Physicochemical Characterizations and Pharmacokinetic Evaluation of Pentazocine Solid Lipid Nanoparticles against Inflammatory Pain Model

Zaheer Ullah Khan; Anam Razzaq; Ahsan Khan; Naeem Ur Rehman; Hira Khan; Taous Khan; Ashraf Ullah Khan; Norah A Althobaiti; Farid Menaa; Haroon Iqbal; Naveed Ullah Khan

doi:10.3390/pharmaceutics14020409

Physicochemical Characterizations and Pharmacokinetic Evaluation of Pentazocine Solid Lipid Nanoparticles against Inflammatory Pain Model

Pharmaceutics. 2022 Feb 14;14(2):409. doi: 10.3390/pharmaceutics14020409.

Authors

Affiliations

¹ Department of Pharmacy, Abbottabad Campus, COMSATS University Islamabad, Abbottabad 22060, Pakistan.
² Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
³ Division of Pharmaceutics and Pharmacology, College of Pharmacy, Ohio State University, Colombus, OH 43210, USA.
⁴ Department of Pharmacy, Quaid-i-Azam University, Islamabad 45320, Pakistan.
⁵ Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar 25000, Pakistan.
⁶ Department of Biology, College of Science and Humanities-Al Quwaiiyah, Shaqra University, Al Quwaiiyah 19257, Saudi Arabia.
⁷ Department of Oncology and Nanomedicine, California Innovations Corporation, San Diego, CA 92037, USA.
⁸ Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences (CAS), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China.
⁹ Department of Pharmacy, Gujrat Campus, University of Lahore, Lahore 50700, Pakistan.

Abstract

Pentazocine (PTZ), a narcotic-antagonist analgesic, has been extensively used in the treatment of initial carcinogenic or postoperative pain. Hepatic first-pass metabolism results in low oral bioavailability and high dose wastage. Herein, 10 mg (-)-Pentazocine (HPLC-grade) was incorporated to solid lipid nanoparticles (SLNs) using a double water-oil-water (w/o/w) emulsion by solvent emulsification-evaporation technique, followed by high shear homogenization to augment its oral bioavailability, considering the lymphatic uptake. The resulting SLNs were characterized for zeta potential (ZP), particle size (PS), and polydispersity index (PDI) using a zetasizer. The entrapment efficiency (EE) and loading capacity (LC) were calculated. Chemical interactions, through the identification of active functional groups, were assessed by Fourier-transformed infrared (FTIR) spectroscopy. The nature (crystallinity) of the SLNs was determined by X-ray diffractometry (XRD). The surface morphology was depicted by transmission electron microscopy (TEM). In vitro (in Caco-2 cells) and in vivo (in male Wistar rats) investigations were carried out to evaluate the PTZ release behavior and stability, as well as the cellular permeation, cytotoxicity, systemic pharmacokinetics, antinociceptive, anti-inflammatory, and antioxidative activities of PTZ-loaded SLNs, mainly compared to free PTZ (marketed conventional dosage form). The optimized PTZ-loaded SLN2 showed significantly higher in vitro cellular permeation and negligible cytotoxicity. The in vivo bioavailability and pharmacokinetics parameters (t_1/2, Cmax) of the PTZ-loaded SLNs were also significantly improved, and the nociception and inflammation, following carrageenan-induced inflammatory pain, were markedly reduced. Concordantly, PTZ-loaded SLNs showed drastic reduction in the oxidative stress (e.g., malonaldehyde (MDA)) and proinflammatory cytokines (e.g., Interleukin (IL)-1β, -6, and TNF-α). The histological features of the paw tissue following, carrageenan-induced inflammation, were significantly improved. Taken together, the results demonstrated that PTZ-loaded SLNs can improve the bioavailability of PTZ by bypassing the hepatic metabolism via the lymphatic uptake, for controlled and sustained drug delivery.

Keywords: controlled and sustained drug release; first-pass metabolism; inflammation; oral bioavailability; pentazocine; solid lipid nanoparticles.