Skip to content
2000
Volume 13, Issue 3
  • ISSN: 2211-7385
  • E-ISSN: 2211-7393

Abstract

Background

Nimodipine (ND) is a vasodilator drug that is used for acute subarachnoid hemorrhage. It has a predominant hydrophobic property, causing low solubility and low bioavailability. Spanlastics are elastic nanovesicular systems based on non-ionic surfactants and edge activators as major components. The goal of this work is to formulate ND as spanlastic nanovesicles to improve the drug's bioavailability.

Methods

Spanlastic formulations containing ND were prepared by using the ethanol injection method. The composition of the ND formulation includes Span60 as a nonionic surfactant and Tween 20 as edge activators in different ratios. Stabilizers like Soluplus (SP) are used in some formulations and then compared with other formulations without that stabilizer. The evaluation study involved Vesicle Size (VS), PolyDispersity Index (PDI), and Entrapment Efficiency (%EE). Then, the optimized formula was subjected to an release study and zeta potential, additionally comparing the optimized formula with the formula without soluplus in the same concentration in Scanning Electron Microscopy (SEM), solubility study, Deformability Index (DI), and stability study.

Results

The results indicated a significant shift in some evaluation criteria and a non-significant change in other characterizations, including the difference in polymer ratio, sonication time (ST), and the existence of a stabilizer. The best formula, F27, was found to have VS, PDI, %EE, and zeta potential of 125.7±0.29 nm, 0.4744±0.002, and 85.43±0.17% and -20.01 ± 0.89 mV, respectively. The photomicrographs of the prepared spanlastic revealed a more uniform and spherical spanlastic, indicating a greater capacity for continuous release. With the addition of Soluplus, the formula became more stable in one month and had a higher deformability index.

Discussion

A significant shift was observed in both and PDI. As the stabilizer concentration increases, and PDI will decrease. The non-significant shift was noted in the %EE with the presence of a stabilizer. Soluplus has the ability to spontaneously self-assemble into spherical particles. Additionally, PEG 6000, as a component of Soluplus's structure, has a tendency to form strong or tightly bound bilayers and prevent aggregation and formulation of large vesicles.

Conclusion

This study explains the accessibility of the formulation of ND as spanlastic nanovesicles by using the ethanol injection method. This spanlastic formulation contains non-ionic surfactants and edge activators (Span 40 and Tween 20) in varying ratios. To get a stable formula, Soluplus is added to prevent the development of crystals and agglomeration.

Loading

Article metrics loading...

/content/journals/pnt/10.2174/0122117385348551241028102256
2024-11-04
2025-10-18
Loading full text...

Full text loading...

References

  1. RaoB.N. ReddyK.R. MounikaB. FathimaS.R. TejaswiniA. Vesicular drug delivery system: a review.Int. J. Chemtech Res.2019125395310.20902/IJCTR.2019.120505
    [Google Scholar]
  2. KonathamT.K.R. AlapatiS. A critical analysis of the vesicular drug delivery system: recent advancements and prospects for the future.JIAPS20238351210.37022/jiaps.v8i3.480
    [Google Scholar]
  3. RenY. NieL. ZhuS. ZhangX. Nanovesicles-Mediated Drug Delivery for Oral Bioavailability Enhancement.Int. J. Nanomedicine2022174861487710.2147/IJN.S38219236262189
    [Google Scholar]
  4. PramodP.S. TakamuraK. ChaphekarS. BalasubramanianN. JayakannanM. Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells.Biomacromolecules201213113627364010.1021/bm301583s23082727
    [Google Scholar]
  5. AnsariM.D. SaifiZ. PanditJ. KhanI. SolankiP. SultanaY. AqilM. Spanlastics a Novel Nanovesicular Carrier: Its Potential Application and Emerging Trends in Therapeutic Delivery.AAPS PharmSciTech202223411210.1208/s12249‑022‑02217‑935411425
    [Google Scholar]
  6. TayelS.A. El-NabarawiM.A. TadrosM.I. Abd-ElsalamW.H. Duodenum-triggered delivery of pravastatin sodium via enteric surface-coated nanovesicular spanlastic dispersions: Development, characterization and pharmacokinetic assessments.Int. J. Pharm.20154831-2778810.1016/j.ijpharm.2015.02.01225666025
    [Google Scholar]
  7. KamathK. JainS. ShabarayaA. Spanlastics: a modern formulation approach in drug delivery.Eur. J. Pharm. Med. Res.2023109610.20959/wjpr202320‑30212
    [Google Scholar]
  8. MosallamS. AlbashR. AbdelbariM.A. Advanced Vesicular Systems for Antifungal Drug Delivery.AAPS PharmSciTech202223620610.1208/s12249‑022‑02357‑y35896903
    [Google Scholar]
  9. AlhammidS.N.A. KassabH.J. HusseinL.S. HaissM.A. AlkufiH. Spanlastics Nanovesicles: An Emerging and Innovative Approach for Drug Delivery.Maaen Journal for Medical Sciences202323910.55810/2789‑9136.1027
    [Google Scholar]
  10. BatzriS. KornE.D. Single bilayer liposomes prepared without sonication.Biochim. Biophys. Acta Biomembr.197329841015101910.1016/0005‑2736(73)90408‑24738145
    [Google Scholar]
  11. JustoO.R. MoraesÂ.M. Analysis of process parameters on the characteristics of liposomes prepared by ethanol injection with a view to process scale-up: Effect of temperature and batch volume.Chem. Eng. Res. Des.201189678579210.1016/j.cherd.2010.09.018
    [Google Scholar]
  12. PonsM. ForadadaM. EstelrichJ. Liposomes obtained by the ethanol injection method.Int. J. Pharm.1993951-3515610.1016/0378‑5173(93)90389‑W
    [Google Scholar]
  13. Jaafar-MaalejC. DiabR. AndrieuV. ElaissariA. FessiH. Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation.J. Liposome Res.201020322824310.3109/0898210090334792319899957
    [Google Scholar]
  14. SalaM. MiladiK. AgustiG. ElaissariA. FessiH. Preparation of liposomes: A comparative study between the double solvent displacement and the conventional ethanol injection—From laboratory scale to large scale.Colloids Surf. A Physicochem. Eng. Asp.2017524717810.1016/j.colsurfa.2017.02.084
    [Google Scholar]
  15. SchubertM. Müller-GoymannC.C. Solvent injection as a new approach for manufacturing lipid nanoparticles – evaluation of the method and process parameters.Eur. J. Pharm. Biopharm.200355112513110.1016/S0939‑6411(02)00130‑312551713
    [Google Scholar]
  16. SebaalyC. Greige-GergesH. StainmesseS. FessiH. CharcossetC. Effect of composition, hydrogenation of phospholipids and lyophilization on the characteristics of eugenol-loaded liposomes prepared by ethanol injection method.Food Biosci.20161511010.1016/j.fbio.2016.04.005
    [Google Scholar]
  17. PandoD. MatosM. GutiérrezG. PazosC. Formulation of resveratrol entrapped niosomes for topical use.Colloids Surf. B Biointerfaces201512839840410.1016/j.colsurfb.2015.02.03725766923
    [Google Scholar]
  18. GentineP. Bourel-BonnetL. FrischB. Modified and derived ethanol injection toward liposomes: development of the process.J. Liposome Res.2013231111910.3109/08982104.2012.71729823020802
    [Google Scholar]
  19. CharcossetC. JubanA. ValourJ.P. UrbaniakS. FessiH. Preparation of liposomes at large scale using the ethanol injection method: Effect of scale-up and injection devices.Chem. Eng. Res. Des.20159450851510.1016/j.cherd.2014.09.008
    [Google Scholar]
  20. ToniazzoT. PeresM.S. RamosA.P. PinhoS.C. Encapsulation of quercetin in liposomes by ethanol injection and physicochemical characterization of dispersions and lyophilized vesicles.Food Biosci.201719172510.1016/j.fbio.2017.05.003
    [Google Scholar]
  21. YangK. DelaneyJ.T. SchubertU.S. FahrA. Fast high-throughput screening of temoporfin-loaded liposomal formulations prepared by ethanol injection method.J. Liposome Res.2012221314110.3109/08982104.2011.58431921682653
    [Google Scholar]
  22. FanM. XuS. XiaS. ZhangX. Preparation of salidroside nano-liposomes by ethanol injection method and in vitro release study.Eur. Food Res. Technol.2008227116717410.1007/s00217‑007‑0706‑9
    [Google Scholar]
  23. GhanbarzadehS. ValizadehH. Zakeri-MilaniP. Sirolimus nano liposomes: optimization of sirolimus nano liposome prepared by modified ethanol injection method using responce suerface methodology.Pharm. Ind.2013201375
    [Google Scholar]
  24. MaitaniY. SoedaH. JunpingW. TakayamaK. Modified ethanol injection method for liposomes containing β-sitosterol β-d-glucoside.J. Liposome Res.200111111512510.1081/LPR‑10010317419530923
    [Google Scholar]
  25. BaiC. LuoG. LiuY. ZhaoS. ZhuX. ZhaoQ. PengH. XiongH. A comparison investigation of coix seed oil liposomes prepared by five different methods.J. Dispers. Sci. Technol.201536113614510.1080/01932691.2014.893524
    [Google Scholar]
  26. MoghassemiS. HadjizadehA. Nano-niosomes as nanoscale drug delivery systems: An illustrated review.J. Control. Release2014185223610.1016/j.jconrel.2014.04.01524747765
    [Google Scholar]
  27. TuomelaA. HirvonenJ. PeltonenL. Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability.Pharmaceutics2016821610.3390/pharmaceutics802001627213435
    [Google Scholar]
  28. KimM.S. Soluplus-coated colloidal silica nanomatrix system for enhanced supersaturation and oral absorption of poorly water-soluble drugs.Artif. Cells Nanomed. Biotechnol.201341636336710.3109/21691401.2012.76236923336707
    [Google Scholar]
  29. YangH. TengF. WangP. TianB. LinX. HuX. ZhangL. ZhangK. ZhangY. TangX. Investigation of a nanosuspension stabilized by Soluplus® to improve bioavailability.Int. J. Pharm.20144771-2889510.1016/j.ijpharm.2014.10.02525455766
    [Google Scholar]
  30. MoffatA.C. OsseltonM.D. WiddopB. WattsJ. Clarke’s analysis of drugs and poisons.Pharmaceutical Press : London2011
    [Google Scholar]
  31. MahmoudS.H. JiX. IsseF.A. Nimodipine Pharmacokinetic Variability in Various Patient Populations.Drugs R D.202020430731810.1007/s40268‑020‑00322‑332902829
    [Google Scholar]
  32. RathodN. BorkhatariaC. ManekR. PatelV. PatelN. PatelK. PaunJ. SakhiyaD. Study on the Correlation Between Nimodipine (BCS Class II) Solubility, Dissolution Improvement, and Brain Tissue Concentration Through Cocrystallization.J. Pharm. Innov.20231842235224810.1007/s12247‑023‑09786‑7
    [Google Scholar]
  33. RamadhanS.H. Al-KinaniK.K. Statistical Optimization and Characterization of Nimodipine Transferosomes.Al-Rafidain Journal of Medical Sciences202471S778310.54133/ajms.v7i1(Special).1015
    [Google Scholar]
  34. ChalikwarS.S. BelgamwarV.S. TaleleV.R. SuranaS.J. PatilM.U. Formulation and evaluation of Nimodipine-loaded solid lipid nanoparticles delivered via lymphatic transport system.Colloids Surf. B Biointerfaces20129710911610.1016/j.colsurfb.2012.04.02722609590
    [Google Scholar]
  35. AlhagiesaA.W. GhareebM.M. The Formulation and Characterization of Nimodipine Nanoparticles for the Enhancement of solubility and dissolution rate.Iraqi J Pharm Sci202130210.31351/vol30iss2pp143‑152
    [Google Scholar]
  36. SandhyaM. RamasamyD. SudhakarK. KadirgamaK. HarunW.S.W. Ultrasonication an intensifying tool for preparation of stable nanofluids and study the time influence on distinct properties of graphene nanofluids – A systematic overview.Ultrason. Sonochem.20217310547910.1016/j.ultsonch.2021.10547933578278
    [Google Scholar]
  37. AlzalzaleeR.A. KassabH.J. Effect of Polymer Type and Concentration on Preparation of Cilnidipine Nanoparticle (A Preformulation Study).Hist. Med.2023911902190610.17720/2409‑5834.v9.1.2023.243
    [Google Scholar]
  38. AlshahraniS.M. Preparation, characterization and in vivo anti-inflammatory studies of ostrich oil based nanoemulsion.J. Oleo Sci.201968320320810.5650/jos.ess1821330760670
    [Google Scholar]
  39. Al-ShaibaniA.J.N. GhareebM.M. Formulation, in vitro and in vivo evaluation of olanzapine nanoparticles dissolving microneedles for transdermal delivery.Pharmacia20247111310.3897/pharmacia.71.e120974
    [Google Scholar]
  40. MahmoodH.S. GhareebM.M. HamzahZ.O. Formulation and in-vitro evaluation of flurbiprofen nanoparticles for transdermal delivery.J Complement Med Res.2020115223
    [Google Scholar]
  41. MichaelsA.S. NelsenL. PorterM.C. Ultrafiltration.In: Membrane Processes in Industry and Biomedicine: Proceedings of a Symposium held at the 160th National Meeting of the American Chemical Society, under the sponsorship of the Division of Industrial and Engineering Chemistry, Chicago, IllinoisSpringer1970197232
    [Google Scholar]
  42. RashidA.M. Abdal-HammidS.N. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility.Iraqi J Pharm Sci201928210.31351/vol28iss2pp124‑133
    [Google Scholar]
  43. KaramiS. RostamizadehK. ShademaniN. ParsaM. Synthesis and investigation of the curcumin-loaded magnetic lipid nanoparticles and their cytotoxicity assessment on human breast carcinoma cell line.Jundishapur J. Nat. Pharm. Prod.202015210.5812/jjnpp.91886
    [Google Scholar]
  44. AbbasI.K. Abd-AlHammidS.N. Design, Optimization and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Bilastine.Iraqi J Pharm Sci20233216476
    [Google Scholar]
  45. GhareebM.M. Formulation and characterization of isradipine as oral nanoemulsion.Iraqi J Pharm Sci202029114353
    [Google Scholar]
  46. NoorA.H. GhareebM.M. Formulation and evaluation of ondansetron HCl nanoparticles for transdermal delivery.Iraqi J Pharm Sci202029270910.31351/vol29iss2pp70‑79
    [Google Scholar]
  47. AbdulbaqiM.R. KassabH.J. AbdulelahF.M. Preparation and evaluation of zinc oxide (ZnO) metal nanoparticles carriers for azilsartan.Arch. Venez. Farmacol. Ter.202140435336010.5281/zenodo.5218710
    [Google Scholar]
  48. AbdelrahmanF.E. ElsayedI. GadM.K. ElshafeeyA.H. MohamedM.I. Response surface optimization, Ex vivo and in vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone.Int. J. Pharm.20175301-211110.1016/j.ijpharm.2017.07.05028733244
    [Google Scholar]
  49. GorajanaA. RajendranA. RaoN.K. Preperation and in vitro evaluation of solid dispersions of nimodipine using PEG 4000 and PVP K30.Asian J Pharm Res Heal Care201022163169
    [Google Scholar]
  50. Shekhar DeyN. MukherjeeB. MajiR. Sankar SatapathyB. Development of Linker-Conjugated Nanosize Lipid Vesicles: A Strategy for Cell Selective Treatment in Breast Cancer.Curr. Cancer Drug Targets201616435737210.2174/156800961666615110612060626548758
    [Google Scholar]
  51. KakkarS. KaurI.P. Spanlastics—A novel nanovesicular carrier system for ocular delivery.Int. J. Pharm.20114131-220221010.1016/j.ijpharm.2011.04.02721540093
    [Google Scholar]
  52. Al-mahallawiA.M. KhowessahO.M. ShoukriR.A. Nano-transfersomal ciprofloxacin loaded vesicles for non-invasive trans-tympanic ototopical delivery: In-vitro optimization, ex-vivo permeation studies, and in-vivo assessment.Int. J. Pharm.20144721-230431410.1016/j.ijpharm.2014.06.04124971692
    [Google Scholar]
  53. GuptaP.N. MishraV. RawatA. DubeyP. MahorS. JainS. ChatterjiD.P. VyasS.P. Non-invasive vaccine delivery in transfersomes, niosomes and liposomes: a comparative study.Int. J. Pharm.20052931-2738210.1016/j.ijpharm.2004.12.02215778046
    [Google Scholar]
  54. ReddyM.S. GurramA.K. DeshpandeP.B. KarS.S. NayakU.Y. UdupaN. Role of components in the formation of self-microemulsifying drug delivery systems.Indian J. Pharm. Sci.201577324925710.4103/0250‑474X.15959626180269
    [Google Scholar]
  55. AbdulqaderA. SultanN.A.R. Preparation and characterization of Posaconazole as a Nano-micelles using d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS).Iraqi J. Pharm Sci.202332Suppl.263210.31351/vol32issSuppl.pp26‑32
    [Google Scholar]
  56. ManarT.A. HananK.J. Optimizing intranasal amisulpride loaded nanostructured lipid carriers: Formulation, development, and characterization parameters.Pharm. Nanotechnol.20242024116
    [Google Scholar]
  57. SalmanA.H. Al-GawhariF.J. Al-kinaniK.K. The effect of formulation and process variables on prepared etoricoxib ‎Nanosponges.J. Adv. Pharm. Educ. Res.2021112828710.51847/Q0QRKUV2kQ
    [Google Scholar]
  58. AhmedM.Z. GuptaA. WarsiM.H. AliA.M.A. HasanN. AhmadF.J. ZafarA. JainG.K. Nano Matrix Soft Confectionary for Oral Supplementation of Vitamin D: Stability and Sensory Analysis.Gels20228525010.3390/gels805025035621548
    [Google Scholar]
  59. GurpreetK. SinghS.K. Review of nanoemulsion formulation and characterization techniques.Indian J. Pharm. Sci.201880510.4172/pharmaceutical‑sciences.1000422
    [Google Scholar]
  60. MohamedH.B. El-ShanawanyS.M. HamadM.A. ElsabahyM. Niosomes: A Strategy toward Prevention of Clinically Significant Drug Incompatibilities.Sci. Rep.201771634010.1038/s41598‑017‑06955‑w28740102
    [Google Scholar]
  61. UgorjiO.L. OkoyeO.I. NwangwuC. AgboC.P. KenechukwuF.C. Soluplus-stabilized 5-fluorouracil-entrapped niosomal formulations prepared via active and passive loading techniques: comparative physico-chemical evaluation.J. Dispers. Sci. Technol.202445589189910.1080/01932691.2023.2186427
    [Google Scholar]
  62. MateosH. GentileL. MurgiaS. ColafemminaG. ColluM. SmetsJ. PalazzoG. Understanding the self-assembly of the polymeric drug solubilizer Soluplus®.J. Colloid Interface Sci.202261122423410.1016/j.jcis.2021.12.01634952275
    [Google Scholar]
  63. Pereira-SilvaM. Diaz-GomezL. Blanco-FernandezB. FerreirósA. VeigaF. ConcheiroA. Paiva-SantosA.C. Alvarez-LorenzoC. Cancer cell membrane-modified Soluplus® micelles for gemcitabine delivery to pancreatic cancer using a prodrug approach.Int. J. Pharm.202466212452910.1016/j.ijpharm.2024.12452939084580
    [Google Scholar]
  64. DanaeiM. DehghankholdM. AtaeiS. Hasanzadeh DavaraniF. JavanmardR. DokhaniA. KhorasaniS. MozafariM.R. Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems.Pharmaceutics20181025710.3390/pharmaceutics1002005729783687
    [Google Scholar]
  65. ObitteN.C. OfokansiK.C. KenechukwuF.C. Development and Evaluation of Novel Self-Nanoemulsifying Drug Delivery Systems Based on a Homolipid from Capra hircus and Its Admixtures with Melon Oil for the Delivery of Indomethacin.J. Pharm. (Cairo)201420141910.1155/2014/34048626556192
    [Google Scholar]
  66. AltamimiM.A. NeauS.H. Investigation of the in vitro performance difference of drug-Soluplus® and drug-PEG 6000 dispersions when prepared using spray drying or lyophilization.Saudi Pharm. J.201725341943910.1016/j.jsps.2016.09.01328344498
    [Google Scholar]
  67. LuB. HuangY. ChenZ. YeJ. XuH. ChenW. LongX. Niosomal Nanocarriers for Enhanced Skin Delivery of Quercetin with Functions of Anti-Tyrosinase and Antioxidant.Molecules20192412232210.3390/molecules2412232231238562
    [Google Scholar]
  68. KenechukwuF.C. KaluC.F. MomohM.A. OnahI.A. AttamaA.A. OkoreV.C. Novel Bos indicus fat-based nanoparticulate lipospheres of miconazole nitrate as enhanced mucoadhesive therapy for oral candidiasis.Biointerface Res. Appl. Chem.20221312410.33263/BRIAC131.024
    [Google Scholar]
  69. JinX. ZhouB. XueL. SanW. Soluplus® micelles as a potential drug delivery system for reversal of resistant tumor.Biomed. Pharmacother.20156938839510.1016/j.biopha.2014.12.02825661387
    [Google Scholar]
  70. NémethZ. CsókaI. Semnani JazaniR. SiposB. HaspelH. KozmaG. KónyaZ. DobóD.G. Quality by Design-Driven Zeta Potential Optimisation Study of Liposomes with Charge Imparting Membrane Additives.Pharmaceutics2022149179810.3390/pharmaceutics1409179836145546
    [Google Scholar]
  71. SalimF.F. RajabN.A. Formulation and Characterization of Piroxicam as Self-Nano Emulsifying Drug Delivery SystemIraqi J Pharm Sci202029110.31351/vol29iss1pp174‑183
    [Google Scholar]
  72. SharmaO.P. PatelV. MehtaT. Design of experiment approach in development of febuxostat nanocrystal: Application of Soluplus® as stabilizer.Powder Technol.201630239640510.1016/j.powtec.2016.09.004
    [Google Scholar]
  73. GhareebM.M. NeamahA.J. Formulation and characterization of nimodipine nanoemulsion as ampoule for oral route.Int. J. Pharm. Sci. Res.201782591
    [Google Scholar]
  74. AlhagiesaA.W. GhareebM.M. Formulation and evaluation of nimodipine nanoparticles incorporated within orodispersible tablets.Int J Drug Deliv Technol.202010454755210.25258/ijddt.10.4.7
    [Google Scholar]
  75. SalihO.S. Al-AkkamE.J. Preparation, in-vitro, and ex-vivo evaluation of ondansetron loaded invasomes for transdermal delivery.Iraqi J Pharm Sci20233237184
    [Google Scholar]
  76. TengZ. YuM. DingY. ZhangH. ShenY. JiangM. LiuP. Opoku-DamoahY. WebsterT.J. ZhouJ. Preparation and characterization of nimodipine-loaded nanostructured lipid systems for enhanced solubility and bioavailability.Int. J. Nanomedicine20181411913310.2147/IJN.S18689930613141
    [Google Scholar]
  77. KassabH.J. AlkufiH.K. HusseinL.S. Use of factorial design in formulation and evaluation of intrarectal in situ gel of sumatriptan.J. Adv. Pharm. Technol. Res.202314211912410.4103/japtr.japtr_603_2237255866
    [Google Scholar]
  78. Shanta TaherS. SadeqZ.A. Al-KinaniK.K. AlwanZ.S. Solid lipid nanoparticles as a promising approach for delivery of anticancer agents.Vojen. Zdrav. Listy202291319720710.31482/mmsl.2021.042
    [Google Scholar]
  79. MastM.P. ModhH. KnollJ. FecioruE. WackerM.G. An update to dialysis-based drug release testing—data analysis and validation using the pharma test dispersion releaser.Pharmaceutics20211312200710.3390/pharmaceutics1312200734959289
    [Google Scholar]
/content/journals/pnt/10.2174/0122117385348551241028102256
Loading
/content/journals/pnt/10.2174/0122117385348551241028102256
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test