In situ Preparation of a Phospholipid Gel Co-Loaded with Methotrexate and Dexamethasone for Synergistic Rheumatoid Arthritis Treatment

Abstract

Qian Pu,1 Kaiyue Wang,1 Bigeng Peng,2 Kexin Chen,3 Tao Gong,4 Fu Liu,1,5 Qin Yang1 1School of Pharmacy, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China; 2Oncology Department of Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China; 3Urban Vocational College of Sichuan, Meishan, 620000, People’s Republic of China; 4Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of ChinaCorrespondence: Fu Liu, Department of Pharmacy, the Affiliated Hospital of Noth Sichuan Medical College, Nanchong, Sichuan, China, Tel [phone], Email [email protected] Qin Yang, School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China, Tel [phone], Email [email protected]: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by arthrocele, cartilage damage and disability. Although several anti-RA drugs have been developed for long-term treatment, they require frequent local injection and lead to multiple adverse effects such as osteoporosis and myelosuppression.Purpose: Reducing the amount and frequency of anti-RA drugs methotrexate (MTX) and dexamethasone sodium phosphate (DSP) by local injection of phospholipid-based phase separation gel (PPSG) coloaded the two drugs, which presented PPSG-(+).Methods: First, We characterized PPSG-(+). And we used UV spectrophotometry and high performance liquid chromatography (HPLC) to detect drug concentration, which can clarify the drug release in vitro and in vivo, respectively. We also injected PPSG-(+) into the joint cavity of healthy rabbits to prove the safety of PPSG-(+). Then, we injected PPSG-(+) into the joint cavity of RA modeled rabbits to demonstrate the effect in anti-RA of PPSG-(+) including the thickness of joints, tumor necrosis factor (TNF)-α and interleukin (IL)-1β detection, hematoxylin–eosin (H&E) staining and computed tomography (CT) of joints.Results: Suspended particles show a tight and uniform arrangement in PPSG-(+). The gel underwent a phase transition at 20 min in vitro and 8 h in vivo, and vesicular structures reflecting its degradation and phase transition were observed in vivo. PPSG-(+) released both drugs in a sustained and fixed ratio for more than 14 days, while it proved to be safe for intra-articular injection and did not induce inflammation in a rabbit. Eventually, PPSG-(+) showed a good anti-RA effect and its potency can be maintained for 3 weeks.Conclusion: PPSG-(+) is a drug delivery system offering good biocompatibility and sustained release of MTX and DSP, leading to long-lasting anti-RA effect.Keywords: drug delivery system, in situ gel, sustained release, anti rheumatoid arthritis

Keywords

• drug delivery system
• in situ gel
• sustained release
• anti rheumatoid arthritis.