Tolmetin Sodium Fast Dissolving Tablets for Rheumatoid Arthritis Treatment: Preparation and Optimization Using Box-Behnken Design and Response Surface Methodology

Abstract

Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug's bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis.

Keywords: Box-Behnken experimental design; fast disintegrating tablets; response surface methodology; tolmetin sodium.

Figure 1

FTIR spectra of pure TLM (A); pure CP (B); pure CCS (C); pure camphor (D) and physical mixtures TLM/all excipients (E).

Figure 2

DSC thermograms of pure TLM (A); pure CP (B); pure CCS (C); pure camphor (D) and physical mixtures TLM/all excipients (E).

Figure 3

XRD profile of pure TLM (A); pure CP (B); pure CCS (C); pure camphor (D) and physical mixtures of TLM/all excipients (E).

Figure 4

The three-dimensional contour plot for the effect of total amounts of super-disintegrates (X₁ and X₂) and percentage of sublimating agent (X₃) on the percentage friability (Y₁).

Figure 5

The three-dimensional contour plot for the effect of total amounts of super-disintegrates (X₁), (X₂) and percentage of sublimating agent (X₃) on the disintegration time (Y₂).

Figure 6

Shows 3D and response surface plots for the effect of super-disintegrates (X₁ and X₂) and total amount of sublimating agents (X₃) on the response Y₃ (% release).

Figure 7

The release profiles of TLM-FDT from different formulations. Release profiles of formulae 1–5 (A), release profiles of formulae 6–10 (B), and release profiles of formulae 11–15 (C).

Figure 8

Shows the 3D and response surface plot for the effect super-disintegrates (X₁ and X₂) and total amount of sublimating agents (X₃) on the response Y₄ (WT).

Figure 9

Changes in the paw volume at different time intervals in carrageenan-induced paw edema rat model. Data are presented as Mean ± SD (n = 6).

Figure 10

HPLC chromatograms of (A) TLM, (B) TLM in blank plasma, (C) plasma samples taken after injection of TLM-FDTs, and (D) blank plasma.

Figure 11

The mean concentration-time curve of TLM (μg/mL) in plasma after oral administration of TOLECTIN^® tablets and TLM-FDTs in rats. Data are presented as the mean ± SD (n = 3).