Journal of Pain Research (Apr 2021)

The Inclusion of Tolfenamic Acid into Cyclodextrins Stimulated by Microenvironmental pH Modification as a Way to Increase the Anti-Migraine Effect

  • Stasiłowicz A,
  • Tykarska E,
  • Rosiak N,
  • Sałat K,
  • Furgała-Wojas A,
  • Plech T,
  • Lewandowska K,
  • Pikosz K,
  • Pawłowicz K,
  • Cielecka-Piontek J

Journal volume & issue
Vol. Volume 14
pp. 981 – 992

Abstract

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Anna Stasiłowicz,1 Ewa Tykarska,2 Natalia Rosiak,1 Kinga Sałat,3 Anna Furgała-Wojas,3 Tomasz Plech,4 Kornelia Lewandowska,5 Katarzyna Pikosz,1 Kamil Pawłowicz,1 Judyta Cielecka-Piontek1 1Department of Pharmacognosy, Poznan University of Medical Sciences, Poznan, Poland; 2Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Poznan, Poland; 3Department of Pharmacodynamics, Jagiellonian University Medical College, Krakow, Poland; 4Department of Pharmacology, Medical University of Lublin, Lublin, Poland; 5Institute of Molecular Physics, Polish Academy of Sciences, Poznan, PolandCorrespondence: Judyta Cielecka-PiontekDepartment of Pharmacognosy, Poznan University of Medical Sciences, Swiecickiego 4, 61– 781, Poznan, PolandTel +48 61 854 67 09Fax +48 61 854 67 01Email [email protected]: The poorly soluble nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA), was studied to maximize its solubility, permeability through biological membranes, and pharmacological activity.Methods: A mixture with magnesium stearate (MS) – microenvironment pH-modifier was prepared, as well as systems additionally containing incorporating substances methyl-β-cyclodextrin (M-β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The identification of TA-MS-CD systems was confirmed using experimental methods: X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FT-IR) with the theoretical support. Apparent solubility study was performed using the paddle apparatus, while in vitro gastrointestinal tract (GIT) and blood-brain barrier (BBB) permeability were conducted by using PAMPA (Parallel Artificial Membrane Permeability Assay). The in vivo part of the study used the mouse nitroglycerin (NTG)-induced migraine pain model.Results: From practically insoluble substance, TA in TA-MS-M-β-CD system dissolved up to 80.13% ± 2.77%, and in TA-MS-HP-β-CD up to 92.39% ± 3.25% in 180 minutes. An increase in TA permeability was also obtained in the TA-MS-M-β-CD and TA-MS-HP-β-CD systems through GIT membranes (Papp values 2.057 x 10− 5 cm s− 1 and 2.091 x 10− 5 cm s− 1, respectively) and through BBB (Papp values 3.658 x 10− 5 cm s− 1 and 3.629 x 10− 5 cm s− 1, respectively). The enlargement of the solubility and permeability impacted analgesia. The dose 25 mg/kg of both TA-MS-HP-β-CD and TA-MS-M-β-CD was almost equally effective and only slightly less effective than the dose 50 mg/kg of pure TA. Both TA-MS-HP-β-CD and TA-MS-M-β-CD used at 50 mg/kg more effectively attenuated tactile allodynia in NTG-treated mice than the same dose of pure TA. None of TA forms influenced heat hyperalgesia.Conclusion: Increasing solubility of TA caused an increase of its analgesic effect in an animal model of migraine pain.Keywords: tolfenamic acid, migraine pain, cyclodextrins, permeability, gastrointestinal tract, blood-brain barrier

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