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

Anna Stasiłowicz; Ewa Tykarska; Natalia Rosiak; Kinga Sałat; Anna Furgała-Wojas; Tomasz Plech; Kornelia Lewandowska; Katarzyna Pikosz; Kamil Pawłowicz; Judyta Cielecka-Piontek

doi:10.2147/JPR.S295795

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

J Pain Res. 2021 Apr 14:14:981-992. doi: 10.2147/JPR.S295795. eCollection 2021.

Affiliations

¹ Department of Pharmacognosy, Poznan University of Medical Sciences, Poznan, Poland.
² Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Poznan, Poland.
³ Department of Pharmacodynamics, Jagiellonian University Medical College, Krakow, Poland.
⁴ Department of Pharmacology, Medical University of Lublin, Lublin, Poland.
⁵ Institute of Molecular Physics, Polish Academy of Sciences, Poznan, Poland.

Abstract

Purpose: 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 (P_app values 2.057 x 10^-5 cm s^-1 and 2.091 x 10^-5 cm s^-1, respectively) and through BBB (P_app 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: blood-brain barrier; cyclodextrins; gastrointestinal tract; migraine pain; permeability; tolfenamic acid.