Skip to main content

Advertisement

SpringerLink
Log in

Preparation of melatonin novel-mucoadhesive nanoemulsion used in the treatment of depression

  • Original Paper
  • Published:
Polymer Bulletin Aims and scope Submit manuscript

Abstract

In this current research work has a main aim to develop a novel Melatonin (MLT: BCS class II drug)-loaded nanoemulsion for the improvement in solubility. A developed novel-NE was to evaluate and compare the efficacy of Melatonin-loaded mucoadhesive nanoemulsion (CS-MLT-NE) with Melatonin-loaded nanoemulsion (MLT-NE) and MLT-solution (MLT-S) pharmacodynamically and also determine the quantity of MLT in the brain after the nasal administration. MLT-NE was prepared with the help of an advanced ultrasonication method after the screening of excipients and the development of pseudoternary phase diagram study. We got the optimized nanoformulation via three-factor four-level central-composite design (CCD). We optimized %oil, %Smix, and sonication time (second) based on selected independent variables. Independent and dependent variables were selected and optimized on the basis constraints oil (2.0%), 10%Smix, and 120 s sonication time. The dependent variables found the experimental their values 49.37 ± 4.09 nm (Y1: Globule size), 0.257 ± 0.0004 (Y2: PDI), − 16.20 ± 1.10 mV (Y3: Zeta Potential), and 98.03 ± 0.59% (Y4: %Transmittance), respectively. The shape of optimized-MLT-NE was found spherical with the pH, viscosity, and drug content (7.40 ± 0.08, 37.86 ± 7.01 cp, and 98.27 ± 0.17%), respectively. Zeta-Potential of CS-MLT-NE was altered from −ve to +ve after the addition of CS followed small increment of globule-size. CS-MLT-NE showed the great mucoadhesive nature as compared to MLT-NE, and MLT-S with a retention time of 0.641 min and m/z of 233.20/174.20 for MLT. A linear range was established from 0.50 to 1500.0 ng mL−1 with %accuracy (92.41–98.61%) and inter- and intraday %precision (2.49–4.93%). Cmax was enhanced (AUC)0−24 which was greatly significant (p < 0.001) in the rat’s brain when it compared with i.n. and intravenous-treated group. Moreover, FST (forced swimming, climbing, and immobility) and locomotor activity test of CS-MLT-NE (i.n.) showed highly improved behavioral analysis as compared to the MLT-NE and MLT-S after 24.0 h of study. CS-MLT-NE showed highly significant role (p < 0.001) for the improvement in brain bioavailability and treatment of depression.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2.
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

Abbreviations

MLT:

Melatonin

CS-MLT-NE:

Melatonin-loaded mucoadhesive nanoemulsion

MLT-NE:

Melatonin-loaded nanoemulsion

MLT-S:

MLT-solution

CCD:

Central-composite design

CS:

Chitosan

NEs:

Nanoemulsions

Opt-NE:

Optimized nanoemulsion

C max :

Maximum concentration

AUC:

Area under curve

UHPLC-MS/MS:

Ultra-high performance liquid chromatography mass spectroscopy and mass spectroscopy

ESI:

Electrospray ionization

PDI:

Polydispersity index

SEM:

Scanning electron microscope

TEM:

Transmission electron microscope

HPA:

Hypothalamic Pituitary Adrenal

ZP:

Zeta Potential

PK:

Pharmacokinetic

Kel:

Elimination rate constant

T max :

Time to Cmax

t½:

Half-life

LOD:

Lower limit of detection

LOQ:

Lower limit of quantitation

ANOVA:

Analysis of variance

MCT:

Microcentrifuge tube

IS:

Internal standard

PTPD:

Pseudoternary phase diagram

BBD:

Box–Behnken design

DSC:

Differential scanning calorimetry

MD:

Method development

MV:

Method validation

LLOQ:

Lower limit of quantification

LLOQQC:

Lower limit of quantification for quality control

MQC:

Middle quality control

LQC:

Low quality control

HQC:

High quality control

m/z :

Mass upon charge ratio

i.n.:

Intranasal

LAT:

Test for study of locomotor activity

FST:

Forced swimming test

References

  1. Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet 349:1498–1504

    CAS  PubMed  Google Scholar 

  2. Zeldetz V, Natanel D, Boyko M, Zlotnik A, Shiyntum HN, Grinshpun J, Frank D, Kuts R, Brotfain E, Peiser J (2018) A new method for inducing a depression-like behavior in rats. J Vis Exp 132:57137

    Google Scholar 

  3. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the national comorbidity survey. Arch Gen Psychiatry 51:8–19

    CAS  PubMed  Google Scholar 

  4. Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    CAS  PubMed  Google Scholar 

  5. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25

    CAS  PubMed  Google Scholar 

  6. Barden N (2004) Implication of the hypothalamic–pituitary–adrenal axis in the physiopathology of depression. J Psychiatry Neurosci 29:185–193

    PubMed  PubMed Central  Google Scholar 

  7. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006) Melatonin: nature’s most versatile biological signal? FEBS J 273:2813–2838

    CAS  PubMed  Google Scholar 

  8. Nowak JZ, Zawilska JB (1998) Melatonin and its physiological and therapeutic properties. Pharm World Sci 20:18–27

    CAS  PubMed  Google Scholar 

  9. Macchi MM, Bruce JN (2004) Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 25:177–195

    CAS  PubMed  Google Scholar 

  10. Altindal DC, Gümüşderelioğlu M (2016) Melatonin releasing PLGA micro/nanoparticles and their effect on osteosarcoma cells. J Microencapsul 33(1):53–63

    CAS  PubMed  Google Scholar 

  11. Rezzani R, Rodella LF, Fraschini F, Gasco MR, Demartini G, Musicanti C, Reiter RJ (2009) Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage. J Pineal Res 46(3):255–261

    CAS  PubMed  Google Scholar 

  12. Mantovani M, Pértile R, Calixto JB, Santos ARS, Rodrigues ALS (2003) Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate receptors and the L-arginine-nitric oxide pathway. Neurosci Lett 343(1):1–4

    CAS  PubMed  Google Scholar 

  13. Ergun Y, Ergun UG, Orhan FO, Kucuk E (2006) Co-administration of a nitric oxide synthase inhibitor and melatonin exerts an additive antidepressant-like effect in the mouse forced swim test. Med Sci Monit 12:BR307–BR312

    CAS  PubMed  Google Scholar 

  14. Mantovani M, Kaster MP, Pertile R, Calixto JB, Rodrigues AL, Santos AR (2006) Mechanisms involved in the antinociception caused by melatonin in mice. J Pineal Res 41:382–389

    CAS  PubMed  Google Scholar 

  15. Golombek DA, Pevet P, Cardinali DP (1996) Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Rev 20:403–412

    CAS  PubMed  Google Scholar 

  16. Papp M, Litwa E, Gruca P, Mocaer E (2006) Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol 17:9–18

    CAS  PubMed  Google Scholar 

  17. Claustrat B, Chazot G, Brun J, Jordan D, Sassolas G (1984) A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression. Biol Psychiatry 19:1215–1228

    CAS  PubMed  Google Scholar 

  18. Beck-Friis J, Kjellman BF, Aperia B, Unden F, von Rosen D, Ljunggren JG, Wetterberg L (1985) Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome. Acta Psychiatr Scand 71:319–330

    CAS  PubMed  Google Scholar 

  19. Brown R, Kocsis JH, Caroff S, Amsterdam J, Winokur A, Stokes PE, Frazer A (1985) Differences in nocturnal melatonin secretion between melancholic depressed patients and control subjects. Am J Psychiatry 142:811–816

    CAS  PubMed  Google Scholar 

  20. Carvalho LA, Gorenstein C, Moreno R, Pariante C, Markus RP (2008) Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol. https://doi.org/10.1177/0269881108089871

    Article  PubMed  Google Scholar 

  21. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr (2000) The absolute bioavailability of oral melatonin. J Clin Pharmacol 40(7):781–784

    CAS  PubMed  Google Scholar 

  22. Gao HL, Jiang XG (2017) The progress of novel drug delivery systems. Yao Xue Xue Bao 52(2):181–188

    PubMed  Google Scholar 

  23. Talkar S, Dhoble S, Majumdar A, Patravale V (2018) Transmucosal nanoparticles: toxicological overview. Adv Exp Med Biol 1048:37–57

    CAS  PubMed  Google Scholar 

  24. Ahmad N, Ahmad R, Alam MA, Samim M, Iqbal Z, Ahmad FJ (2016) Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. Int J Biol Macromol 88:320–332

    CAS  PubMed  Google Scholar 

  25. Ahmad N, Ahmad R, Alrasheed RA, Almatar HMA, Al-Ramadan AS, Amir M, Sarafroz M (2020) Quantification and evaluations of catechin hydrate polymeric nanoparticles used in brain targeting for the treatment of epilepsy. Pharmaceutics 12(3):203

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ahmad N, Umar S, Ashafaq M, Akhtar M, Iqbal Z, Samim M, Ahmad FJ (2013) A comparative study of PNIPAM nanoparticles of curcumin, demethoxycurcumin, and bisdemethoxycurcumin and their effects on oxidative stress markers in experimental stroke. Protoplasma 250:1327–1338

    CAS  PubMed  Google Scholar 

  27. Qian C, McClements DJ (2011) Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: factors affecting particle size. Food Hydrocoll 25(5):1000–1008

    CAS  Google Scholar 

  28. Tadros T, Izquierdo P, Esquena J, Solans C (2004) Formation and stability of nanoemulsions. Adv Colloid Interface Sci 108–109:303–318

    PubMed  Google Scholar 

  29. McClements DJ (2012) Nanoemulsions versus microemulsions: terminology, differences, and similarities. Soft Matter 8:1719–1729

    CAS  Google Scholar 

  30. Sivakumar M, Tang SY, Tan KW (2014) Cavitation technology—a greener processing technique for the generation of pharmaceutical nanoemulsions. Ultrason Sonochem 21(6):2069–2083

    CAS  PubMed  Google Scholar 

  31. Zandi M, Dardmeh N, Pirsa S, Almasi H (2017) Identification of cardamom encapsulated alginate-whey protein concentrates microcapsule release kinetics and mechanism during storage, stew process and oral consumption. J Food Process Eng 40(1):e12314. https://doi.org/10.1111/jfpe.12314

    Article  CAS  Google Scholar 

  32. Sani IK, Geshlaghi SP, Pirsa S, Asdagh A (2021) Composite film based on potato starch/apple peel pectin/ZrO2 nanoparticles/microencapsulated Zataria multiflora essential oil; investigation of physicochemical properties and use in quail meat packaging. Food Hydrocoll 117:106719. https://doi.org/10.1016/j.foodhyd.2021.106719

    Article  CAS  Google Scholar 

  33. Sharifi KA, Pirsa S (2021) Biodegradable film of black mulberry pulp pectin/chlorophyll of black mulberry leaf encapsulated with carboxymethylcellulose/silica nanoparticles: Investigation of physicochemical and antimicrobial properties. Mater Chem Phys 267:124580. https://doi.org/10.1016/j.matchemphys.2021.124580

    Article  CAS  Google Scholar 

  34. Sani IK, Khaledabad MA, Pirsa S, Kia EM (2020) Physico-chemical, organoleptic, antioxidative and release characteristics of flavoured yoghurt enriched with microencapsulated Melissa officinalis essential oil. Int J Dairy Technol 73(3):542–551. https://doi.org/10.1111/1471-0307.12691

    Article  CAS  Google Scholar 

  35. Sani IK, Alizadeh M, Pirsa S, Kia EM (2019) Impact of operating parameters and wall material components on the characteristics of microencapsulated Melissa officinalis essential oil. Flavour Fragr J 34(2):104–112. https://doi.org/10.1002/ffj.3482

    Article  CAS  Google Scholar 

  36. Fernandez-Urrusuno R, Romani D, Calvo D (1999) Development of a freeze dried formulation of insulin-loaded chitosan nanoparticles intended for nasal administration. STP Pharm Sci 9:429–436

    CAS  Google Scholar 

  37. Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK, Ali J (2013) Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci 48(3):393–405

    CAS  PubMed  Google Scholar 

  38. Ahmad N (2017) Rasagiline-encapsulated chitosan-coated PLGA nanoparticles targeted to the brain in the treatment of Parkinson’s disease. J Liq Chromatogr Relat Technol 40(13):677–690

    CAS  Google Scholar 

  39. Eriksson K, Ostin A, Levin J-O (2003) Quantification of melatonin in human saliva by liquid chromatography–tandem mass spectrometry using stable isotope dilution. J Chromatogr B Anal Technol Biomed Life Sci 794(1):115–123

    CAS  Google Scholar 

  40. Girgin B, Korkmaz O, Yavaşer R, Karagözler AA (2016) Production and drug release assessment of melatonin-loaded alginate/gum Arabic beads. J Turkish Chem Soc Sect A Chem (JOTCSA) 3(3):205–216

    CAS  Google Scholar 

  41. Ahmed S, Gull A, Alam M, Aqil M, Sultana Y (2018) Ultrasonically tailored, chemically engineered and “QbD” enabled fabrication of agomelatine nanoemulsion; optimization, characterization, ex-vivo permeation and stability study. Ultrason Sonochem 41:213–226

    CAS  PubMed  Google Scholar 

  42. Kumar S, Ali J, Baboota S (2016) Design Expert® supported optimization and predictive analysis of selegiline nanoemulsion via the olfactory region with enhanced behavioural performance in Parkinson’s disease. Nanotechnology 435101

  43. Ahmad N, Ahmad R, Al-Qudaihi A, Alaseel SE, Fita IZ, Khalid MS, Pottoo FH (2019) Preparation of a novel curcumin nanoemulsion by ultrasonication and its comparative effects in wound healing and the treatment of inflammation. RSC Adv 9:20192–20206

    CAS  PubMed  PubMed Central  Google Scholar 

  44. US FDA. Guidance for Industry Bioanalytical Method Validation. 2001. Available online: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf. Accessed 24 May 2018

  45. Haque S, Md S, Sahni JK, Ali J, Baboota S (2014) Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression. J Psychiatr Res 48:1–12

    PubMed  Google Scholar 

  46. Pandey YR, Kumar S, Gupta BK, Ali J, Baboota S (2016) Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation. Nanotechnology 27:025102

    PubMed  Google Scholar 

  47. Alam MI, Baboota S, Ahuja A, Ali M, Ali J, Sahni JK (2012) Intranasal administration of nanostructured lipid carriers containing CNS acting drug: pharmacodynamic studies and estimation in blood and brain. J Psychiatr Res 46(9):1133–1138

    PubMed  Google Scholar 

  48. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    CAS  PubMed  Google Scholar 

  49. Faiyazuddin M, Ahmad N, Khar RK, Bhatnagar A, Ahmad FJ (2012) Stabilized terbutaline submicron drug aerosol for deep lungs deposition: drug assay, pulmonokinetics and biodistribution by UHPLC/ESI-q-TOF-MS method. Int J Pharm 434(1–2):59–69

    CAS  PubMed  Google Scholar 

  50. Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 177(3):245e55

    Google Scholar 

  51. Khattabi AM, Talib WH, Alqdeimat DA (2018) The effect of polymer length on the in vitro characteristics of a drug loaded and targeted silica nanoparticles. Saudi Pharm J 26(7):1022–1026

    PubMed  PubMed Central  Google Scholar 

  52. Li Y, Zhao X, Zu Y et al (2017) Melatonin-loaded silica coated with hydroxypropyl methylcellulose phthalate for enhanced oral bioavailability: preparation, and in vitro-in vivo evaluation. Eur J Pharm Biopharm 112:58–66

    CAS  PubMed  Google Scholar 

  53. Uchendu EE, Keller ERJ (2016) Melatonin-loaded alginate beads improve cryopreservation of yam (Dioscorea alata and D. cayenensis). Cryo Lett 37(2):77–87

    CAS  Google Scholar 

  54. Maggio ET (2011) Intranasal administration of active agents to the central nervous system. US patent 2011; 0129462A1

  55. Simonneaux V, Ribelayga C (2003) Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 55:325–395

    CAS  PubMed  Google Scholar 

  56. Tonon AC, Pilz LK, Markus RP, Hidalgo MP, Elisabetsky E (2021) Melatonin and depression: a translational perspective from animal models to clinical studies. Front Psychiatry 12:638981

    PubMed  PubMed Central  Google Scholar 

  57. Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 121(1):66e72

    Google Scholar 

  58. Si M, Sun Q, Ding H, Cao C, Huang M, Wang Q, Yang H, Yao Y (2020) Melatonin-loaded nanoparticles for enhanced antidepressant effects and HPA hormone modulation. Adv Polym Technol Article ID 4789475: 1–9

  59. Hoehn R, Monse M, Pohl E, Wranik S, Wilker B, Keitsch S, Soddemann M, Kornhuber J, Kohnen M, Edwards MJ, Grassmé H, Gulbins E (2016) Melatonin acts as an antidepressant by inhibition of the acid sphingomyelinase/ceramide system. Neurosignals 24(1):48–58

    PubMed  Google Scholar 

  60. Favero G, Moretti E, Bonomini F, Reiter RJ, Rodella LF, Rezzani R (2018) Promising antineoplastic actions of melatonin. Front Pharmacol 9:1086

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fic M, Podhorska-Okolow M, Dziegiel P, Gebarowska E, Wysocka T, Drag-Zalesinska M, Zabel M (2007) Effect of melatonin on cytotoxicity of doxorubicin toward selected cell lines (human keratinocytes, lung cancer cell line A-549, laryngeal cancer cell line Hep-2). In Vivo 21(3):513–518

    CAS  PubMed  Google Scholar 

  62. Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T (2003) In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials 24(7):1121–1131

    CAS  PubMed  Google Scholar 

  63. Alshetaili AS (2021) Gefitinib loaded PLGA and chitosan coated PLGA nanoparticles with magnified cytotoxicity against A549 lung cancer cell lines. Saudi J Biol Sci 28(9):5065–5073. https://doi.org/10.1016/j.sjbs.2021.05.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We have received the animal ethical approval (IRB-UGS-2021-05-125) from Ethical Committee of IAU (Imam Abdulrahman Bin Faisal University) to study PK and PD study performed under IAU-animal ethical guidelines.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Kingdom of Saudi Arabia

    Niyaz Ahmad, Ayman Makki Al Ramadhan, Mohammed Zaki Alaradi & Mohammed Riyad Al Hammad

  2. Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia

    Mohammed Saifuddin Khalid

  3. Department of Respiratory Care, College of Applied Medical Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

    Khalid Ansari & Yousef D. Alqurashi

  4. Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia

    Mohd Faiyaz Khan & Ahmed A. Albassam

  5. Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia

    Mohammad Javed Ansari

  6. Department of Physics, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, PO Box: 1982, Dammam, 31441, Saudi Arabia

    Sultan Akhtar

  7. College of Medicine, Era Medical University, Lucknow, Uttar Pradesh, 226003, India

    Mubah Dilshad

Authors
  1. Niyaz Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammed Saifuddin Khalid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayman Makki Al Ramadhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammed Zaki Alaradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammed Riyad Al Hammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Khalid Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yousef D. Alqurashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohd Faiyaz Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmed A. Albassam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mohammad Javed Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sultan Akhtar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mubah Dilshad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niyaz Ahmad.

Ethics declarations

Conflict of interest

All the authors declared, they do not have any conflict of interest with each other.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahmad, N., Khalid, M.S., Al Ramadhan, A.M. et al. Preparation of melatonin novel-mucoadhesive nanoemulsion used in the treatment of depression. Polym. Bull. 80, 8093–8132 (2023). https://doi.org/10.1007/s00289-022-04436-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00289-022-04436-3

Keywords

Search

Navigation