Celecoxib-Loaded Self-micellizing Solid Dispersion Suppresses Its Delayed Absorption in Rats with Impaired Gastrointestinal Motility.

The aim of this study was to develop a self-micellizing solid dispersion of celecoxib (SMSD/CEL) with enhanced dissolution to suppress a delay in absorption under impairment of gastrointestinal (GI) secretion and motility induced by severe pain. Soluplus®-based SMSD/CEL was prepared by lyophilization and physiochemically characterized. A pharmacokinetic study of orally-dosed CEL samples was carried out in rats with propantheline (PPT)-induced the impairment of GI secretion and motility. SMSD/CEL was micellized in aqueous media with a mean diameter of 153 nm, and it showed improved dissolution behavior of CEL under acidic conditions with 2.1-fold higher dissolved CEL at 120 min than crystalline CEL. SMSD/CEL was found to be in an amorphous state, and there was no significant crystallization even after storage under accelerated conditions for 8 weeks, indicating relatively high storage stability of the amorphous form. Orally-dosed crystalline CEL in PPT-treated rats showed a delayed mean absorption time (MAT) and area under the curve of plasma concentration versus time from 0 to 4 h (AUC0-4) was reduced to 12% compared with that in normal rats, whereas SMSD/CEL suppressed the delay and decrease of absorption in PPT-treated rats. From these findings, SMSD/CEL might be efficacious to suppress poor and delayed absorption of CEL for better pain medication in the presence of impaired GI secretion and motility associated with severe pain.

Self-Emulsifying Drug Delivery System of Celecoxib for Avoiding Delayed Oral Absorption in Rats with Impaired Gastric Motility.

This study aimed to develop a self-emulsifying drug delivery system (SEDDS) of celecoxib (CEL) for suppressed delay in oral absorption under impaired gastric motility. A pseudo-ternary phase diagram was constructed for the determination of the optimal component ratio in SEDDS of CEL (SEDDS/CEL), and the SEDDS/CEL was physicochemically characterized. A pharmacokinetic study on orally dosed CEL samples (5-mg CEL/kg) was carried out in normal and propantheline (PPT)-treated rats to mimic impaired gastric motility. SEDDS/CEL rapidly formed a fine emulsion with a mean size of 147 nm in distilled water and significantly improved the dissolution behavior of CEL under pH 1.2 condition with a 20-fold higher dissolved amount than crystalline CEL. In normal rats, orally dosed SEDDS/CEL provided a 4.6-fold higher systemic exposure than that of crystalline CEL, due to the improved dissolution properties of CEL. Crystalline CEL showed delayed and decreased oral absorption of CEL in PPT-treated rats as evidenced by a 6.9-h-delayed mean absorption time and only 12% of the systemic exposure of CEL compared with those in normal rats. In contrast, SEDDS/CEL enhanced the oral absorption of CEL with a 14.6-fold higher systemic exposure with significant suppression of delay in absorption than crystalline CEL even in PPT-treated rats. SEDDS/CEL could be an efficacious option for suppressing delay in CEL absorption even under impairment of gastric motility, possibly leading to rapid and reproducible management of severe acute pain.

Physicochemical and biopharmaceutical characterization of celecoxib nanoparticle: Avoidance of delayed oral absorption caused by impaired gastric motility.

The present study aimed to develop a celecoxib (CEL) nanoparticle with improved dissolution/dispersion and consistent absorption even in the presence of impaired gastric motility. CEL was pulverized by a wet-milling with hydroxypropyl cellulose (HPC), and the prepared nanoparticles were physicochemically characterized after freeze-drying. CEL nanoparticle with HPC-SSL (NP/CEL) exhibited better dissolution/dispersion behavior in pH1.2 solution compared with CEL nanoparticles with other polymers, as evidenced by a 21.8-fold higher initial dissolution/dispersion rate than crystalline CEL. The mean particle diameter of water suspended-NP/CEL was 250 nm, and the CEL nanoparticle existed in an amorphous state. Even after storage at 40 °C for 4 weeks, there were no significant changes in the dissolution/dispersion behavior. Oral absorption of CEL samples (5 mg-CEL/kg) was evaluated in normal and propantheline (PPT)-treated rats with simulated gastric motility impairment. In PPT-treated rats, oral crystalline CEL led to a decrease in oral absorption by 12% of the AUC0-4 compared with that in normal rats, whereas NP/CEL suppressed the pharmacokinetic transition of CEL by 43% of the AUC0-4 due to the improved dissolution/dispersion behavior of CEL. The NP/CEL system might be promising to avoid decreased absorption of CEL caused by impaired gastric motility.

Amorphous Solid Dispersion of Meloxicam Enhanced Oral Absorption in Rats With Impaired Gastric Motility.

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 AUC0-4 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 AUC0-4 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.

Ginger Extract-Loaded Solid Dispersion System with Enhanced Oral Absorption and Antihypothermic Action.

The aim of this study is to enhance the antihypothermic action of ginger extract (GE) employing a solid dispersion (SD) approach. The prepared SD of GE (GE/SD) was characterized in terms of physicochemical and pharmacokinetic properties. The antihypothermic action of GE samples was evaluated in a rat model of hypothermia. GE/SD exhibited improved dissolution behavior of the major active ingredients in GE, 6-gingerol (6G) and 8-gingerol (8G), with levels of dissolution 12- and 31-fold higher than that of GE, respectively. Even after storage under accelerated conditions, limited degradations of 6G and 8G were observed in GE/SD, although 6G and 8G were slightly degraded in GE. After oral administration of GE (300 mg/kg) and GE/SD (100 mg of GE/kg), the relative bioavailabilities of 6G and 8G in GE/SD were 5.0- and 5.8-fold higher than those in GE, respectively. Orally administered GE/SD (30 mg of GE/kg) inhibited ethanol-evoked hypothermia because of improved oral absorption of 6G and 8G. From these observations, the SD approach might be efficacious for enhancing the nutraceutical potentials of GE.

Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation.

PURPOSE: This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation. METHODS: Nano-matrix particles of CsA with mannitol (nCsAm) were prepared by a flash nano-precipitation technique employing a multi-inlet vortex mixer and evaluated in terms of physicochemical properties, anti-inflammatory effect in the rat model of airway inflammation, pharmacokinetic behavior, and distributions of CsA to side-effect-related organs after intratracheal administration. RESULTS: In nCsAm, spherical nano-particles of CsA were covered with mannitol and the mean particle size was 1.3 µm. The in vitro Next Generation Impactor analysis demonstrated fine inhalation performance with a fine particle fraction value of 65.8%. Intratracheal nCsAm (100 µg-CsA/rat) significantly attenuated the recruitment of inflammatory cells into the airway in the rat model of airway inflammation, followed by suppression of the inflammatory biomarkers. After intratracheal nCsAm at a pharmacologically effective dose (100 µg-CsA/rat), there was a 42-47-fold decrease in the distribution of CsA to side-effect-related organs such as the kidney and liver compared with oral CsA at a toxic dose (10 mg-CsA/kg), potentially leading to avoidance of systemic side-effects of CsA. CONCLUSION: Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin.

Strategic application of self-micellizing solid dispersion technology to respirable powder formulation of tranilast for improved therapeutic potential.

PURPOSE: The present study aimed to develop an inhalable self-micellizing solid dispersion of tranilast (SMSD/TL) using poly[MPC-co-BMA] to improve the therapeutic potential and safety. METHODS: The safety of poly[MPC-co-BMA] in lungs was assessed using rat lung epithelium-derived L2 cells. SMSD/TL and respirable powder of SMSD/TL (SMSD/TL-RP) were prepared using a wet milling system and jet mill, respectively. The physicochemical properties of TL formulations were characterized in terms of dissolution, morphology, and particle size. Pharmacological and pharmacokinetic studies were also conducted on inhaled SMSD/TL-RP. RESULTS: The lactate dehydrogenase level from L2 cells treated with poly[MPC-co-BMA] was lower than that with polysorbate 80, a positive control. SMSD/TL showed enhanced dissolution behavior of TL. The jet milled SMSD/TL particles easily separated from the lactose carrier, and the particle size was suitable for inhalation. Compared with RP of TL, inhaled SMSD/TL-RP (100 µg-TL/rat) could more strongly suppress the inflammatory responses in antigen-sensitized rats. The TL level in plasma after intratracheal administration of SMSD/TL-RP at a pharmacological effective dose (100 µg-TL/rat) was ca. 4.2-fold lower than that after oral administration of TL solution at a clinical dose (1.67 mg/kg). CONCLUSION: SMSD/TL-RP might be an attractive dosage form to improve the anti-inflammatory effects and safety of TL.