RESUMO
Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen-DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen-DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 ± 6.2, 3.9 ± 5.3, 5.3 ± 4.9 and 9.1 ± 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p<0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Portadores de Fármacos , Mucosa Gástrica/efeitos dos fármacos , Ibuprofeno/toxicidade , Fosfolipídeos/química , Úlcera Gástrica/prevenção & controle , Administração Oral , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Química Farmacêutica , Clorofórmio/química , Cristalização , Cristalografia por Raios X , Citoproteção , Dimiristoilfosfatidilcolina/química , Composição de Medicamentos , Etanol/química , Mucosa Gástrica/patologia , Ibuprofeno/administração & dosagem , Ibuprofeno/química , Masculino , Microscopia Eletrônica de Varredura , Fosfatidilcolinas/química , Fosfatidilgliceróis/química , Difração de Pó , Ratos , Ratos Sprague-Dawley , Solubilidade , Solventes/química , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Tecnologia Farmacêutica/métodos , Fatores de TempoRESUMO
Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug). On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG) was ranked as the first potent dissolution rate enhancer for the model drug. Subsequently, the solid dispersions of varying piroxicam/DMPG ratios were prepared and further investigated. Within the concentration range studied (6.4-16.7 wt %), the dissolution rate of piroxicam from the solid dispersions appeared to increase as a function of the carrier weight fraction, whereas the cumulative drug concentration was not significantly affected by piroxicam/DMPG ratio, presumably due to a unique phase behavior of the aqueous dispersions of this carrier phospholipid. Solid state analysis of DMPG-based formulations reveled that they are two-component systems, with a less thermodynamically stable form of piroxicam (Form II) being dispersed within the carrier. Finally, oral bioavailability of piroxicam from the DMPG-based formulations in rats was found to be superior to that of the control, as indicated by the bioavailability parameters, cmax and especially Tmax (53 µg/mL within 2 h vs. 39 µg/mL within 5.5 h, respectively). Hence, DMPG was regarded as the most promising carrier phospholipid for enhancing oral bioavailability of piroxicam and potentially other Class II drugs.