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Peer-Review Record

Zolmitriptan Intranasal Spanlastics for Enhanced Migraine Treatment; Formulation Parameters Optimized via Quality by Design Approach

Reviewer 1: Deena Kuruvilla
Reviewer 2: Anonymous
Received: 9 April 2021 / Revised: 11 May 2021 / Accepted: 25 May 2021 / Published: 27 May 2021

Round 1

Reviewer 1 Report

Abstract:

  1. What does splanastic mean? I have not heard that term before. How is this nasal formulation different? I would first describe this in the abstract before getting into the weeds about the efficacy of the formulation.

Introduction

  1. The vascular theory of migraine was thrown out many years ago. There are many new mechanisms for migraine - i.e. inflammatory cascade via CGRP, neurokinins, substance P, cortical spreading depression, etc that are the newer studied mechanisms. It is NO longer considered a vascular headache as stated in the introduction.
  2. Zolmitriptan doesn't work by directly causing vasoconstriction only. There are several mechanisms in play such as serotonin agonism, anti-inflammatory mechanisms by reducing levels of CGRP, etc. 

Methods:

  1. what is a splanastic gel?
  2. Can you provide examples of how this method was used in other drug formulations for comparison?

Author Response

We are submitting the revised manuscript scipharm-1196619 Revision, entitled: “Zolmitriptan intranasal spanlastics for enhanced migraine treatment; formulation parameters optimized via Quality by Design approach”.

            First of all, I would like to thank the reviewers for their valuable comments and suggestions, which in turns, will enhance the accuracy and clarity of the manuscript. We are grateful to the reviewers for their valuable insight and input, which subsequently, would enhance the quality and presentability of our manuscript.

            We hope the revised manuscript meets the journal standards and reviewers’ expectations. The reviewers’ comments have been totally and individually considered. We have uploaded this letter which includes our response to each of the reviewers’ comments. In addition, we have uploaded the revised manuscript. All changes made are shaded yellow to highlight changes from original submission.

Authors’ response to reviewers’ comments

In the following part of this document, the reviewer’s original comments are underlined, and our responses are presented in Italic.

  1. Reviewer 1:

Point 1: What does splanastic mean? I have not heard that term before. How is this nasal formulation different? I would first describe this in the abstract before getting into the weeds about the efficacy of the formulation.

Response 1: We would like to thank the reviewer for his valuable comment. The abstract was edited to include clear definition of spanlastics. The added part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

Line 15-16: Spaanlastics are surfactants based elastic vesicular drug carrier system.”

Moreover, spanlastics were further described in the introduction as follows:

Lines: (68-72) “Spanlastics are surfactant-based nano-vesicular systems that are modified from niosomes by addition of edge activators [19]. Spanlastics are formed of a Span® (Surface active agent) and an edge activator (Tween 80). Spanlastics can be used to deliver both hydrophilic and hydrophobic drugs which are encapsulated in interior hydrophilic compartment and outer lipid layer, respectively [1]

Point 2: Introduction

The vascular theory of migraine was thrown out many years ago. There are many new mechanisms for migraine - i.e. inflammatory cascade via CGRP, neurokinins, substance P, cortical spreading depression, etc that are the newer studied mechanisms. It is NO longer considered a vascular headache as stated in the introduction

Response 2: We would like to thank the reviewer for his valuable suggestion. The authors edited the part addressing the possible pathophysiological mechanisms underlying migraine. The edited part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

Lines: (33-35)Migraine is a neurovascular disorder characterized by a severe headache, and tri-geminovascular system activation involving the release of calcitonin-gene related peptide (CGRP) [1].”

Lines: (36-43) The exact pathophysiology underlying migraine headache is still not fully understood. For long period, the vascular origin of migraine was adopted relating the headache to prolonged vasodilatation of cranial blood vessels [2]. However, abundant of evidence in the past decades suggested an integrated theory of vascular and neuronal components. The neurogenic inflammation theory involves the release of vasoactive neuropeptides (calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A) causing a cascade of inflammatory tissue responses [3].

Point 3: 2- Zolmitriptan doesn't work by directly causing vasoconstriction only. There are several mechanisms in play such as serotonin agonism, anti-inflammatory mechanisms by reducing levels of CGRP, etc. 

Response 3: We would like to thank the reviewer for his valuable comment. The part discussing zolmitriptan mechanism in migraine treatment was edited according to the reviewer’s suggestion. The edited part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

Lines: (44-51) Treatment usually includes NSAID, ergot alkaloids and 5-HT receptor agonist (triptan) [4].  Triptans including Zolmitriptan are 5HT1B/1D serotonin receptor agonists and considered forefront in migraine treatment [2,5]. It attenuates CGRP levels evoked by electrical stimulation of the trigeminal ganglion and superior sagittal sinus [6]. The agonistic action on 5HT1B/1D receptors inhibits the release of vasoactive neuropeptides by trigeminal nerves, inhibits nociceptive neurotransmission along with vasoconstriction of painfully dilated cerebral blood vessels [7]. Zolmitriptan reduces migraine symptoms efficiently and therefore considered an excellent therapy [8,9]

 

Point 4: Methods

1- what is a splanastic gel?

Response 4: The optimized spanlastic formula according to the Quality by Design study were dispersed in gel base to be applied in the nasal cavity. The gel base was 2% methyl cellulose. This part was highlighted in the methodology and a reference was added as follows (red text herein):

Lines: (150, 152-155) Preparation of Zolmitriptan-loaded spanlastic (ZLS) nasal gel:

A cooling centrifuge was used to remove the unentrapped drug of ZLS dispersion. The residue of ZLS was then dispersed in a gel base (2% methyl cellulose), and stirred until homogenous gel obtained. Meanwhile, a control gel for comparison purpose was prepared by dissolving 2.5 mg of Zolmitriptan in 2 % Methyl cellulose gel and both were kept in refrigerator [13].

Point 5: 2- Can you provide examples of how this method was used in other drug formulations for comparison?

Response 5: We would like to thank the reviewer for his valuable suggestion. Some studies have been added to highlight the utilization of spanlastic formulation for brain and ocular delivery. The added part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

Lines: (76-81) “Abdelmonem et al, formulated granisetron hydrochloride spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve drug bioavailability and brain targeting [16]. Moreover, spanlastics have been utilized for targeting topically applied drug(s) to the posterior segment of the eye [21]. Yassin et al, used spanlastics for more efficient targeting of Carbamazepine to the brain via the intranasal route [22].”

Finally, if there are any modifications, clarifications or explanations required, authors are more than happy to do.

We Thank the editor and the reviewers for their time and effort refining this manuscript to ensure quality presentation and manuscript clarity and readability.

Waiting for your valuable response.

With best regards,

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Saleh and coll. performed a very interesting pharmacological study about the intranasal spanlastic formulation of zolmitriptan created by Quality by Design approach.

Methods seems very appropriate by this reviewer point of view (I'm not an expert of QbD approach).
Under a clinical point of view, in order to improve the quality of paper I've just some limited observations.
1. The benefical effect of triptans is not due to the vasocostrictive effect, but because they stop the sequence of events that leads to CGRP release by trigeminal fibers, with the further sterile inflammation, NO release, pain and vasodilatation. It is an important aspect since the next family of molecules used for the acute treatment of migranie, called ditans, are an evolution of triptans: they have  asimilar antimigraine effect in lack of vasoconstrictive effect. Morover there are some molecues thac can induce migraine irrespectively from the vasodilatative action on brain vassles. It is the case of sildenafil. On the contrery, VIP induces vasodilatation of superficial temporal and middle cerebral arteries, but does not induce migraine attack.
2. It is appropriate to highlight the role of the hepatic first-pass in the limitation of drug bioavailability; however, should also be mentioned the by-pass of gastric absorption, which can be altered during the migraine attack beacuse of gastric palsy.
3. Zolmiriptan effect on migraine is exerted by its activity on perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on nerve terminals. It is a peripheric effect, the drug does not have to pass the BBB. Are the authors aware of this? Veiling the molecule within the barrier could result in side effects in the absence of additional clinical benefit

Author Response

First of all, I would like to thank the reviewers for their valuable comments and suggestions, which in turns, will enhance the accuracy and clarity of the manuscript. We are grateful to the reviewers for their valuable insight and input, which subsequently, would enhance the quality and presentability of our manuscript.

            We hope the revised manuscript meets the journal standards and reviewers’ expectations. The reviewers’ comments have been totally and individually considered. We have uploaded this letter which includes our response to each of the reviewers’ comments. In addition, we have uploaded the revised manuscript. All changes made are shaded yellow to highlight changes from original submission.

Authors’ response to reviewers’ comments

In the following part of this document, the reviewer’s original comments are underlined, and our responses are presented in Italic.

Reviewer 2:

Methods seems very appropriate by this reviewer point of view.

We would like to thank the reviewer for his encouraging comment and positive feedback.

Point 1:

Under a clinical point of view, in order to improve the quality of paper I've just some limited observations.

  1. The benefical effect of triptans is not due to the vasocostrictive effect, but because they stop the sequence of events that leads to CGRP release by trigeminal fibers, with the further sterile inflammation, NO release, pain and vasodilatation. It is an important aspect since the next family of molecules used for the acute treatment of migranie, called ditans, are an evolution of triptans: they have asimilar antimigraine effect in lack of vasoconstrictive effect. Morover there are some molecues thac can induce migraine irrespectively from the vasodilatative action on brain vassles. It is the case of sildenafil. On the contrery, VIP induces vasodilatation of superficial temporal and middle cerebral arteries, but does not induce migraine attack.

Response 1: We would like to thank the reviewer for his valuable comment. The beneficial effect of zolmitriptan has been edited in the revised manuscript highlighting its role on CGRP levels. The added part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

 

Lines: (45-51) Triptans including Zolmitriptan are 5HT1B/1D serotonin receptor agonists and considered forefront in migraine treatment [2,5]. It attenuates CGRP levels evoked by electrical stimulation of the trigeminal ganglion and superior sagittal sinus [6]. The agonistic action on 5HT1B/1D receptors inhibits the release of vasoactive neuropeptides by trigeminal nerves, inhibits nociceptive neurotransmission along with vasoconstriction of painfully dilated cerebral blood vessels [7]. Zolmitriptan reduces migraine symptoms efficiently and therefore considered an excellent therapy [8,9].

Moreover, the neurogenic theory in migraine pathophysiology was addressed as follows.

 

Lines: (36-43) The exact pathophysiology underlying migraine headache is still not fully understood. For long period, the vascular origin of migraine was adopted relating the headache to prolonged vasodilatation of cranial blood vessels [2]. However, abundant of evidence in the past decades suggested an integrated theory of vascular and neuronal components. The neurogenic inflammation theory involves the release of vasoactive neuropeptides (calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A) causing a cascade of inflammatory tissue responses [3].

Point 2:

It is appropriate to highlight the role of the hepatic first-pass in the limitation of drug bioavailability; however, should also be mentioned the by-pass of gastric absorption, which can be altered during the migraine attack beacuse of gastric palsy.

Response 2: We would like to thank the reviewer for his valuable suggestion. The part that discuss the inconsistent absorption of medications due to gastric palsy was added in the revised manuscript. The added part is highlighted in yellow in the updated revised manuscript file. The added part is as follows (red text herein):

 

Lines: (51-55) However, slow onset of action and poor bioavailability (40%) due to hepatic first-pass metabolism are the major drawbacks of Zolmitriptan oral formulations [8]. Zolmitriptan has a half-life of 1-2 hr [10]. Moreover, migraine is accompanied with gastric stasis and vomiting which may cause a delay or inconsistent absorption of medications [11].

Point 3:

Zolmiriptan effect on migraine is exerted by its activity on perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on nerve terminals. It is a peripheric effect, the drug does not have to pass the BBB. Are the authors aware of this? Veiling the molecule within the barrier could result in side effects in the absence of additional clinical benefit.

Response 3: We would like to thank the reviewer for his valuable comment. To the best of our knowledge from literature that 5-HT1B receptors are expressed in the CNS in both presynaptic and post synaptic locations. They are mainly found as presynaptic inhibitory receptors in pain sensory neurons, in the basal ganglia and in the frontal cortex, where they act as terminal auto receptors. They are also expressed outside the CNS on cerebral arteries and other vascular tissues (Vila-Pueyo M. Targeted 5-HT1F Therapies for Migraine. Neurotherapeutics. 2018;15(2):291-303).

zolmitriptan has both peripheral and central actions over the espinal trigeminal nucleus, which is rich in 5-HT1B/D receptors. Thus, the mechanism of action of zolmitriptan is double. (Girotra P, Singh SK, Kumar G. Development of zolmitriptan loaded PLGA/poloxamer nanoparticles for migraine using quality by design approach. International Journal of Biological Macromolecules. 2016;85:92-101; Bergström M, Yates R, Wall A, Kågedal M, Syvänen S, Långström B. Blood-brain barrier penetration of zolmitriptan--modelling of positron emission tomography data. J Pharmacokinet Pharmacodyn. 2006 Feb;33(1):75-91. doi: 10.1007/s10928-005-9001-1. PMID: 16402287.)

Moreover, it was reported that CGRP receptor antagonists, apparently require very high doses to produce significant clinical effects in migraine patients, raises the possibility that those promising components have to cross the BBB in order to exert their effects. This supports the concept that CNS mechanisms are predominantly involved in the migraine pathophysiology (DosSantos, M. F., Holanda-Afonso, R. C., Lima, R. L., DaSilva, A. F., & Moura-Neto, V. (2014). The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders. Frontiers in cellular neuroscience, 8, 302. https://0-doi-org.brum.beds.ac.uk/10.3389/fncel.2014.00302).

Finally, if there are any modifications, clarifications or explanations required, authors are more than happy to do.

We Thank the editor and the reviewers for their time and effort refining this manuscript to ensure quality presentation and manuscript clarity and readability.

Waiting for your valuable response.

With best regards,

 

Author Response File: Author Response.pdf

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.


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