Targeted drug delivery of Methotrexate in situ gels for the treatment of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is considered a debilitating disease that increases the risk of significant morbidity and premature mortality. To circumvent drug-related toxicity and ineffectiveness of anti-inflammatory drugs, there is a significant need for an advanced delivery system that increases bioavailability. The feasibility of in situ gel of methotrexate sodium (MTS) as an effective management for Rheumatoid arthritis was investigated. It was formulated with pluronic F-127 (PLF-127) as primary polymer, hydroxypropyl methylcellulose K4M (HK4M), and polycarbophil (PCL) as a copolymer and characterized by various parameters. The efficacy evaluation by Freund's complete adjuvant (FCA) model, biocompatibility assessment by histopathological studies conducted. The optimized in situ gel (M4) was thermoresponsive, released 93.26 ± 2.39% MTS at 96 hours. In addition, distribution of MTS was even in the optimized sterile and syringeable in situ gel. In vivo studies on wistar rats demonstrated a substantial reduction in paw oedema during the 28-day study period and were biocompatible with the tissues at the injection site. The study was successful in formulating, optimizing MTS in situ gel for effective management of RA.

Keywords: Drug targeting; In situ gel; Methotrexate sodium; Rheumatoid arthritis.

Fig. 1

FT-IR spectrum (A- Methotrexate, B- Formulation M4, C- Formulation M7).

Fig. 2

Formulation of Methotrexate in-situ gels.

Fig. 3

DSC thermogram of Methotrexate.

Fig. 4

Effect of polymer (HK4M and PCL) concentration on gelation time (Sec) and gelation temperature (°C).

Fig. 5

Effect of polymers (HK4M and PCL) concentration on syringeability (Sec), in vitro drug release studies (cumulative % drug release).

Fig. 6

Effect of polymers (HK4M and PCL) concentration on viscosity (cps) at two different temperature i.e. 8 °C & 37 °C.

Fig. 7

Comparative in vitro release profile of MTS in situ gels (Formulation- M2, M3 & M4).

Fig. 8

Comparative in vitro release profile of MTS in situ gels (Formulation- M5, M6 & M7).

Fig. 9

The anti-inflammatory effect of MTS in situ gels as assessed by a reduction in paw volume in rats with adjuvant arthritis model. (One day after treatment).

Fig. 10

Representative H and E (hematoxylin and eosin) stained histological slides of joint tissues from healthy rat knees after injection with (A) 100 µL of saline and (B) 100 µL of MTS in situ gels (magnification: 100×).

Supplementary figure 1