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Meloxicam (MEL) shows a slow onset of action in severe pain patients on account of delayed gastric motility. This study aimed to develop an amorphous solid dispersion (ASD) of MEL to achieve rapid oral absorption in severe pain patients. ASD formulations of MEL with hydroxypropylmethylcellulose (ASD-MEL/HPMC) and polyacrylates and polymethacrylates (ASD-MEL/EUD) were prepared and physicochemically characterized. Oral absorption behavior of MEL samples was also clarified in both normal and propantheline (PPT)-pretreated rats with impaired gastric motility. MEL in the formulations was amorphous, and ASD formulations of MEL exhibited high dissolution behavior in acidic solution. After oral administration of crystalline MEL (1 mg-MEL/kg), a 69% reduction in AUC was observed between normal and PPT-pretreated rats. For orally dosed ASD-MEL/HPMC (1 mg-MEL/kg), there were approximately 9- and 12-fold increases of AUC in normal and PPT-pretreated rats, respectively, in comparison with crystalline MEL (1 mg-MEL/kg). However, the oral absorption behavior of ASD-MEL/EUD (1 mg-MEL/kg) was low and similar to that of crystalline MEL. The infrared spectroscopic study revealed potent interactions between MEL and EUD, possibly leading to marked attenuation of MEL absorption. This ASD approach might provide rapid oral absorption of MEL in severe pain patients, possibly leading to better clinical outcomes.

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The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit ® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier. Key words dipyridamole; dissolution; enteric polymer; pH-modifier; solid dispersionRecently, a lot of drug candidates with poor solubility have been developed and such drugs constituted about 40% of all drug products. 1) In many cases, low solubility or slow dissolution of a poorly soluble drug in the gastrointestinal (GI) tract causes insufficient absorption of the drug for treatment. In order to improve the dissolution rate and solubility of poorly soluble drugs, various solubilization technologies have been developed, including amorphization, reduction of particle size, emulsification and solid dispersion (SD).2) However, these technologies might not always be effective for improving the dissolution behavior of drugs with pH-dependent solubility. 3)Weak basic drugs are one included among pH-dependent soluble drugs, and exhibit high solubility under gastric pH conditions, but low solubility under intestinal pH conditions. Such pH-dependent solubility of weak basic drugs leads to high variability of absorption among individuals with different GI pH conditions.4) It has been reported that pH-modifier technology could effectively improve the dissolution of drugs with pH-dependent solubility.5) A pH-modifying agent could change the microenvironmental pH of the drug particles to a lower or higher pH at which the drug could dissolve easily. 6) In order to improve the dissolution behavior of weak basic drugs, organic acids have been used as pH-modifying agents. 7)Dipyridamole [2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d] pyrimidine] (DP), widely used as an antiplatelet for its attractive antithrombotic propertie...