Compression-coated pulsatile chronomodulated therapeutic system: QbD assisted optimization

Abstract

Pulsatile drug delivery systems have drawn attention in contemporary research for designing chronotherapeutic systems. The current work aims to design pulsatile ketorolac tromethamine tablets using compression coating for delayed delivery with a lag time suitable for the treatment of morning stiffness in arthritis. Rapidly disintegrating core tablets of ketorolac tromethamine were formulated using super-disintegrants, and the optimized formulation was compression using PEO WSR coagulant and Eudragit RLPO for delaying the release. The central composite design and response surface methodology were employed to optimize the formulation and process parameters namely PEO WSR Coagulant (X₁), Eudragit RLPO (X₂), and Hardness (X₃). The dependent variables optimized were lag time and time required for 95% drug release. Analysis using response surface graphs and mathematical modeling of the results allowed identifying and quantifying the formulation variables active on the selected responses. A polynomial equation fitted to the data was used to predict the composition with optimum responses. Compression-coated pulsatile tablets' optimized composition exhibited a lag time of 9 h and released 95% of the ketorolac tromethamine in 17.42 h. Validation of the mathematical model assured the reliability of QBD in formulation design. In vivo X-ray imaging and pharmacokinetic studies established a strong relationship between the coated polymers maintaining the desired lag time for delayed delivery of the active to coincide with the chronobiology for enhanced bioavailability at the right time when needed.

Keywords: Compression coating; Eudragit RLPO; PEO WSR coagulant; chronobiology; ketorolac tromethamine; quality by design.

Figure 1.

Disintegration (A) and drug release profiles (B) of core tablets of KT.

Figure 2.

Normal probability plots and model residuals Vs. test orders of the residuals for A) Lag time and B) T-95% CDR.

Figure 3.

Response surface [contour] graphs and 3-Dimensional plots for lag time (A) and T-95% [B] (contour and three-dimensional).

Figure 4.

Desirability plot in optimizing the selected factors to achieve the desired responses.

Figure 5.

In vitro drug release profile of CCT-KT. (Values represent the mean of 6 determinations; n = 6, Avg ± SD).

Figure 6.

SEM images of optimized formulation at 0 h (a) and after 10 h of disintegration (b).

Figure 7.

FTIR spectra of (a) Pure KT, (b) Physical mixture of optimized formulation and (c) Eudragit RLPO polymer (i) to (iv) indicates for functional groups of KT existing in both (a) and (b) confirms the compatibility of KT with selected excipients.

Figure 8.

X-ray radiographs showing the location of CCT-KT tablet labeled with a radioopaque marker, Barium sulfate a) Before administration and after b) 2 h, and c) 10 h of formulation administration.