Orodispersible Films—Current State of the Art, Limitations, Advances and Future Perspectives

Round 1

Reviewer 1 Report

1.  This review manuscripts focus on the introduction of current advances of the orodispersible films in the aspect of mechanism, production and on market medicine, etc. The content is simple and clear, and It is suitable for researchers or general audiences who are not in their field to read.

 

2. The resolutions of Figure 3 and Figure 4 are not enough for publication.

3. Reference 135, 136 and 138 have type errors or misleading, please fix it. 

Author Response

Reviewer 1 wrote: 1.  This review manuscripts focus on the introduction of current advances of the orodispersible films in the aspect of mechanism, production and on market medicine, etc. The content is simple and clear, and It is suitable for researchers or general audiences who are not in their field to read.

Our response: Dear Reviewer, thank you for reviewing our paper and the provided suggestions. We have implemented them as disclosed below.

Reviewer 1 wrote: 2. The resolutions of Figure 3 and Figure 4 are not enough for publication.

Our response: Thank you for your advice. Figures 3 and 4 have been uploaded with the best reachable resolution directly from the publishers sites.

Reviewer 1 wrote: 3. Reference 135, 136 and 138 have type errors or misleading, please fix it. 

Our response: References have been corrected.

Reviewer 2 Report

This paper reports an interesting review on the state of the art of Orodispersible films. Overall, the document is well structured and simple to read, and updated. There are some important issues to be taken in consideration, before any publication in Pharmaceutics.

Issues:

1.       Title: would change the order to “Current state of the art, limitations, advances and future perspectives”

2.       An approach on the future perspectives for Orodispersible films, in an independent subtitle in the end, or in the Conclusions, would be a plus.

3.       Quality of figures should be improved before any publication.

4.       References must be revised prior publications, such as 34, 69, 108, 135 (as examples). For instance, Ref 135 says only “No Title”.

Author Response

Reviewer 2 wrote: This paper reports an interesting review on the state of the art of Orodispersible films. Overall, the document is well structured and simple to read, and updated. There are some important issues to be taken in consideration, before any publication in Pharmaceutics.

 

Our response: Dear Reviewer, thank you for reviewing our paper and the provided suggestions. We implemented them as disclosed below.

 

Reviewer 2 wrote: 1. Title would change the order to “Current state of the art, limitations, advances and future perspectives”

 

Our response: Revised as recommended.

 

Reviewer 2 wrote: 2.  An approach on the future perspectives for Orodispersible films, in an independent subtitle in the end, or in the Conclusions, would be a plus.

 

Our response: Revised as recommended.

 

Future perspectives

 

The combination of discovering of the new and continuous improvement approach is at the heart of pharmaceutical industry. It allows to overcome barriers and limitations providing progress in drug products development and also hope and better future for patients. Considering the number of pending patent applications and granted patents [18] with their innovative approaches make us believe that the progress in production of ODFs is unquestionable. The future of ODFs seems to have a dual nature. From the one hand, manufacturing on a big scale is necessary because it provides the access of ODF’s to a large number of patients. From the other hand, personalized therapy for a small scale is the promising approach for patients that need individual therapy. Both of the development ways have its limitations that need to be overcome in the future. Currently the solvent casting method is the main method used for a big scale and there are no signs that something will change in this matter. It is possible that 3D printing would be a main manufacturing method used for personalized therapy in hospitals and pharmacies. To allow that the introduction of a regulatory pathway that permits the development and use of personalized medical products is necessary. The another thing that need to be done is overcoming of the limited loading of ODFs and providing harmonized method for quality control. There is no doubt that the progress in developing of ODFs will continue as there are many groups of patients with swallowing problems (elderly, pediatric, schizophrenia and many others) for which this drug form is most convenient. A need for tailored doses as well as dosage forms that are easy to administer is a trigger for further development.

 

Reviewer 2 wrote: 3. Quality of figures should be improved before any publication.

 Our response: Revised as recommended.

Reviewer 2 wrote: 4. References must be revised prior publications, such as 34, 69, 108, 135 (as examples). For instance, Ref 135 says only “No Title”.

 Our response: Revised as recommended.

Reviewer 3 Report

The topic submitted is very trending and upcoming in pharma dosageforms, on Oral films has very few reviews published earlier but does cover the latest significant research data to the existing field of research. The article is not very well articulated and needs English language revisions and even formatting of the manuscript as per the MDPI guidelines. The manuscript needs to be checked for proper numbering and citation of references. The introduction needs to be enlarged with more background. Abstract and conclusion should include a sentence proposing the future direction of the presented research topic at least 1-2 lines. A seperate section on how oral thin films have been in nutraceutical delivery needs to be added. A table addressing all the marketed nutra based oral thin films should be listed.  Also the commercial aspects of how pediatrics or geatrics patients and pharmaceutical industries can benefit by oral thin films need to be commented.  Most of the sections discussed lack citing the references from the latest and previous studies. 

Author Response

Reviewer 3 wrote: The topic submitted is very trending and upcoming in pharma dosage forms, on Oral films has very few reviews published earlier but does cover the latest significant research data to the existing field of research.

Our response: Dear Reviewer, thank you for reviewing our paper and the provided suggestions. We implemented them as disclosed below

Reviewer 3 wrote: The article is not very well articulated and needs English language revisions and even formatting of the manuscript as per the MDPI guidelines. The manuscript needs to be checked for proper numbering and citation of references.

Our response: English revised and corrected. References have been corrected.

Reviewer 3 wrote: The introduction needs to be enlarged with more background.

Our response: Revised as recommended.

Conception of this drug form is dated back to 1955. Nevertheless, the real interest on a big scale started in 2001 with launching of Listerine by Pfizer [18]. Since then ODFs are successfully developed what results in a wide range of products available on the markets around the world. ODFs are carrier not only for typical API like Sildenafil, Ondansetron or Zolpidem but also for vaccines [19], probiotics [20], herbal extracts [21] and nutrients like vitamins [22]. Improving the bioavailability of some APIs was a trigger for implementing solutions that enable controlling the rate of drug release. In this way ODFs became a carrier for microparticles [23], nanoparticles [24] or nanocrystals [18] and self-emulsifying systems [25]. The development is also visible in another aspect, namely in manufacturing methods. Among them the solvent casting is the most popular but there are also other methods like hot-melt extrusion or electrospinning and very promising printing technologies (two-dimensional ink-jet printing, three-dimensional, additive printing and flexographic printing methods) [18]. The combination of above-mentioned methods or their different varieties are often patented and therefore will probably determine the future of ODFs.

 

 

Reviewer 3 wrote: Abstract and conclusion should include a sentence proposing the future direction of the presented research topic at least 1-2 lines.

 

Our response: Revised as recommended.

 

Future perspectives

 

The combination of discovering of the new and continuous improvement approach is at the heart of pharmaceutical industry. It allows to overcome barriers and limitations providing progress in drug products development and also hope and better future for patients. Considering the number of pending patent applications and granted patents [18] with their innovative approaches make us believe that the progress in production of ODFs is unquestionable. The future of ODFs seems to have a dual nature. From the one hand, manufacturing on a big scale is necessary because it provides the access of ODF’s to a large number of patients. From the other hand, personalized therapy for a small scale is the promising approach for patients that need individual therapy. Both of the development ways have its limitations that need to be overcome in the future. Currently the solvent casting method is the main method used for a big scale and there are no signs that something will change in this matter. It is possible that 3D printing would be a main manufacturing method used for personalized therapy in hospitals and pharmacies. To allow that the introduction of a regulatory pathway that permits the development and use of personalized medical products is necessary. The another thing that need to be done is overcoming of the limited loading of ODFs and providing harmonized method for quality control. There is no doubt that the progress in developing of ODFs will continue as there are many groups of patients with swallowing problems (elderly, pediatric, schizophrenia and many others) for which this drug form is most convenient. A need for tailored doses as well as dosage forms that are easy to administer is a trigger for further development.

 

Abstract: Considering the number of pending patent applications and granted patents with their innovative approaches makes the progress in manufacturing of ODFs unquestionable.

 

Reviewer 3 wrote: A seperate section on how oral thin films have been in nutraceutical delivery needs to be added. A table addressing all the marketed nutra based oral thin films should be listed.

 

Our response: Revised as recommended. A separate table (no 4) has been prepared.

 

The active substances contained in ODFs belong not only to the group of conventional drugs, but also to groups like: vaccines, probiotics, substances of plant origin or various nutrients as well as vitamins [18,22]. Attempts have even been made to incorporate dried plant extracts [21]. Nutraceuticals are dietary supplements used to improve health, delay aging, prevent disease and support the proper functioning of the human body. Currently, nutraceuticals are gaining a lot of interest due to their nutritional and therapeutic potential [169]. Manufacturers have recognized this market need, which is why more and more different nutraceuticals are produced in the form of ODF (Table 4). Moreover, there are companies (so called third-parties) that produce and supply oral films to other pharmaceutical entities. One of this company produces more than 15 million films a day [170].

Reviewer 3 wrote: Also the commercial aspects of how pediatrics or geatrics patients and pharmaceutical industries can benefit by oral thin films need to be commented.

Our response: Revised as recommended.

Apart from products summarized in Table 2 and 4 worth mentioning is also the growing number of researches on ODFs dedicated for small scale (hospitals, pharmacies). It seems to be a good alternative for traditional tablets that are available in limited number of doses and mainly manufactured on a big scale and are not preferred by infants or elderly patients who require more individual doses not available on the markets [16,17]. ODFs allow to adjust doses to individual needs [8,23]. In a randomized controlled trial involving the youngest children, ODFs were found to be a safe alternative to liquid drugs that could provide promising clinical results [171]. What’s more, the addition of flavor enhancers or the use of API taste masking technology may significantly increase preferences for this form of the drug, especially in children [7,8]. It is also worth noting that once the ODF formulation is placed in the mouth, it tends to stick to the mucosa before disintegrating. Thanks to this feature, patients (especially children, elderly or mentally ill) cannot spit out the drug, what may happen after taking a conventional tablet [172].

Reviewer 3 wrote: Most of the sections discussed lack citing the references from the latest and previous studies. 

Our response: Revised as recommended. Additional citations have been included.

Erna Turkovi´c, et al., Orodispersible films — Pharmaceutical development for improved performance: A review Journal of Drug Delivery Science and Technology Volume 75, September 2022, 103708.
https://www.sciencedirect.com/science/article/abs/pii/S1773224722006190#kwrds0010

M. Musazzi, et al., Trends in the production methods of orodispersible films. International Journal of Pharmaceutics Volume 576, 25 February 2020, 118963.

Gupta, et al., A Comprehensive Review of Patented Technologies to Fabricate Orodispersible Films: Proof of Patent Analysis (2000-2020) Pharmaceutics 2022 Apr 8;14

Janigová, N.; Elbl, J.; Pavloková, S.; Gajdziok, J. Effects of Various Drying Times on the Properties of 3D Printed Orodispersible Films. Pharmaceutics 2022, 14, doi:10.3390/pharmaceutics14020250.

Steiner, D.; Tidau, M.; Finke, J.H. Embedding of Poorly Water-Soluble Drugs in Orodispersible Films—Comparison of Five Formulation Strategies. Pharmaceutics 2022, 15, 17, doi:10.3390/pharmaceutics15010017.

Shah, K.A.; Li, G.; Song, L.; Gao, B.; Huang, L.; Luan, D.; Iqbal, H.; Cao, Q.; Menaa, F.; Lee, B.-J.; et al. Rizatriptan-Loaded Oral Fast Dissolving Films: Design and Characterizations. Pharmaceutics 2022, 14, 2687, doi:10.3390/pharmaceutics14122687.

Abou‐taleb, H.A.; Mustafa, W.W.; Makram, T.S.; Abdelaty, L.N.; Salem, H.; Abdelkader, H. Vardenafil Oral Dispersible Films (ODFs) with Advanced Dissolution, Palatability, and Bioavailability. Pharmaceutics 2022, 14, doi:10.3390/pharmaceutics14030517.

Steiner, D.; Emmendörffer, J.F.; Bunjes, H. Orodispersible Films: A Delivery Platform for Solid Lipid Nanoparticles? Pharmaceutics 2021, 13, doi:10.3390/pharmaceutics13122162

Citra Rani, K.; Parfati, N.; Luh Dewi Aryani, N.; Nuniek Winantari, A.; Wahyu Fitriani, E.; Trias Pradana, A.; Nawatila, R.; Rizky Putranti, A.; Irine, F.; Angelica, F.; et al. Pharmaceutics Development, Evaluation, and Molecular Docking of Oral Dissolving Film of Atenolol. Pharmaceutics 2021, 13, 1727, doi:10.3390/pharmaceutics

Tawfik, E.A.; Scarpa, M.; Abdelhakim, H.E.; Bukhary, H.A.; Craig, D.Q.M.; Barker, S.A.; Orlu, M. A Potential Alternative Orodispersible Formulation to Prednisolone Sodium Phosphate Orally Disintegrating Tablets. Pharmaceutics 2021, 13, 1–17, doi:10.3390/pharmaceutics13010120.

Cho, H.W.; Baek, S.H.; Lee, B.J.; Jin, H.E. Orodispersible Polymer Films with the Poorly Water-Soluble Drug, Olanzapine: Hot-Melt Pneumatic Extrusion for Single-Process 3D Printing. Pharmaceutics 2020, 12, 1–16, doi:10.3390/pharmaceutics12080692.

Tian, Y.; Bhide, Y.C.; Woerdenbag, H.J.; Huckriede, A.L.W.; Frijlink, H.W.; Hinrichs, W.L.J.; Visser, J.C. Development of an Orodispersible Film Containing Stabilized Influenza Vaccine. Pharmaceutics 2020, 12, doi:10.3390/pharmaceutics12030245.

Chaiwarit, T.; Aodsab, N.; Promyos, P.; Panraksa, P.; Udomsom, S.; Jantrawut, P. Fabrication of Hydroxypropyl Methylcellulose Orodispersible Film Loaded Mirtazapine Using a Syringe Extrusion 3D Printer. Sci Pharm 2022, 90, 68, doi:10.3390/scipharm90040068.

Olechno, K.; Grilc, N.K.; Zupančič, Š.; Winnicka, K. Incorporation of Ethylcellulose Microparticles Containing a Model Drug with a Bitter Taste into Nanofibrous Mats by the Electrospinning Technique—Preliminary Studies. Materials 2022, 15, doi:10.3390/ma15155286.

Reviewer 4 Report

Orodispersible films (ODFs), which have been recently developed, display advanced dosing flexibility and improved patient acceptability. ODFs disintegrate in the mouth after contact with saliva without the addition of water, so they present an alternative option to tablets and capsules typically used in solid oral drug formulations.

The manuscript presents a very interesting review related to the technological and formulation aspects of ODFs including manufacturing method and their limitations and how to overcome these limitations. The review contains 158 scientific publications covering different aspects of ODFs. Unfortunately, the authors did not indicate recently published reviews, which could be very helpful:

Erna Turkovi´c, et al., Orodispersible films — Pharmaceutical development for improved performance: A review Journal of Drug Delivery Science and Technology Volume 75, September 2022, 103708.

U. M. Musazzi, et al., Trends in the production methods of orodispersible films. International Journal of Pharmaceutics Volume 576, 25 February 2020, 118963.

M. Gupta, et al., A Comprehensive Review of Patented Technologies to Fabricate Orodispersible Films: Proof of Patent Analysis (2000-2020) Pharmaceutics 2022 Apr 8;14

 

Author Response

Reviewer 4 wrote: Orodispersible films (ODFs), which have been recently developed, display advanced dosing flexibility and improved patient acceptability. ODFs disintegrate in the mouth after contact with saliva without the addition of water, so they present an alternative option to tablets and capsules typically used in solid oral drug formulations.  The manuscript presents a very interesting review related to the technological and formulation aspects of ODFs including manufacturing method and their limitations and how to overcome these limitations. The review contains 158 scientific publications covering different aspects of ODFs.

 Our response: Dear Reviewer, thank you for reviewing our paper and the provided suggestions. We implemented them as disclosed below

Reviewer 4 wrote: Unfortunately, the authors did not indicate recently published reviews, which could be very helpful:

Erna Turkovi´c, et al., Orodispersible films — Pharmaceutical development for improved performance: A review Journal of Drug Delivery Science and Technology Volume 75, September 2022, 103708.
https://www.sciencedirect.com/science/article/abs/pii/S1773224722006190#kwrds0010

M. Musazzi, et al., Trends in the production methods of orodispersible films. International Journal of Pharmaceutics Volume 576, 25 February 2020, 118963.

Gupta, et al., A Comprehensive Review of Patented Technologies to Fabricate Orodispersible Films: Proof of Patent Analysis (2000-2020) Pharmaceutics 2022 Apr 8;14

Our response: Thank you for suggestions of new publications, we have added them to the text.