RESUMEN
Sustained-release matrix tablets based on Eudragit RL and RS were manufactured by injection moulding. The influence of process temperature; matrix composition; drug load, plasticizer level; and salt form of metoprolol: tartrate (MPT), fumarate (MPF) and succinate (MPS) on ease of processing and drug release were evaluated. Formulations composed of 70/30% Eudragit RL/MPT showed the fastest drug release, substituting part of Eudragit RL by RS resulted in slower drug release, all following first-order release kinetics. Drug load only affected drug release of matrices composed of Eudragit RS: a higher MPT concentration yielded faster release rates. Adding triethyl citrate enhanced the processability, but was detrimental to long-term stability. The process temperature and plasticizer level had no effect on drug release, whereas metoprolol salt form significantly influenced release properties. The moulded tablets had a low porosity and a smooth surface morphology. A plasticizing effect of MPT, MPS and MPF on Eudragit RS and Eudragit RL was observed via DSC and DMA. Solubility parameter assessment, thermal analysis and X-ray diffraction demonstrated the formation of a solid solution immediately after production, in which H-bonds were formed between metoprolol and Eudragit as evidenced by near-infrared spectroscopy. However, high drug loadings of MPS and MPF showed a tendency to recrystallise during storage. The in vivo performance of injection-moulded tablets was strongly dependent upon drug loading.
Asunto(s)
Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Metoprolol/química , Comprimidos/química , Resinas Acrílicas/química , Disponibilidad Biológica , Química Farmacéutica/métodos , Citratos/química , Composición de Medicamentos/métodos , Estabilidad de Medicamentos , Cinética , Plastificantes/química , Polímeros/química , Porosidad , Solubilidad , TemperaturaRESUMEN
The aim of the present study was to evaluate the importance of matrix flexibility of hot-melt extruded (HME) ethylene vinyl acetate (EVA) matrices (with vinyl acetate (VA) contents of 9%, 15%, 28% and 40%), through the addition of hydrophilic polymers with distinct swelling capacity. Polyethylene oxide (PEO 100K, 1M and 7M) was used as swelling agent and metoprolol tartrate (MPT) as model drug. The processability via HME and drug release profiles of EVA/MPT/PEO formulations were assessed. Solid state characteristics, porosity and polymer miscibility of EVA/PEO matrices were evaluated by means of DSC, X-ray tomography and Raman spectroscopy. The processability via HME varied according to the VA content: EVA 40 and 28 were extruded at 90°C, whereas higher viscosity EVA grades (EVA 15 and 9) required a minimum extrusion temperature of 110°C to obtain high-quality extrudates. Drug release from EVA matrices depended on the VA content, PEO molecular weight and PEO content, matrix porosity as well as pore size distribution. Interestingly, the interplay of PEO leaching, matrix swelling, water influx and changes in matrix porosity influenced drug release: EVA 40- and 28-based matrices extruded with PEO of higher MW accelerated drug release, whereas for EVA 15- and 9-based matrices, drug release slowed down. These differences were related to the distinct polymer flexibility imposed by the VA content (lower VA content presents higher crystallinity and less free movement of the amorphous segments resulting in a higher rigidity). In all cases, diffusional mass transport seems to play a major role, as demonstrated by mathematical modeling using an analytical solution of Fick's second law. The bioavailability of EVA 40 and 28 matrices in dogs was not significantly different, independent of PEO 7M concentration.
Asunto(s)
Portadores de Fármacos/química , Metoprolol/administración & dosificación , Polietilenglicoles/química , Polivinilos/química , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Cristalización , Preparaciones de Acción Retardada , Perros , Composición de Medicamentos , Calor , Masculino , Metoprolol/química , Metoprolol/farmacocinética , Modelos Teóricos , Porosidad , Espectrometría Raman , Tomografía por Rayos X , ViscosidadRESUMEN
BACKGROUND: Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol. MATERIALS AND METHODS: The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol and Pac/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of < or = 10% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min. RESULTS: Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol. Hyperthermia yielded no significant differences in bioavailability data. CONCLUSION: These results showed that both formulations had a similar toxicity profile but differed significantly in bioavailability.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinógenos/farmacología , Hipertermia Inducida , Paclitaxel/farmacología , Peritoneo/efectos de los fármacos , beta-Ciclodextrinas/farmacología , Animales , Antineoplásicos Fitogénicos/química , Disponibilidad Biológica , Carcinógenos/química , Quimioterapia del Cáncer por Perfusión Regional , Dosis Máxima Tolerada , Paclitaxel/química , Ratas , beta-Ciclodextrinas/químicaRESUMEN
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising strategy in the treatment of peritoneal carcinomatosis. To perform HIPEC, a tensioactive- and solvent-free paclitaxel formulation consisting of water-soluble paclitaxel/randomly methylated-beta-cyclodextrin (Pac/RAMEB) complexes was developed previously. Using MTT and SRB assays the cytotoxic activity of this formulation versus Taxol, was evaluated as well as the cytotoxicity of the different formulation excipients (RAMEB and Cremophor EL. The possible synergistic effect of heat and paclitaxel-based chemotherapy during HIPEC was also evaluated in vitro. The cytotoxicity assays revealed differences in viability between Cremophor EL and RAMEB treated cells of 40 and 50% for the CaCo-2 human and the CC531s rat colon cancer line, respectively, in favour of RAMEB. Despite the higher cytotoxicity of Cremophor EL, Pac/RAMEB complexes and Taxol were equipotent. Using the MTT and SRB assays the average difference in viability between both cell lines was below 10% and IC50 values showed no significant difference. Hyperthermia after drug administration (41 degrees C during 1h) had no effect on cell viability. These results indicated that it was possible to reformulate paclitaxel with a less cytotoxic vehicle while maintaining the cytotoxic activity of the formulation and that there is no synergism between paclitaxel and heat for in vitro cytotoxicity.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Portadores de Fármacos/química , Hipertermia Inducida/métodos , Paclitaxel/farmacología , Neoplasias Peritoneales/terapia , beta-Ciclodextrinas/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Células CACO-2 , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Portadores de Fármacos/farmacología , Excipientes/química , Excipientes/farmacología , Calor , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/química , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/patología , Ratas , beta-Ciclodextrinas/farmacologíaRESUMEN
Previous data on periparturient relaxation of immunity during gastrointestinal nematode infection in goats are scarce and conflicting; one study carried out in fiber (Angora) goats showed a positive association of fecal egg counts with prolactin concentrations around parturition, whereas the two other available studies dealing with dairy goats, gave divergent results. The objectives of the study were thus to assess the occurrence of a periparturient rise in fecal egg counts in dairy goats and to examine a possible relationship between the level of milk production and the intensity of the periparturient rise. A total of 28 French Alpine grazing dairy goats naturally infected with Teladorsagia, Trichostrongylus, and Oesophagostomum were allocated into two groups according to their reproductive status; group 1 (n = 7) consisted of nonpregnant lactating animals in the 3rd month of lactation, whereas group 2 (n = 21) was composed of dry goats at 6 weeks before term. Fecal egg counts, pepsinogen and phosphate blood concentrations, blood eosinophil counts, and prolactin concentrations were individually monitored at weekly intervals for 12 weeks (from midwinter to early spring). The mean fecal egg counts were significantly higher in pregnant goats during the 2 weeks before (668 versus 242 eggs per gram of feces (epg), P < 0.05) and the 2 weeks after (962 versus 279 epg, P < 0.01) parturition as compared with nonpregnant lactating animals. No significant difference was seen in the composition of larval cultures between the two groups of animals, with Oesophagostomum infective larvae being found predominantly, particularly at the time of parturition. Pepsinogen and phosphate concentrations as well as blood eosinophil counts were similar between the two groups throughout the survey and indicated a moderate larval challenge. The mean prolactin concentration measured in pregnant goats was significantly higher (P < 0.01) at the time of parturition (298 versus 130 ng ml(-1)) and at 4 weeks after parturition (387 versus 193 ng ml(-1)) than that determined in nonpregnant animals. Furthermore, a significant correlation (rs = 0.30, df = 79; P < 0.01) between fecal egg counts and prolactin concentrations was recorded for the pregnant goats during the 4-weeks period around parturition.