages of NSs can be used to enhance the bioavailability of poorly soluble drugs in oral, dermal, parenteral, pulmonary, ocular, or nasal routes for systemic or local effects. This review focused to discuss the effect of the formulation and process parameters on the properties of the NSs and to highlight the recent advances, novel strategies, and practical considerations for the application of NSs to various administration routes. The article looks like a Review article and may be published after minor revision.
Thanks to Reviewer for his valuable comments. Based on Rewiever's suggestions, some fixes and improvements have been made.
Notes:
- The quality of the Figure 1 should be increased for clarity. The interval between letters should be increased.
The quality of Figure 1 has been improved.
- What are the most commonly used stabilizers for different types of administration? Some discussion should be added.
The choice of stabilizer in the preparation of nanosuspensions poses a challenge.
In this article, polymeric stabilizers or surfactants are used to provide physical stability of nanosuspensions.
Stabilizer selection and frequently used stabilizers are briefly given in the "Selection of Stabilizer" section and Table 2 in our manuscript.
Based on the reviewer's suggestion, the following additions and extensions were made to this section:
“The development of successful NSs is mainly based on the selection of suitable stabilizers. Several stabilizers such as surfactants or polymeric excipients were evalu-ated for the optimization of the NS. Parameters of stabilizers such as type, ratio, and molecular weight must be evaluated for the stability of prepared NS. Also, the optimum parameters of stabilizers are dependent on the formulation preparation method and on the active pharmaceutical ingredients. For these critical properties, researchers make individual evaluations on the basis of active substances in the screening of stabilizers and decide on optimum stabilizers by a simple trial-and-error approach [39].”
“Stabilization in NSs can be steric and/or electrostatic. In steric stabilization, a steric barrier is created by the adsorption of a polymer on the particle surface of the nano-crystals, and aggregation of particles is prevented. In electrostatic stabilization, which is the other mechanism, the NS is stabilized by reducing the surface tension at the inter-phase interface thanks to electrostatic repulsion from the ionic surfactants added to the particle surface [24]. Stabilizers commonly used in NSs are surfactants such as polox-amer 188, poloxamer 407, vitamin E TPGS, polysorbate 80, sodium lauryl sulfate, and polymeric substances such as polyvinyl pyrrolidone, polyvinyl alcohol, cellulose de-rivatives (Hydroxypropyl methyl cellulose - HPMC, Hydroxypropyl cellulose - HPC, Hydroxyethyl cellulose - HEC, and Methyl cellulose -MC etc.) [39].”
“In NS formulation, the drug: stabilizer ratio (w/w) can vary widely, from 1:20 to 20:1 [39,47]. Stabilizers can be used in NS formulations using different preparation methods after the optimum ratio is had been determined by preliminary studies. In the use of stabilizers, specific choices are not made for drug administration routes. The stabilizers and results obtained in NSs prepared using different preparation methods for different routes of administration are summarized in the following sections of this review.”
- Why are not for all studied nanosuspensions indicated PDIs in the tables 5-7, 9, 11? Does the monodispersity (PDI value) of the nanosuspensions play the crucial role at the administration?
PDI value is one of the most important control parameters together with particle size and zeta potential in characterizing nanosuspensions.
A high PDI value (wide particle size distribution) creates a physical stability problem, especially for Ostwald ripening (crystal growth). Studies have requested that the PDI value should be between 0.1-0.3. However, nanosuspensions with physical stability could be obtained at higher PDI values.
Although the PDI value was studied in many nanosuspension studies, some researchers may not have given the PDI values in their studies according to the physical stability values or the focus of the study. PDI value is used in characterization and values are given for most references in other tables as well as in all of the examples given in Table 5. The focus of the results given in the table was determined accordingly in the studies that only interpret the stability according to the particle size and zeta potential and show the suitability of the stability of the final product.
Also, in Table 7, “PI”s was changed as “PDI”s.
Author Response File: Author Response.pdf
Reviewer 4 Report
The review titled “ Formulation Strategies of Nanosuspensions for Various Administration Routes” reviewed how formulation and process parameters of nanosuspensions influence their administration routes. Basically, the review was well organized and should be accepted for publication.
1. No figures were cited in this review. Supplement several related figures will increase the significance of this review.
Author Response
Reviewer comment: The review titled “Formulation Strategies of Nanosuspensions for Various Administration Routes” reviewed how formulation and process parameters of nanosuspensions influence their administration routes. Basically, the review was well organized and should be accepted for publication.
We would like to thank Reviewer for the evaluation and acceptance of the article.
- No figures were cited in this review. Supplement several related figures will increase the significance of this review.
Based on the reviewer's suggestion, a figure summarizing nanosuspension preparation methods has been added and the legend “A schematic representation of all the preparation methods described above is summarized in Figure 5.” was placed to the manuscript.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
The manuscript can be accepted in present form
Reviewer 2 Report
The authors have greatly improved the quality of the manuscript. The English language has been thoroughly revised and the paper is much easier to understand. In addition, new information has been added and the structure of the paper is now much clearer. I would recommend that the authors format the tables to try to shrink them and minimize the row width so that the information is easier to perceive.
