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Open AccessArticlePost Publication Peer ReviewVersion 3, Approved

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing (Version 3, Approved)

1
Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Region of Central Macedonia, Greece
2
Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Region of Central Macedonia, Greece
3
Laboratory of General and Inorganic Chemical Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24 Thessaloniki, Greece
4
Pharmathen S.A., Pharmaceutical Industry, Dervenakion Str 6, Pallini Attikis, GR-15351 Attiki, Greece
*
Author to whom correspondence should be addressed.
Received: 27 January 2019 / Accepted: 23 February 2019 / Published: 15 August 2019
Peer review status: 3rd round review Read review reports
Version 3, Approved
Published: 15 August 2019
DOI: 10.3390/sci1020048
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Version 2, Revised
Published: 10 June 2019
DOI: 10.3390/sci1010029
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Version 1, Original
Published: 28 February 2019
DOI: 10.3390/sci1010011.v1
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In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus® (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 °C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism. View Full-Text
Keywords: Aprepitant; soluplus; poloxamer 188; ternary solid dispersions; hot-melt mixing; dissolution enhancement Aprepitant; soluplus; poloxamer 188; ternary solid dispersions; hot-melt mixing; dissolution enhancement
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Nanaki, S.; Eleftheriou, R.M.; Barmpalexis, P.; Kostoglou, M.; Karavas, E.; Bikiaris, D. Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing. Sci 2019, 1, 48.

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1

Reviewer 1

Sent on 01 Jun 2019 by Konstantinos Avgoustakis | Approved with revisions
University of Patras

This is a well planned and performed study. Few comments to improve the scientific quality of the manuscript.

(1) The authors should justify the drug and polymer proportions chosen in the solids dispersions in relation to the size of the drug doses used clinically. What would be an optimum drug content of an APT solid dispersion dosage form?

(2) Details on how EDAX measurements were conducted should be reported.How drug nanocrystals were analyzed without interference from the polymer matrix?

(3) Drug release does not appear to be controlled by matrix erosion, as the authors concluded. As the difficult to dissolve part of the system is the hydrophobic drug, drug release should be controlled by drug particles dissolution. This is the reason why drug release falls with drug content, i.e. with the size of the drug particles, in the matrix. A Hixson Crowell dissolution model should better describe obtained release data. In any case, it is difficult to make a reliable analysis of drug release mechanism when at the first sampling time point drug release is higher than 70% (Figure 11).


Response to Reviewer 1

Sent on 13 Jul 2020 by Stavroula Nanaki, Rodanthi Maria Eleftheriou, Panagiotis Barmpalexis, Margaritis Kostoglou, Evangelos Karavas, Dimitrios Bikiaris

General Comment: This is a well-planned and performed study. Few comments to improve the scientific quality of the manuscript. Authors Reply: We thank the reviewer for his/her nice comments. Comment 1: The authors should justify the drug and polymer proportions chosen in the solids dispersions in relation to the size of the drug doses used clinically. What would be an optimum drug content of an APT solid dispersion dosage form? Authors Reply: Based on Emend SmPC there are several strengths starting from 40mg/dose up to 125mg/dose. Hence, in the case of 90/10 SD the lowest total dose weight will be 360mg and the highest total dose will be 1125mg, quantities that are acceptable for per os administration. Clarifications are given in the revised manuscript. Comment 2: Details on how EDAX measurements were conducted should be reported.How drug nanocrystals were analyzed without interference from the polymer matrix? Authors Reply: Details are given in the revised manuscript. Comment 3: Drug release does not appear to be controlled by matrix erosion, as the authors concluded. As the difficult to dissolve part of the system is the hydrophobic drug, drug release should be controlled by drug particles dissolution. This is the reason why drug release falls with drug content, i.e. with the size of the drug particles, in the matrix. A Hixson Crowell dissolution model should better describe obtained release data. In any case, it is difficult to make a reliable analysis of drug release mechanism when at the first sampling time point drug release is higher than 70% (Figure 11). Authors Reply: We thank the reviewer for his/her suggestion and we agree that it is difficult tricky to have a reliable fitting model when 70% of the API is released in the first sampling point. However, since our approach fits perfectly the obtained results, we fill that the approach followed may adequately describe APT’s release mechanism.

Reviewer 2

Sent on 09 May 2019 by Syed A Rizvi | Approved with revisions
Nova Southeastern University

As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability.


Response to Reviewer 2

Sent on 13 Jul 2020 by Stavroula Nanaki, Rodanthi Maria Eleftheriou, Panagiotis Barmpalexis, Margaritis Kostoglou, Evangelos Karavas, Dimitrios Bikiaris

Thessaloniki 5/10/2019 Dear Editor We would like to thank both -You and Reviewers- for the time spending on the evaluation of our paper and the helpful/accurate comments and valuable suggestions. In the following, you can find our responses –one by one answer to the reviewer comments- and changes that we have included in the revised manuscript with red colour taking into account all reviewers suggestions. Reviewer #1: General 1: As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. Authors Reply: We agree with the reviewer that the paper looks nicer when the chemical structures are presented, however, both API and used excipients are widely known and hence, we have decided not to include their chemical structure in manuscript. Comment 2: The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Authors Reply: The determination of the ratio of each polymorph in the prepared formulations was outside of the scope of the present manuscript. Comment 3: Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability. Authors Reply: According to published data (US20100298327A1) “crystalline Form I of aprepitant has been shown to have a lower solubility (0.9±0.1 mg/ml) when compared with Form II (1.3±0.2 mg/ml)”, however the evaluation of API’s polymorph solubility in the prepared SDs was outside of the scope of the present paper. Sincerely Yours Dimitrios Bikiaris Professor

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