RESUMEN
OBJECTIVE: We conducted an ex-vivo analysis and a study in healthy subjects to compare magnesium bioavailability after administration of Sucrosomial® magnesium or commercially available preparations of magnesium citrate, magnesium oxide and magnesium bisglycinate. MATERIALS AND METHODS: In the ex-vivo study we simulated magnesium intestinal absorption after digestion through sections of intestinal mucosa isolated from rats. We compared the absorption of magnesium oxide and Sucrosomial® magnesium at two different concentrations: 32.9 mg/ml and 329 mg/ml. The human study was a single day double-blinded repeated crossover study in healthy subjects. Each subject was administered 350 mg magnesium in different formulations (Sucrosomial® magnesium, magnesium citrate, magnesium oxide or magnesium bisglycinate) after 1 week of washout. We collected blood and urine samples to measure magnesium concentration in blood, urine and red blood cells. RESULTS: The ex-vivo evaluation showed that magnesium absorption after administration of Sucrosomial® magnesium was faster and with higher rates compared to a standard formulation of magnesium oxide. This finding was further confirmed by the results of the study in healthy subjects, that showed a more evident increase in magnesium concentration after administration of Sucrosomial® magnesium compared to the other formulations. In particular, the increase in magnesium concentration from baseline to 24 h was statistically higher in blood and in urine for Sucrosomial® magnesium compared to magnesium oxide, while in red blood cells Sucrosomial® magnesium had a statistically significant advantage compared to magnesium bisglycinate. CONCLUSIONS: Our findings suggest that Sucrosomial® magnesium leads to an increased bioavailability of magnesium compared to other formulations. Further studies are needed to investigate if this advantage turns into more evident clinical efficacy.
Asunto(s)
Magnesio/farmacocinética , Adulto , Anciano , Animales , Disponibilidad Biológica , Estudios Cruzados , Método Doble Ciego , Composición de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Absorción Intestinal , Magnesio/administración & dosificación , Óxido de Magnesio/farmacocinética , Masculino , Persona de Mediana Edad , Ratas , Ratas WistarRESUMEN
Different substitution degrees of palmitoyl glycol chitosan (PGC), prepared according to the literature, were used to obtain polymeric micelles that have been assessed in comparison with Pluronic F127 micelles as possible carriers for poorly soluble drugs, such as cyclosporine A. Both PGC and Pluronic micelles were studied for their interactions with cell culture substrates. The least substituted and most hydrophilic derivative, PGC21 (approximately 5% substitution), showed a strong association with cyclosporine, more than tripling the colloidal concentration with respect to the saturated solution. It showed a greater ability to open Caco-2 tight junctions and to enhance the permeability of Caco-2 substrates with respect to micelles based on higher palmitoyl substitution, conceivably due to the lower modification of the chitosan chains. Permeation and penetration experiments were performed with PGC21 and Pluronic micelles on a rabbit corneal epithelial cell line (RCE) and on excised pig corneas. It was found that both PGC and Pluronic micelles could increase the permeation of the fluorescent probe rhodamine B through RCE cells by more than ten-fold. In RCE and in pig cornea, the micelles improved the penetration of both rhodamine and cyclosporine. For cyclosporine, the PGC21 micelles allowed penetration of approximately 1 µg/mg cyclosporine A in corneal tissue, demonstrating a potential for use in immunosuppression therapies.
Asunto(s)
Quitosano/química , Córnea/química , Ciclosporina/administración & dosificación , Ciclosporina/química , Nanocápsulas/química , Animales , Difusión , Inmunosupresores/administración & dosificación , Inmunosupresores/química , Inyecciones Intraoculares , Micelas , Nanocápsulas/administración & dosificación , PorcinosRESUMEN
The kinetics of in vitro drug release from nanoparticulate systems is extensive, though uncritically, being studied by dialysis. Evaluating the actual relevance of dialysis data to drug release was the purpose of this study. Diclofenac- or ofloxacin-loaded chitosan nanoparticles crosslinked with tripolyphosphate were prepared and characterized. With each drug, dynamic dialysis was applied to nanoparticle dispersion, solution containing dissolved chitosan·HCl, and solution of plain drug. Drug kinetics in receiving phase (KRP), nanoparticle matrix (KNM) and nanoparticle dispersion medium (KDM) were determined. Release of each drug from nanoparticles was also assessed by ultracentrifugation. Although KRP data may be interpreted in terms of sustained release from nanoparticles, KNM and KDM data show that, with both drugs, the process was in fact controlled by permeation across dialysis membrane. Analysis of KRP data reveals a reversible interaction of diclofenac with dispersed nanoparticle surface, similar to the interaction of this drug with dissolved chitosan·HCl. No such interactions are noticed with ofloxacin. The results from the ultracentrifugation method agree with the above interpretation of dialysis data. This case study shows that dialysis data from a nanoparticle dispersion is not necessarily descriptive of sustained-release from nanoparticles, hence, if interpreted uncritically, it may be misleading.
Asunto(s)
Diálisis/métodos , Diclofenaco/química , Nanopartículas , Ofloxacino/química , Química Farmacéutica/métodos , Quitosano/química , Reactivos de Enlaces Cruzados/química , Preparaciones de Acción Retardada , Diclofenaco/administración & dosificación , Portadores de Fármacos/química , Cinética , Ofloxacino/administración & dosificación , Polifosfatos/química , Reproducibilidad de los Resultados , Tecnología Farmacéutica/métodos , UltracentrifugaciónRESUMEN
The issue of incomplete release of poorly soluble drugs from sustained-release oral formulations is addressed using prednisolone (PDS) as the model drug and a novel highly swelling hydrogel as the rate-controlling material. The hydrogel was formed by heating N-carboxymethylchitosan (CMC) to 80 degrees C for 24 h. Swelling, alkalimetry, FTIR, DSC, and solid-state NMR studies showed that the treatment produced physical crosslinking, i.e., polymer chain entanglement. A controlled-release system was prepared by coating an inert compacted support of ethylcellulose (50 mg; diameter, 6 mm) with a CMC layer containing dispersed PDS powder (10-50 microm). The system was heated to crosslink the CMC coating, then drug release to simulated GI fluids was studied in vitro. The drug release pattern and term were modulated via the layer mass (LM) (10 or 14 mg cm(-2)) and/or the drug-polymer wt ratio (D/P) (1:5 or 2:5). The rate parameter, K, and the time exponent, n, of the Peppas equation were: K=26.6+/-0.3 h(-n), n = 0.78+/-0.02 (LM, 10 mg cm(-2); D/P, 1:5); K = 24.7+/-0.7 h(-n), n = 0.56+/-0.02 (LM, 14 mg cm(-2); D/P, 1:5); K = 20.7+/-0.3 h(-n), n = 0.76+/-0.01 (LM, 10 mg cm(-2); D/P, 2:5). Hydrogel swelling was faster than drug release. This was controlled, in a first stage, by drug dissolution-diffusion in the swollen gel, and subsequently, by diffusion. The drug release rate was unaffected by the GI pH variations, and slightly affected by the environmental hydrodynamics. The system promises an extended and complete release of poorly soluble drugs in the GI tract.
Asunto(s)
Hidrogeles/química , Prednisolona/química , Quitosano/química , Preparaciones de Acción Retardada , Difusión , Tracto Gastrointestinal/química , Tracto Gastrointestinal/metabolismo , Técnicas In Vitro , Cinética , Modelos Biológicos , Tamaño de la Partícula , Polímeros/química , Prednisolona/metabolismo , Solubilidad , Agua/químicaRESUMEN
Colon-specific controlled-delivery 5-fluorouracil (5-FU) matrices for the treatment of colorectal carcinoma were prepared and evaluated. Matrices are destined to be introduced into enteric-coated capsules and thereby carried to and liberated in the ileum. There, drug release should be prevented until matrices reach descending colon where release should occur. Matrices (50 mg, diameter 0.6 mm) were prepared by compression of powders or of granules prepared by melt granulation. The ingredients comprised 30-70% w/w 5-FU, glyceryl palmitostearate as rate-controlling material and 5% w/w Aerosil as glidant. Drug release was measured by the rotating basket method. The matrix containing 60% w/w drug, prepared by compression of powders, was appropriate to make the planned system, in virtue of its fairly high drug load and its nearly constant and reasonable release rate. This matrix was spray-coated with Eudragit S100 (EUD). Subsequently, an external layer of chitosan hydrochloride (CH-HCl) was applied by a dipping-drying technique. When transit of coated matrix through ileum (phosphate buffer (PB) pH 7.4), ascending colon (PB pH 6 containing rat cecal contents) and descending colon (PB pH 7.4) was simulated in vitro, the pH 4.7 of the CH-HCl gel layer and the pH 6 of the ascending colon prevented dissolution of the protective EUD film until descending colon was reached, then controlled release started. The present small matrices can enter size no. 00 capsules. Considering that each capsule contains 10 matrices, the maximal dose is 300 mg.
Asunto(s)
Colon Descendente/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Fluorouracilo/administración & dosificación , Animales , Colon Descendente/metabolismo , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Fluorouracilo/farmacocinética , Ratas , Ratas WistarRESUMEN
The effects of chitosan hydrochloride (Ch-HCl) and of N-carboxymethylchitosan (CMCh), formulated in ophthalmic solutions, on the ocular pharmacokinetics of ofloxacin were studied in rabbits. The carboxymethylation of a chitosan of high molecular mass (1460 kDa) and deacetylation degree (89.9%) introduced 0.84 N-carboxymethyl groups per repeating unit. Aqueous solutions containing 1% (w/v) of either polymer showed a pseudoplastic rheologic behaviour, and, when instilled in rabbit eyes, produced no irritation. The kinetics of drug disappearance from tear fluid and the profiles of drug concentration in the aqueous humour versus time were determined and interpreted in the light of a pharmacokinetic model and of drug-polymer binding. Ch-HCl significantly enhanced intraocular drug penetration with respect to an isoviscous drug solution containing poly(vinyl alcohol) and to commercial ofloxacin eyedrops. This effect, which resulted in about 190% increase of the peak concentration in the aqueous, was ascribed to an increased corneal permeability. The polyanionic CMCh failed to enhance intraocular drug penetration. It nevertheless increased precorneal drug retention in virtue of its viscosity and of ofloxacin binding. Consequently, the residence time at concentrations higher than the MIC90 and the bioavailability of the antibiotic in the aqueous were increased by about 150 and 240%, respectively, with respect to the reference vehicle.
Asunto(s)
Antiinfecciosos/farmacocinética , Quitina/análogos & derivados , Quitina/farmacología , Ojo/metabolismo , Ofloxacino/farmacocinética , Soluciones Oftálmicas/farmacocinética , Animales , Antiinfecciosos/química , Humor Acuoso/química , Disponibilidad Biológica , Quitina/química , Quitosano , Instilación de Medicamentos , Masculino , Ofloxacino/química , Soluciones Oftálmicas/química , Permeabilidad/efectos de los fármacos , Conejos , Lágrimas/químicaRESUMEN
The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH-HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression. The addition of 10, 20 or 30% medicated CH-HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts. The effect was stronger with higher CH-HCl fractions. Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following insertion in the lower conjunctival sac of the rabbit's eye, such an insert produced no substantial increase of AUC(eff) (AUC in the aqueous humour for concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%) for the more resistant ocular pathogens (7 microg/ml vs. 4 microg/ml). It has been argued that the increase was due to the ability of CH-HCl to enhance the transcorneal permeability of the drug.
Asunto(s)
Quitina/análogos & derivados , Quitina/administración & dosificación , Córnea/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Ofloxacino/farmacocinética , Polietilenglicoles/farmacocinética , Animales , Humor Acuoso/efectos de los fármacos , Humor Acuoso/metabolismo , Quitosano , Córnea/efectos de los fármacos , Masculino , Microesferas , Ofloxacino/administración & dosificación , Polietilenglicoles/administración & dosificación , ConejosRESUMEN
When topical controlled delivery of ophthalmic drugs is realised via erodible inserts, drug bioavailability is maximised, if release is controlled exclusively by insert erosion, since parallel mechanisms which increase the release rate, also increases the dose fraction cleared from the precorneal area by tear fluid draining. The respective contributions of diffusion and erosion to the release mechanism of different drugs, namely, prednisolone (PDS), oxytetracycline hydrochloride (OTH) and gentamicin sulfate (GTS), from erodible ocular inserts based on poly(ethylene oxide) (PEO) of molecular weight 400 or 900kDa was determined by an in vitro technique adequate to predict the release mechanism in vivo. PDS and OTH were released with erosion-controlled kinetics. With therapeutic doses of these drugs in the inserts (0.3mg, 1.5%), the possibility of a purely erosive mechanism was shown to rely upon drug-PEO molecular interactions, which limit drug diffusion in the swollen matrix. This was the case with OTH, for which strong interactions with PEO were measured, whereas some contribution from the parallel diffusive mechanism was evidenced for PDS, which showed weaker interactions with polymer. Such a contribution disappeared when the PDS concentration in the insert was increased to 6%, which suggested that the erosive mechanism is favoured by a drug concentration in the hydrated insert substantially higher than solubility. On the other hand, the release of about 50% GTS dose was controlled by diffusion, due to the high water solubility of this drug, accompanied by weak drug-PEO interactions. In this case the residence time of drug in the precorneal area is expected to be significantly shorter than that of the PEO carrier.
Asunto(s)
Excipientes/química , Soluciones Oftálmicas/química , Polietilenglicoles/química , Benzocaína/química , Fenómenos Químicos , Química Farmacéutica , Química Física , Preparaciones de Acción Retardada/química , Gentamicinas/química , Cinética , Peso Molecular , Ofloxacino/química , Prednisolona/químicaRESUMEN
Oral absorption of the antihyperglycaemic agent metformin (MF x HCl) is confined to the upper part of the intestine, therefore controlled-release oral formulations of this drug should ensure a complete release during transit from stomach to jejunum. Compressed matrix tablets based on pH-sensitive poly(ethylene oxide) (PEO)-Eudragit L100 (EUD L) compounds have shown in vitro a compliance with the above requirement. The polymer compounds were prepared by a coevaporation process. The release pattern of MF x HCl from matrices depended on the PEO-EUD L ratio in the coevaporate. The 1:1 (w/w) ratio was unable to control MF x HCl release in simulated gastric fluid (SGF, pH 1.2), because the matrix material was excessively hydrophilic. Nevertheless, the release rate in SGF could be modulated by increasing the EUD L fraction in the coevaporate. With a PEO (M(w), 400 kDa)-EUD L (1:2, w/w) ratio the percent dose released in 2 h to SGF, where the coevaporate was insoluble, was around 23 or 50% with 10 or 20% loading dose. The release was then completed within the successive 2 h of elution with simulated jejunal fluid (SJF, pH 6.8) where EUD L and the coevaporate gradually dissolved. Release in SGF was controlled by matrix swelling and/or drug diffusion in matrix, whereas matrix dissolution controlled release in SJF. The unique release-controlling properties of the polymer compounds were due to PEO-EUD L macromolecular interactions. Matrices show promise of a gradual and complete release of MF x HCl from stomach to jejunum, unaffected by gastric pH fluctuations. This mode of administration might allow the use of lower therapeutic doses compared to existing immediate- or sustained-release products, thus minimising side effects.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Administración Oral , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Sistemas de Liberación de Medicamentos/estadística & datos numéricos , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Concentración de Iones de Hidrógeno , Hipoglucemiantes/farmacocinética , Metformina/farmacocinéticaRESUMEN
A previous study of the present authors on gel-forming erodible inserts, based on high molecular weight (MW, 400 kDa) poly(ethylene oxide) (PEO), for ocular controlled delivery of ofloxacin (OFX) has been extended to investigate the effects of PEO MW, in the 200-2000 kDa range, on insert properties relevant to therapeutic efficacy. Mucoadhesion has shown a dependence on MW, with a maximum for PEO 400. The in vitro drug release from inserts based on PEO 200, PEO 400 and PEO 900 was mainly controlled by insert erosion, whereas with PEO 2000 it was mainly diffusion-controlled in a first phase, followed by an erosion-controlled phase. The erosion time scale depended directly on MW. Immediately after application in the lower conjunctival sac of the rabbit eye, the inserts based on PEO of whichever MW formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. PEO 2000 was unsuitable as an insert material, since the resulting gel spilled from the eye, due to excessive swelling. The gel residence time in the precorneal area, the drug permanence time in the aqueous humor at concentrations > MIC and the time to reach the maximal drug concentration in the aqueous humor (C(max)) depended directly on MW, indicating that transcorneal absorption was governed by gel erosion. All inserts increased Cmax and AUCeff (AUC for concentrations > MIC) with respect to the commercial eyedrops. The increases caused by PEO 400 and PEO 900 were similar (3.78- and 3.16-fold, respectively, for Cmax; 11.06- and 12.37-fold, respectively, for AUCeff), whereas smaller increases were produced by PEO 200. The PEO 400 and PEO 900 inserts have shown a potential for a topical treatment of endophthalmitis.
Asunto(s)
Antiinfecciosos/farmacocinética , Humor Acuoso/metabolismo , Ofloxacino/farmacocinética , Polietilenglicoles , Animales , Antiinfecciosos/administración & dosificación , Disponibilidad Biológica , Excipientes , Masculino , Peso Molecular , Ofloxacino/administración & dosificación , Soluciones Oftálmicas , ConejosRESUMEN
A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.