Mucositis, a common adverse event in anti-cancer treatments such as chemotherapy and/or radiotherapy, accompanies severe pain resulting in poor quality of life. Indomethacin (IM), a non-steroidal anti-inflammatory drug (NSAID), is one of the therapeutic options as a spray preparation (0.25% IM dissolved in phosphate buffer, pH 7.4) for pain control of oral mucositis. The stability of IM and the production of its degradative compounds are unclear in spray preparation. The aim of this study was to assess the stability of IM-spray preparation by determining the concentration of IM and its degradation products, 5-methoxy-2-methylindole-3-acetic acid (MM) and p-chlorobenzoic acid (CB). IM-spray preparation was stored under room temperature (25°C) or a cycling of room and refrigerator (4°C-25°C, each 12 hour) for 4 weeks. Under room temperature storage, IM concentration in the preparation decreased from 2.48 mg/mL to 2.29 mg/mL and MM and CB increased from an undetectable level to 0.12 and 0.06 mg/mL, respectively, a week after starting the study. Under the cycling of room and refrigerator, reduction of IM and the elevation of MM and CB in the spray preparation were also observed for a week's storage, though the magnitude was smaller (IM: from 2.48 mg/mL to 2.36 mg/mL, MM/CB: 0.06/0.03 mg/mL) when compared with the room temperature conditions. The time variation on the residual ratio of IM in the spray preparation at 4°C and -20°C was greater than 98.4% for 2-24 months' storage. Freezing and thawing did not affect IM concentration in the spray preparation until ten repetitions. The present results led to the conclusion that IM-spray preparation should be kept in a refrigerator for daily use and could be stored for at least 2 months at 4°C and 24 months at -20°C.
Mannitol particles have been designed as a main additive for oral disintegrating (OD) tablets by a spray freeze-drying technique. An aqueous solution of mannnitol was sprayed onto the surface of liquid nitrogen and the frozen droplets were freeze-dried to prepare the spherical porous particles. The resultant mannitol particles (SFD particles) were compressed under lower pressure to obtain a tablet with a high porosity of around 50%. It was found that the mechanical strength of the tablet significantly increased under short-time exposure to heating/humidification, holding its porous structure. As a result, tablets with satisfactory physical hardness (tensile strength ≥ 1.0 MPa) and rapid disintegration properties (disintegration time ≤ 30 s) could be prepared in the current manufacturing processes. The hardening phenomenon of the mannitol tablet was analyzed by X-ray powder diffractometry. The SFD particles and the resultant tablet from these particles were found to be composed of the a form of mannitol, which is a meta-stable crystalline form. Under stress conditions, the crystal form of mannitol was transformed into the stable b form within several hrs. This crystal transition promoted the solid-bridging between particles in the tablet, resulting in the strong compactness with high porosity. The porous structure accelerated the water penetration into the tablet, leading to the rapid disintegration behavior. The SFD mannitol particles developed in this research can be used as a direct tableting additive for OD tablets in the pharmaceutical industry.