Review Reports - Absorption of Vitamin B12 in Older Adults: Advances and Challenges in Sublingual Administration

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Even though the review paper is rather short it is well written.

Furthermore very recently, there was a very similar article published (DOI 10.3389/fphar.2025.1602976)

My only comment has to do with an improvement on wording. I suggest replacing ' synthesis challenges' mentioned in the abstract, with 'Pharmaceutical processes challenges'

Author Response

Thank you very much for taking the time to review this manuscript

Comments 1: My only comment has to do with an improvement on wording. I suggest replacing ' synthesis challenges' mentioned in the abstract, with 'Pharmaceutical processes challenges'

Response 1: Thank you for pointing this out. We agree with this comment. We have changed the synthesis challenges for 'pharmaceutical processes challenges' as you requested. This change can be found in the abstract section

Reviewer 2 Report

Comments and Suggestions for Authors

The review that explores the physiological challenges of Vitamin B12 absorption in the geriatric population. It specifically focuses on the potential of sublingual orodispersible films (ODFs) as a non-invasive, patient-centered alternative to traditional intramuscular (IM) injections and oral (O) tablets. The topic is highly relevant given the global aging population and the prevalence of B12 deficiency due to gastric atrophy and medication use.The review effectively summarizes various administration routes (IM, O, IN, SL) in a comparative table, highlighting the advantages of the sublingual route in bypassing gastrointestinal barriers.

Just few linguistic and formatting issues can be reported to the Authors:

- Anomalous symbols (e.g., "$adults", "$anemia", "$SL") appear throughout the text.
- Grammatical errors in subject-verb agreement (e.g., "ODFs is an innovative alternative...").
- Incorrect use of decimal separators for English scientific standards (e.g., "1,5 mg" instead of "1.5 mg").

Recommendation: Minor Revision. The authors should correct the linguistic errors.

Author Response

Thank you very much for taking the time to review this manuscript.

Comments 1: Anomalous symbols (e.g., "$adults", "$anemia", "$SL") appear throughout the text.

Response 1: We have checked and corrected the manuscript for anomalous symbols

Comments 2: Grammatical errors in subject-verb agreement (e.g., "ODFs is an innovative alternative...").

Response 2: "ODFs is an innovative alternative" has been changed to "ODFs are an innovative alternative." (Line 157)

Comments 3: Incorrect use of decimal separators for English scientific standards (e.g., "1,5 mg" instead of "1.5 mg").

Response 3: For clarity in scientific and technical English documents, all the manuscripts have been checked to stick with the decimal point, instead of commas

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript offers a broad overview of vitamin B12 absorption in older adults, highlighting sublingual administration via orodispersible films. However, its scientific merit and contribution are somewhat limited. While the topic is clinically relevant, much of the content reiterates information from previously published reviews, with only modest novelty, largely due to the absence of new mechanistic insights or original clinical data. Methodologically, the review would benefit from a clearer justification of the literature selection process and a stronger critical synthesis instead of a purely descriptive summary. Additionally, there are several inconsistencies in terminology; for instance, the oral route should consistently be abbreviated as PO rather than O, in accordance with standard clinical and pharmacological conventions. While the tables are extensive, they can be difficult to interpret. The conclusions largely reiterate existing knowledge without clearly delineating how this review advances the field. To strengthen the manuscript, a sharper focus on unresolved clinical gaps is needed, along with a more rigorous comparison of different administration routes using clinically meaningful endpoints. Furthermore, it’s important to articulate more precisely why sublingual orodispersible films represent a significant advancement beyond mere convenience and adherence. The authors should also maintain consistent terminology (e.g., OTF vs. ODF). A brief graphical abstract or schematic illustrating gastrointestinal versus sublingual absorption would add value if permitted by the journal. Lastly, consider streamlining the language in the Conclusions section to emphasize the impact on clinical decision-making rather than the formulation details.

Author Response

Comments: The manuscript offers a broad overview of vitamin B12 absorption in older adults, highlighting sublingual administration via orodispersible films. However, its scientific merit and contribution are somewhat limited. While the topic is clinically relevant, much of the content reiterates information from previously published reviews, with only modest novelty, largely due to the absence of new mechanistic insights or original clinical data.

Response : Thank you for pointing this out. We agree with this comment and have incorporated mechanistic insights at the end of section 3.1, 3.2 and 3.3, that may justify the relationship between the polymeric structure of ODFs, interaction with vitamin B12 and the possible effects on absorption and bioavailability in in vivo models and benefict in eaderly people.

Comments: Methodologically, the review would benefit from a clearer justification of the literature selection process and a stronger critical synthesis instead of a purely descriptive summary.

Response : We have added a new section 2. named Search Strategy that explain the literture selection

Comments : "the oral route should consistently be abbreviated as PO rather than O"

Response : Thank you for pointing this out. We agree with this comment and have changed the "O" abbreviation for "oral" to "OP."

Comments : While the tables are extensive, they can be difficult to interpret.

Response : We appreciate your observation regarding the density of the tables. However, we have decided to maintain this comprehensive format to provide the reader with a unique and comparative reference. To mitigate the difficulty of interpretation, we have added an explanatory paragraph before each table.

Comments: The conclusions largely reiterate existing knowledge without clearly delineating how this review advances the field.

Response : We appreciate this crucial observation. We have rewritten the conclusions to avoid redundancy and highlight the original contribution of this review: the integration of ODF technology as a targeted solution to the pathophysiology of the aging digestive system. A critical discussion has been included regarding the use of functional endpoints (methylmalonic acid and homocysteine) rather than serum levels alone, identifying this as the main gap to widespread clinical adoption. The conclusion also outlines future challenges to be addressed in the clinical development of ODFs.

Comments: To strengthen the manuscript, a sharper focus on unresolved clinical gaps is needed, along with a more rigorous comparison of different administration routes using clinically meaningful endpoints. Furthermore, it’s important to articulate more precisely why sublingual orodispersible films represent a significant advancement beyond mere convenience and adherence.

Response : We appreciate the observation, as it allows us to highlight the technical value of our review. We have discussed the unsolved clinnical gap, compared routes of administration according to fisiologycal aspect and relate the polymeric structure of ODFs with vitamin B12 interaction and the possible effects on absorption and bioavailability (section 3.2, 3.3 and 4).

Comments: The authors should also maintain consistent terminology (e.g., OTF vs. ODF)

Response: We have removed the abbreviation for oral thin films (OTFs) because it caused confusion with the abbreviation for orodispersible films (ODFs).

Comments: A brief graphical abstract or schematic illustrating gastrointestinal versus sublingual absorption would add value if permitted by the journal

Response: We have included a graphical abstract at the beginning of the manuscript. This will be used whenever the journal allows it.

Comments: Lastly, consider streamlining the language in the Conclusions section to emphasize the impact on clinical decision-making rather than the formulation details.

Response: Thank you very much for your recommendation. The conclusion has been rewritten for clarity.

Reviewer 4 Report

Comments and Suggestions for Authors

Table 2 is incomplete and poorly formatted – critical data is missing and rows are cut off mid-sentence.
Confusing and inconsistent terminology – terms like ODFs, OTFs, buccal films, and sublingual administration are used interchangeably without clear definitions.
Title promises “challenges” but paper lacks dedicated discussion – challenges are only briefly mentioned in the conclusion, not systematically addressed.
Text duplication on Page 6 – paragraphs in lines 157–163 are nearly identical, appearing to be a copy-paste error.
Inconsistent focus on the elderly population – several cited studies include younger or mixed-age participants, diluting the geriatric focus of the review.
Weak link between formulation science and clinical outcomes – the paper jumps from ODF composition to clinical efficacy without connecting material properties to age-related physiological challenges.
Citation and reference inconsistencies – discrepancies in author names and formatting between in-text citations and the reference list.
Underdeveloped conclusion – too brief and generic, lacking synthesis of key advances and clear future directions.
Acronyms not consistently defined – several technical acronyms are introduced without full explanations.
Awkward phrasing and grammatical errors – several sentences require editing for clarity and flow.
Lack of visual or schematic aids – no figures or diagrams to illustrate administration routes or ODF mechanisms.
Overlap and repetition in study descriptions – some studies are described multiple times across different sections.

Author Response

Thank you for taking the time to review

Comments: Table 2 is incomplete and poorly formatted – critical data is missing and rows are cut off mid-sentence.

Response: We have reviewed the formatting of Table 2 to ensure that all information regarding vitamin B12 formulations, polymers, and study outcomes is clearly presented and that no text is truncated.

Comments: Confusing and inconsistent terminology – terms like ODFs, OTFs, buccal films, and sublingual administration are used interchangeably without clear definitions.

Response: Following the suggestions of the editorial process, we have standardized the terminology. We have removed the term “OTFs” to avoid confusion and have consistently used “Orodispersable Films (ODFs)” throughout the revised manuscript.

Comments: Title promises “challenges” but paper lacks dedicated discussion – challenges are only briefly mentioned in the conclusion, not systematically addressed.

Response: We appreciate the observation, as it allows us to highlight the technical value of our review. To address the challenges and clinical gaps more systematically, we have expanded the discussion in sections 3.2, 3.3, and 4. In these sections, we compare administration routes based on physiological aspects and relate the polymeric structure of ODFs to their interaction with vitamin B12, emphasizing the resulting effects on absorption and bioavailability in the elderly.

Comments: Text duplication on Page 6 – paragraphs in lines 157-163 are nearly identical, appearing to be a copy-paste error.

Response: We have corrected the text on page 6 to eliminate redundancies and ensure a smooth transition between the discussion of conventional routes and ODF technology.

Comments: Inconsistent focus on the elderly population – several cited studies include younger or mixed-age participants, diluting the geriatric focus of the review.

Response: The review specifically focuses on the physiological changes of the elderly (such as gastric atrophy and reduced intrinsic factor). We have used the available literature to contrast traditional supplementation with the advantages of ODFs in this specific demographic.

Comments: Weak link between formulation science and clinical outcomes – the paper jumps from ODF composition to clinical efficacy without connecting material properties to age-related physiological challenges.

Response: We have strengthened this connection in the revised version. As seen in sections 3.2 and 3.3, we now relate the polymeric structure of ODFs and their interaction with vitamin B12 to the specific absorption challenges and bioavailability need in elderly populations.

Comments: Citation and reference inconsistencies – discrepancies in author names and formatting between in-text citations and the reference list.

Response: We have conducted a thorough review of the references and in-text citations to ensure consistency and adherence to the journal’s formatting guidelines.

Comments: Underdeveloped conclusion – too brief and generic, lacking synthesis of key advances and clear future directions.

Response: The conclusion has been revised to better synthesize the integration of ODF technology as a solution to the pathophysiology of the aging digestive system, highlighting the gap in clinical adoption and future directions.

Comments: Acronyms not consistently defined – several technical acronyms are introduced without full explanations.

Response: We have ensured that all acronyms, including clinical markers (MMA, Hcy) and technical terms (ODF, OP), are defined at their first mention in the text.

Comments: Awkward phrasing and grammatical errors – several sentences require editing for clarity and flow.

Response: The manuscript has been revised for clarity and professional tone, particularly in the newly added sections regarding search strategy and mechanistic insights.

Comments: Lack of visual or schematic aids – no figures or diagrams to illustrate administration routes or ODF mechanisms.

Response: We agree that a visual representation enhances the clarity of the manuscript. We have included a new Figure 1, which illustrates the comparative pathways of vitamin B12 absorption: the traditional gastrointestinal route (affected by age-related gastric atrophy and IF deficiency) versus the sublingual route provided by ODFs, which bypasses these physiological barriers.

Comments: Overlap and repetition in study descriptions – some studies are described multiple times across different sections.

Response: We have streamlined the descriptions of the cited studies to avoid redundancy, ensuring that each mention adds specific value to the section (e.g., focusing on material properties in one section and clinical outcomes in another).

Reviewer 5 Report

Comments and Suggestions for Authors

The manuscript submitted by Quijada et al. represents a review in the field of recent developments aimed at improving vitamin B12 dosage forms to enhance its absorption in elderly patients. The review is generally well-structured and includes tables summarizing works in the subject area. However, there are several significant issues that the authors should address to present the material more thoroughly.

Are there any other reviews dedicated to vitamin B12 delivery systems? In the concluding part of the introduction, the authors should highlight the novelty of their review in comparison with existing ones.
In particular, the review completely lacks illustrative material. I would recommend that the authors add 1 general figure depicting the chemical structure of vitamin B12 and its administration routs. Furthermore, in the section on sublingual administration, it would also be beneficial to add at least a couple of figures. The latter can be original or borrowed from other articles with permission from the publishers if the articles are published under a subscription model. Figures from articles published Open Access do not require permission for reproduction.
As is known, vitamin B12 has very good intestinal absorption. This property of vitamin B12 is often used as a ligand for conjugation in the development of delivery systems for other orally administered drugs that inherently have low absorption. To enhance the comprehensiveness and strengthen the review, it would be useful to mention this information as well (in the introduction or in the discussion within other sections).
The conclusions appear rather sparse. They should be expanded by incorporating the potential limitations for the application of various sublingual vitamin B12 systems, as well as outlining possible future directions for development in this field.

Author Response

We thank the reviewer for their constructive comments and for recognizing the structure and relevance of our work. We have addressed the specific points as follows:

Comments: Are there any other reviews dedicated to vitamin B12 delivery systems? In the concluding part of the introduction, the authors should highlight the novelty of their review in comparison with existing ones.

Response: We appreciate this suggestion. While there are reviews on vitamin B12 deficiency and general supplementation, the novelty of our review lies in the specific integration of material science (polymer properties of ODFs) with the geriatric pathophysiology of B12 absorption. We have reinforced this in the introduction, emphasizing how our work bridges the gap between formulation characteristics and the specific clinical needs of the elderly population.

Comments: In particular, the review completely lacks of illustrative material. I would recommend that the authors add 1 general figure depicting the chemical structure of vitamin B12 and its administration route. Furthermore, in the section on sublingual administration, it would also be beneficial to add at least a couple of figures.

Response: We agree that visual aids significantly enhance the manuscript. We have included a new Figure 1, which provides a comprehensive schematic comparison between the traditional oral/intramuscular routes and the sublingual ODF pathway. This figure also highlights the physiological barriers in the elderly (such as the lack of intrinsic factor) and how ODFs bypass these issues. Regarding the chemical structure and additional figures, we have prioritized the mechanistic schematic (Figure 1) to provide the most relevant clinical and pharmaceutical context for the reader.

Comments: As is known, vitamin B12 has a very good intestinal absorption (as a ligand for other drugs). To enhance the comprehensiveness and strengthen the review it would be useful to mention this information as well.

Response: We appreciate the reviewer’s insightful comment regarding the potential of vitamin B12 as a ligand in delivery systems due to its physiological transport mechanisms. However, as our review specifically focuses on the geriatric population, where the primary clinical problem is precisely the impairment of intestinal absorption due to age-related factors (such as gastric atrophy and intrinsic factor deficiency), we believe that discussing B12 as a delivery ligand for other drugs falls outside the scope of this particular manuscript. Our objective is to highlight how ODF technology can bypass these specific physiological barriers that characterize the elderly, rather than exploring the broader pharmacological applications of B12 in healthy intestinal transport.

Comments: The conclusions appear rather sparse. They should be expanded by incorporating the potential limitations for the application of various sublingual vitamin B12 systems, as well as outlining possible future directions for developments in this field.

Response: The conclusion has been significantly expanded to address these points. It now synthesizes the key advances in ODF technology, discusses current limitations (such as the need for more clinical trials with functional biomarkers like MMA and Hcy), and outlines future directions for the clinical implementation of these systems in geriatric care.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Authors have successfully addressed my concerns.

Reviewer 4 Report

Comments and Suggestions for Authors

Accept in present form

Reviewer 5 Report

Comments and Suggestions for Authors

The authors have substantially revised the manuscript and have provided reasoned arguments regarding the reviewer's comments which, in their opinion, are not applicable to this work. The manuscript is now acceptable for publication in its present form.