Development and In Vitro Evaluation of Controlled Release Viagra^® Containing Poloxamer-188 Using Gastroplus^™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments

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• Comment 1: The manuscript need extensive English correction many mistakes can be found throughout the text, the first one here in the title (contoning). Missing letters, parentheses or commas can be found frequently. A thorough correction regarding this is mandatory
• Reopens 1:  Yes, English of the entire manuscript has been edited extensively, and all typographical errors and missing letters have been fixed. All editing are highlighted in yellow color in the entire manuscript.

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• Comment 2: The preparation of controlled release drug delivery systems based on polymers is interesting and as such a good idea for many drugs. For Sildenafil used in this work the benefit is not completely clear to me. As a starting point I’m not sure if this formulation should be used as a treatment for erectile dysfunction or pulmonary hypertension. Both are mentioned in the manuscript and I was not able to find an explanation if there are different plasma concentration curves needed for these very different treatments and for which treatment the dosage forms are planned
• Reopens 2:    Thank you for your question. In this study our focus was on sildenafil in terms of erectile dysfunction. Controlled release might not only help to avoid the risk of side effects caused by burst release, but also makes the drug more accessible for men with pre-existing conditions, supporting their psyche, or enhancing the overall life-balance. But yes, the application of controlled release in pulmonary hypertension is an important point as the typical treatment is either IV or several PO doses per day between 5 to 100 mg. In this case, controlled release formulation it would be useful in terms of minimizing dose frequencies pre day.

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• Comment 3: In figure 5 the simulated plasma concentration-time profiles of the formulations 5-8 do not fit to the release curves in figure 2 and 3. Formulation 5 and 6 revealed slower release than formulation 4 and the plasma concentration-time profiles are depicted with a higher and/or earlier Cmax. Such a profile should not be possible after a slower release of the drug
• Reopens 3:    Yes, in Fig 5, the order of simulated plasma concentration-time profiles of sildenafil of different formulation has been fixed (line 40).

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• Comment 4: In the discussion (line 193) the authors state that MGS melts during the particle preparation in the water bath and coat the drug particles with molten MGS. The melting point of MGS is at approx. 88°C, please explain how you were able to reach this in a water bath thermostated to 50°C
• Reopens 4:    Yes, error has been fixed and molten MGS has been removed, the entire paragraph was paraphrased to “In general, the highly hydrophobic MGS forms a strong surface coating around the other excipients and drug, reducing wettability, water uptake, and slowing down the dissolution rate. Owing to its delaying properties, MGS is a common additive in many solid pharmaceutical formulations, and numerous studies can be found investigating the concentration-dependent effect of MGS on the drug release performance of tablets” (lines 176 -181)

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·       Comment 5: In line 256 the authors state that the ratio of drug to polymer is 1:1 (w/w) in Table 4 it is clearly stated that 50mg sildenafil were mixed with a total amount of 250mg polymer, that is not a 1:1 ration.

• Reopens 5:    Yes, it has been fixed to 1:5 according to table 4, (highlighted in red color, lines 225)

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• Comment 6: In line 280 the calibration curve of sildenafil was prepared with similar solvent, please give more detailed information on the solvent similar to distilled water you used here

·       Reopens 6:    Yes, it has been fixed to distilled water. (highlighted in red color, lines 247)

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·       Comment 7: In line 298 and 299 Table 4 is cited to contain information on physicochemical and biopharmaceutical parameters. Table 4 in my version of the manuscript contains information in matrix compositions not biopharmaceutical parameters, they are given in table 2. In this table 2 (line 139) there is a small a in every line to which I can’t find any explanation anywhere in the manuscript. In the text it is mentioned that the parameters were obtained from the literature but no reference is mentioned. Include all references used please

• Reopens 7: Yes, it has been corrected to Table 2 (highlighted in red color, lines 268). For, the small “a” it was removed from the table and for parameters in the tables, it was obtained from the ADMET predictor of build in Gastro plus software and some values were confirmed from the literature.  Its fixed now and reference was added. (highlighted in red color, lines 124-126).

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Comment 1: Titles, subtitles were to be unified (some has numbers, others not)

Reopens 1:    Yes, it has been fixed and highlighted in red color in the entire manuscript.

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Comment 2: Page 2, reference No. 18 should have bracket

Reopens 2:    Yes, it has been fixed and highlighted in red (line 60).

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Comment 3: Page 6, legend of Table 3 should be attached with table

Reopens 3:    Yes, it has been attached and highlighted in red color (line 145-147).

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Comment 4: Page 7, line 153 Gastroplus TM. (space) The~

Reopens 4:    Yes, it has been fixed and highlighted in red color (line 148).

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Comment 5: Page 7, line 154 as follow:

Reopens 5:    Yes, it has been fixed and removed from the text (highlighted in red color, line 150).

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Comment 6: Page 7, line 171 abstaining?

Reopens 6: Yes, it has been corrected and the entire sentence has been paraphrased to “Exposed to the dissolution medium, the polymer slowly hydrates, solubilizing the incorporated drug particles to be finally released into solution” (line 164-168)

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Comment 7: Page 7, line 185 may be not con(should be removed) convenient

Reopens 7:    Yes, it has been fixed to “as the dosage form may be not convenient for oral swallowing” (highlighted in red color, line 172)

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Comment 8: Page 8, degrees Celcius needs to be selected right one

Reopens 8:    Yes, it has been fixed and corrected (highlighted in red color, line 212, 214 and 220)

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Comment 9: Page 9, line 254 series (space) 1

Reopens 9:    Yes, it has been fixed (highlighted in red color, line 226)

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Comment 10: Page 9, line 273-274: the sentence needs to be revised

Reopens 10:    Yes, it has been fixed paraphrased to “Pedal method with 100 rpm rotational speed was used and 900 mL of distilled water served as media at a set temperature of 37 ± 0.5 °C. Samples of 5 mL were withdrawn at the following times: 0.16, 0.33, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, and 12 h. All withdrawn samples were filtered and analyze for drug content using UV-spectrophotometer (wavelength was set at 292 nm)”, (highlighted in red color, line 239-244)

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Comment 11: Page 10, line 287 equation font size and style need to be revised

Reopens 11:    Yes, it has been fixed (highlighted in red color, line 252)

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Comment 12: Page 11 reference font size and style need to be unified

Reopens 12:    Yes, it has been fixed (highlighted in red color, lines 307-409).