New Carriers for Bioadhesive Gastroretentive Drug Delivery Systems Based on Eudragit® EPO/Eudragit® L100 Interpolyelectrolyte Complexes
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript needs major revisions.
1) Authors need to improve English language used in the entire manuscript.
2) Authors should revise the abstract. It should start with topic background and need of work, then technique, results and finally conclusion.
3) Introduction is too lengthy. Two paragraphs, (line #65-86) are just explaining the past work held by the same research group. It should be short, explaining the significance only.
4) Rephrase line #106-109. Include the aim was also to investigate IPECs for two model drugs, ACR and MZ…for GRDDS…..
5) In section 2.1, include the supplier of other general chemicals used with its grade (e.g. HCl…).
6) Authors have mentioned that they used UV spectrophotometer for the detection of released MZ and ACR at the wavelength of 274 and 202 nm respectively. These UV λ(max) values are very close to water (190 nm) and many other organic solvents UV cutoff. Very low UV λ(max) in UV-visible spectrophotometric method may create errors in drug absorbance detection. That’s why the HPLC method is preferable for such studies. Any reason authors not used HPLC for drug release studies? How authors eliminated the solvent UV cutoff which may interfere with drug λ(max)?
7) In figure 2, 7 & 8 along with table 2, mention batch size (n=?) and standard deviation.
8) Where are Tg thermograms?
9) Rephrase line #326, 327, 341-343. Line #328, spelling mistake! “adhedion” should be “adhesion”.
10) Any reason authors concluded that “the release data fitted according to the Peppas-Sahlin equation”? What about other models? Did authors check R2 for other equations as well? Where is the data?
11) Revise conclusion section. The authors repeated the results section. The conclusion should include the purpose of the experiment, a brief discussion of the “major” findings and recommendations for further study.
Comments on the Quality of English LanguageAuthors need to improve English language used in the entire manuscript.
Author Response
Response to Reviewer 1 Comments
Dear reviewer, thank you for the work done on reviewing our manuscript. We tried to answer questions and make adjustments in the manuscript.
Comment 1: Authors need to improve English language used in the entire manuscript.
Response 1: thank you, we have corrected English language in the manuscript.
Comment 2: Authors should revise the abstract. It should start with topic background and need of work, then technique, results and finally conclusion.
Response 2: thank you, we have revised abstract.
Comment 3: Introduction is too lengthy. Two paragraphs, (line #65-86) are just explaining the past work held by the same research group. It should be short, explaining the significance only.
Response 3: Thank you, introduction was corrected.
Comment 4: Rephrase line #106-109. Include the aim was also to investigate IPECs for two model drugs, ACR and MZ…for GRDDS…..
Response 4: Thank you, it was corrected.
Comment 5: In section 2.1, include the supplier of other general chemicals used with its grade (e.g. HCl…).
Response 5: Thank you, it was corrected.
Comment 6: Authors have mentioned that they used UV spectrophotometer for the detection of released MZ and ACR at the wavelength of 274 and 202 nm respectively. These UV λ(max) values are very close to water (190 nm) and many other organic solvents UV cutoff. Very low UV λ(max) in UV-visible spectrophotometric method may create errors in drug absorbance detection. That’s why the HPLC method is preferable for such studies. Any reason authors not used HPLC for drug release studies? How authors eliminated the solvent UV cutoff which may interfere with drug λ(max)?
Response 6: UV-spectrophotometry as well as HPLC is usually used as analytical method for release study of metronidazole and acyclovir. To eliminate the solvent UV cutoff, we used reference solution when measured absorption. The reference solution was the same as dissolution medium (0.1 M solution of HCl).
Comment 7: In figure 2, 7 & 8 along with table 2, mention batch size (n=?) and standard deviation.
Response 7: Thank you, it was corrected.
Comment 8: Where are Tg thermograms?
Response 8: Thank you for your question, but we decided to present the DSC data in the form of glass transition temperatures in the table. You can also find DSC thermograms in supplementary materials (Figures S1-S6).
Comment 9: Rephrase line #326, 327, 341-343. Line #328, spelling mistake! “adhedion” should be “adhesion”.
Response 9: Thank you, it was corrected.
Comment 10: Any reason authors concluded that “the release data fitted according to the Peppas-Sahlin equation”? What about other models? Did authors check R2 for other equations as well? Where is the data?
Response 10: Thank you for your comment, data for Zero-order and First-order models were added as well.
Comment 11: Revise conclusion section. The authors repeated the results section. The conclusion should include the purpose of the experiment, a brief discussion of the “major” findings and recommendations for further study.
Response 11: Thank you, conclusion section was corrected.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThe topic of this manuscript is important and current, and results could be interesting for readers. The work is well planned and written with the support of current literature. However, some changes have to be entered into the revised version of the manuscript before it can be further processed:
1. Please provide the composition of the tablets in table form. It is not clear from the description at what stage the model substances (MZ and ACR) were added and were further used as markers in the release studies. Both substances were added to formulations 1 and 2?
2. A short description of the method referenced as 29 should be added
3. Lack of tests regarding uniformity of weight and dimensions and assessment of tabletability.
4. No comment on why the SI plots in Figure 2 are decreasing.
5. What is the residence time of each formulation on the mucous membrane?
6. Figure 7 - what might be the reason for the shape of the IPEC2 plot?
7. Why weren't the release kinetics compared to a zero-order model?
Author Response
Response to Reviewer 2 Comments
Dear reviewer, thank you for the work done on reviewing our manuscript. We tried to answer questions and make adjustments in the manuscript.
Comment 1: Please provide the composition of the tablets in table form. It is not clear from the description at what stage the model substances (MZ and ACR) were added and were further used as markers in the release studies. Both substances were added to formulations 1 and 2?
Response 1: MZ and ACR were used as model drugs. Tablets with these substances were prepared separately – each IPEC sample with MZ, each Physical mixture with MZ, each IPEC sample with ACR, each Physical mixture with ACR. Only 100 mg of pharmaceutical substance (MZ or ACR) and 50 mg of IPEC or PhM. Thus, we didn’t used any other additives for making the compacts. Due to the fact that we did not mention prepared samples of the matrices as formulations 1 or 2, we think that it is not reasonable to prepare the additional table for describing the compositions.
Comment 2: A short description of the method referenced as 29 should be added.
Response 2: thank you, short description was added.
Comment 3: Lack of tests regarding uniformity of weight and dimensions and assessment of tabletability.
Response 3: We haven’t performed such test because the samples being studied are mixtures of carrier (IPEC) and model drug but not dosage forms yet. The next stage of the research may be the development of dosage form based on these samples including such tests as uniformity of weight etc.
Comment 4: No comment on why the SI plots in Figure 2 are decreasing
Response 4: Thank you, explanation was added.
Comment 5: What is the residence time of each formulation on the mucous membrane?
Response 5: the residence time of each formulation on the mucous membrane was 60 seconds. Information was added.
Comment 6: Figure 7 - what might be the reason for the shape of the IPEC2 plot?
Response 6: The different shape of the IPEC 2 curve may associated with the disintegration of the matrix that occurred during the experiment. Information was added into manuscript.
Comment 7: Why weren't the release kinetics compared to a zero-order model?
Response 7: We have added data, thank you.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have extended their prior research into IPECs as oral drug delivery platforms with work on the swelling, bioadhesion and drug release behaviour of IPECs based on specific Eudragit mixture complexes.
The described research is likely of interest to the audience for Scientia Pharmaceutica but the comments below should be considered in further revising the manuscript before it is further evaluated as suitable for publication.
Page 1, line 10: recommend that you insert the acronym IPECS between "complexes" and "Eudragit" so it is understood in the next sentence of the abstract where the acronym appears for the first time.
Page 1, line30: the absorption window will not be the stomach, it will be the proximal small intestine.
Page 1 line 35: citation 15 you give here as support for the use of ion exchange resins in increasing upper GI tract drug residence time makes no reference to that property. Please add in a more appropriate reference where the increased upper GI residence time afforded by ion exchange resins is clearly demonstrated, or delete this claim from the introduction and citation 15 from the reference list.
Page 3 line 134- 136: please give particle size distribution of the ground IPEC powder.
Page 4 line150-159: this is not really a determination of matrix swelling, i.e. change in the volume of the matrix over time, it is determination of water uptake rate and extent. For swelling please measure and report the volume changes of the matrix over time.
Page 4 line 153: "tarred" should be "tared"
Page 5 lines 233 239: please give full detail how the elemental analysis results were used to determine the ratio of the polymers. Was it based on nitrogen content of the IPEC?
Page 7 Figure 2: swelling or water uptake?
Page 10 line 330: "excessive" might be better than "excellent", as the latter implies good properties whereas as the former suggests undesirable properties?
Figure 7 and discussion of this in the text: in a likely enhanced gastric residence time, say 6 hours, incomplete drug release is occurring therefore an ineffective dose may be delivered. You must comment on this problem.
References: you cite your own work 12 times which is 21 % of the total citations. Is this high degree of self citation justified?
Comments on the Quality of English LanguageEnglish is satisfactory. A couple of recommendation to correct/improve the written English are made.
Author Response
Response to Reviewer 3 Comments
Dear reviewer, thank you for the work done on reviewing our manuscript. We tried to answer questions and make adjustments in the manuscript.
Comment 1: Page 1, line 10: recommend that you insert the acronym IPECS between "complexes" and "Eudragit" so it is understood in the next sentence of the abstract where the acronym appears for the first time.
Response 1: thank you, the acronym IPECs was added.
Comment 2: Page 1, line30: the absorption window will not be the stomach, it will be the proximal small intestine.
Response 2: thank you for your comment, information was changed.
Comment 3: Page 1 line 35: citation 15 you give here as support for the use of ion exchange resins in increasing upper GI tract drug residence time makes no reference to that property. Please add in a more appropriate reference where the increased upper GI residence time afforded by ion exchange resins is clearly demonstrated, or delete this claim from the introduction and citation 15 from the reference list.
Response 3: we deleted this claim from the introduction section and citation 15 from the reference list.
Comment 4: Page 3 line 134- 136: please give particle size distribution of the ground IPEC powder.
Response 4: We did not study the size of the particles due to the fact that we did not developing nano- or micro-sized particles, due to, in frame of this manuscript, we’ve prepared a matrix-based systems (tableting matrices) by using synthesized IPECs.
Comment 5: Page 4 line150-159: this is not really a determination of matrix swelling, i.e. change in the volume of the matrix over time, it is determination of water uptake rate and extent. For swelling please measure and report the volume changes of the matrix over time.
Response 5: We agree with this comment, but in this case we evaluated the behavior of the matrix under conditions mimicking fasted stomach. We believe that changing of matrix mass together with visual monitoring of the state of the matrix can be used in the same way as monitoring of volume changes.
Comment 6: Page 4 line 153: "tarred" should be "tared"
Response 6: it was corrected, thank you.
Comment 7: Page 5 lines 233 239: please give full detail how the elemental analysis results were used to determine the ratio of the polymers. Was it based on nitrogen content of the IPEC?
Response 7: we have added information in section 2.5.
Comment 8: Page 7 Figure 2: swelling or water uptake?
Response 8: we agree with reviewer that it can be named as “water uptake”, but taking into account that we performed monitoring of visual behavior of the samples, we would like to leave the name of the characteristic as “swelling” as we used in our previously published papers.
Comment 9: Page 10 line 330: "excessive" might be better than "excellent", as the latter implies good properties whereas as the former suggests undesirable properties?
Response 9: thank you for your comment, it was corrected.
Comment 10: Figure 7 and discussion of this in the text: in a likely enhanced gastric residence time, say 6 hours, incomplete drug release is occurring therefore an ineffective dose may be delivered. You must comment on this problem.
Response 10: Drug release assessment with model drugs has been done to understand the behavior of the developed IPEC with API. 6 hours duration, in our opinion, is enough to make conclusion about character of the different model drug release from the IPEC matrices. The aim of this experiment was not to achieve the 100 % drug release.
Comment 11: References: you cite your own work 12 times which is 21 % of the total citations. Is this high degree of self citation justified?
Response 11: thank you, number of self citation was decreased.
Author Response File: Author Response.docx
Reviewer 4 Report
Comments and Suggestions for AuthorsThe manuscript presents a possible mucoadhesive system that forms an acidic pH gelling matrix. The authors used MDZ and ACV as active ingredients. The paper differs in content only in the active ingredients from their previously published results without newer methods. In my opinion, these results alone are thus of little value for publication and do not contain any novel content that would make them suitable. Thus, I recommend the article for further review only after adding new methods. The GR system should be characterized from several points of view, adding novelty content, such as ex vivo or in vivo proof of efficacy.
Author Response
Response to Reviewer 4 Comments
Dear reviewer, thank you for the work done on reviewing our manuscript. We tried to answer questions and make adjustments in the manuscript.
Comments: The manuscript presents a possible mucoadhesive system that forms an acidic pH gelling matrix. The authors used MZ and ACV as active ingredients. The paper differs in content only in the active ingredients from their previously published results without newer methods. In my opinion, these results alone are thus of little value for publication and do not contain any novel content that would make them suitable. Thus, I recommend the article for further review only after adding new methods. The GR system should be characterized from several points of view, adding novelty content, such as ex vivo or in vivo proof of efficacy.
Response: thank you for your point of view and given suggestion. Submitted work is different from our previously published results not only new active ingredients. We used new methods also such as assessment of bioadhesive properties. Bioadhesive properties of IPEC matrices were evaluated on mucin compacts (in vitro) and on pig stomach mucosa (ex vivo).
Regarding additional in vivo experiments, of course, we agree with you, however the carrying out of them need much more time and efforts for evaluation of the results and including them. Thus, in our group we did the in vivo experiments later and published the results separately. For proving that, please see our previously published papers with in vivo data and evaluation of them:
- Mustafin, R.I.; Kabanova, T.V.; Semina, I.I.; Bukhovets, A.V.; Garipova, V.R.; Shilovskaya, E.V.; Nasibullin, Sh. F.; Sitenkov, A.Yu.; Kazakova, R.R.; Kemenova, V.A. Biopharmaceutical assessment of polycomplex matrix system based on Carbomer 940 and Eudragit® EPO for colon-specific drug delivery. Chem. J., 2011, 45, 491-494. DOI: 0091-150X/11/4508-0491
- Mustafin, R.I.; Semina, I.I.; Bukhovets, A.V., Sitenkov A.Yu., Garipova V.R., Salakhova A.R., Kemenova V.A. Comparative pharmacokinetic assessment of diclofenac sodium polycomplex drug delivery systems based on Eudragit copolymers. Pharm. Chem. J., 2014, 48, 1-4. DOI: 0091-150X/14/481-0001
- Mustafin R.I., Semina I.I., Garipova V.R., Bukhovets A.V., Sitenkov A.Yu., Salakhova A.R., Gennari C.G.M., Cilurzo F. Comparative study of polycomplexes based on Carbopol® and oppositely charged polyelectrolytes as a new oral drug delivery system. Chem. J., 2015, 49, 1-6. DOI: 0091-150X/15/4901-0001
- Timergalieva (Garipova), V.R.; Sitenkov, A.Yu.; Bukhovets (Sitenkova), A.V.; Elizarova, E.S.; Gordeeva D.S.; Semina, I.I.; Moustafine, R.I. Development of lyophilisates based on polymer-drug and interpolyelectrolyte complexes: pharmacokinetic assessment. Drug Dev. & Reg. 2023, 12, 173–18 DOI:10.33380/2305-2066-2023-12-4-159
According to the above-mentioned papers that we published, our assumptions about possibility for using polycomplex carriers based on oppositely charged Eudragits for the development of oral gastroretentive bioadhesive DDS, could be reasonable.
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsAuthors have adequately addressed the comments in the revised manuscript and I will suggest to accept the manuscript.
Reviewer 2 Report
Comments and Suggestions for AuthorsAccept in present form
Reviewer 3 Report
Comments and Suggestions for AuthorsNo further comments.
Reviewer 4 Report
Comments and Suggestions for AuthorsI accept the given answers.
