RESUMEN

Typically, smooth lactose particles are used as carrier in dry powder formulations for inhalation. Two classical approaches to improve their aerodynamic behaviour are the addition of fines (milled lactose) or magnesium stearate (MgSt). Mannitol (Parteck® M DPI) as an alternative carrier was used in this study. It has an irregular particle size distribution and a large and rough surface. This could be challenging for the detachment of micronised drug upon inhalation and it is unclear whether classic strategies for the optimisation of aerodynamic performance can be applied. In contrast, its rough surface could be an advantage in terms of drug load. To address these questions, the mannitol carrier was blended with two different drugs using various concentrations up to 50%. Self-produced mannitol fines and MgSt in different amounts and in combination were added. Blends were investigated regarding their in vitro aerodynamic performance, dosing behaviour and powder rheology. An addition of up to 30% drug load was possible while retaining good flowability and constant dosing behaviour. Despite the rough and indented carrier surface of the mannitol carrier, the addition of fines or MgSt increased the inhalable fraction, but higher concentrations of fines, as used for lactose blends, were necessary.

Asunto(s)

Inhaladores de Polvo Seco , Manitol , Administración por Inhalación , Portadores de Fármacos , Lactosa , Tamaño de la Partícula , Polvos

RESUMEN

In dry powder inhalation (DPI), larger carrier particles, typically lactose, are blended with micronised active pharmaceutical ingredient (API) particles to improve handling, processability and inhalable fraction. Alternative carrier materials were researched for years, but did not enter the market yet. In this study, a common lactose carrier for DPI formulations and a spray granulated mannitol carrier were compared to evaluate if the particle engineered mannitol can be considered a serious alternative. Blends with five different API concentrations (0.1 to 4%) were prepared with two APIs. Physical carrier and blend characterisation regarding particle size, morphology, density, shear cell testing and dosing behaviour were performed. Aerodynamic assessment was done using two different inhaler devices (one capsule-based inhaler and one reservoir-based inhaler). In addition, the influence of different flow rates was examined. Results indicated that uniform dosing in metered mass and delivered dose over this API concentration range was achieved due to good flowability of the blends. Furthermore, linear dose delivery could be seen over the added API concentrations. Impaction analysis showed that the respirable fractions of mannitol blends were comparable (for salbutamol sulphate blends) or higher (for budesonide blends) than with a standard lactose carrier.

Asunto(s)

Administración por Inhalación , Budesonida/administración & dosificación , Portadores de Fármacos , Inhaladores de Polvo Seco/estadística & datos numéricos , Lactosa/administración & dosificación , Manitol/administración & dosificación , Fenómenos Mecánicos , Albuterol/administración & dosificación , Tamaño de la Partícula

RESUMEN

Recently, many efforts are taken to identify the intestinal uptake and efflux transporters since they are responsible for the absorption of many drugs as their interactions. Norfloxacin (NFX) is a fluoroquinolone that presents low solubility and low permeability, and as a consequence, low bioavailability. In this context, the aim of this study is evaluate for the first time the intestinal permeability mechanisms of NFX by Ussing chamber model. The low permeation of NFX at low temperature, where the efflux pumps are not active, reveals that NFX permeation is transporter-dependent. The permeation study at different level of intestine demonstrated that NFX passage is in the decrescent order: ileum > jejunum > duodenum > colon, probably attributed to transporters that are expressed differently along the intestinal tract. NFX intestinal flow was evaluated in the presence of many inhibitors and substrates to identify the uptake and efflux transporters implicate in NFX permeability mechanism. It could be observed that BCRP and MRPs are involved in the NFX efflux and PEPT1, PMAT and OCT in the NFX uptake transport. Furthermore, this work revealed that NFX has itself an affinity for OCTN and OATP, demonstrating that NFX could inhibit these transporters and influence the absorption of other drugs. The updated description of NFX intestinal permeability factors could contribute to the development of rational pharmaceutical formulations that could circumvent the efflux problems and consequently improve NFX biopharmaceutical properties and avoid drug-drug interactions.

Asunto(s)

Antibacterianos/metabolismo , Absorción Intestinal , Mucosa Intestinal/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Norfloxacino/metabolismo , Animales , Transporte Biológico , Masculino , Ratas Wistar

RESUMEN

The blending process is a key step in the production of dry powder inhaler formulations, but only little is known about the influence of process parameters. This is especially true for high shear blending of ternary formulations. For this reason, this study aims to investigate the influence of high shear mixing process parameters (mixing time and rotation speed) on the fine particle fraction (FPF) of ternary mixtures when using budesonide as model drug, two different carrier materials and two different mixing orders. Prolonged mixing time and higher rotation speeds led to lower FPFs, possibly due to higher press-on forces acting on the active pharmaceutical ingredients (API). In addition, a clear correlation between the energy consumption of the blender (the energy input into the blend) and the reduction of the FPF could be shown. Furthermore blending the carrier and the fines before adding the API was also found to be favorable.

Asunto(s)

Budesonida/química , Polvos/química , Administración por Inhalación , Química Farmacéutica/métodos , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Inhaladores de Polvo Seco/métodos

RESUMEN

The present study investigates the effect of different carrier surface modifications on the aerosolisation performance and on the effective carrier payload of interactive blends for inhalation. Two different active pharmaceutical ingredients (APIs) were used: Formoterol fumarate dihydrate (FF) and budesonide (BUD). Blends were prepared with glass beads as model carriers which have been subjected to mechanical surface modifications in order to introduce surface roughness via treatment with hydrofluoric acid (HF) and/or milling with tungsten carbide (TC). As far as effective carrier payload, in this study expressed as true surface coverage (TSC), is concerned, surface modification had varying effects on blends containing BUD or FF. Aerodynamic characterisation in vitro showed a significant decrease in respirable fraction for glass beads treated with HF (40.2-50.1%), due to the presence of clefts and cavities, where drug particles were sheltered during inhalation. In contrast, grinding with TC leads to surface roughness on a nano scale, ultimately increasing aerodynamic performance up to 20.0-38.1%. These findings are true for both APIs, regardless of their chemical properties.

Asunto(s)

Portadores de Fármacos/química , Inhaladores de Polvo Seco , Vidrio/química , Aerosoles , Broncodilatadores/química , Budesonida/química , Composición de Medicamentos , Fumarato de Formoterol/química , Ácido Fluorhídrico/química , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Propiedades de Superficie , Compuestos de Tungsteno/química

RESUMEN

The aim of the study was to evaluate the association between in utero exposure to drugs that potentially exhibit immunosuppressive activity and occurrence of infections during the first year of life. We conducted a cohort study on the prescription data of pregnant women and their children registered in EFEMERIS cohort (France), during a one-year period. We classified in utero child exposure according to the number of reimbursements for immunosuppressive drugs during pregnancy. The number of infectious episodes during the first year of life was estimated through the number of anti-infective drugs dispensed. The association was estimated by a quasi-Poisson regression with adjustment for confounders. The study population consisted of 9614 children, 3141 of whom had been exposed to immunosuppressive drugs during pregnancy. The most frequently immunosuppressive drugs prescribed were corticosteroids. The mean number of infectious episodes during the first year after birth gradually increased with the number of immunosuppressive drugs dispensed during pregnancy (from 2.38 in controls to 3.88 in the most exposed group). After adjustment for potential confounders, in utero exposure to immunosuppressive drugs was significantly associated with the number of infectious episodes during the first year of life (RR 3ormoreexposuresVS0=1.35, 95% CI 1.24-1.46). Intrauterine exposure to potentially immunosuppressive drugs could be associated with an increased susceptibility to infections in early childhood.

Asunto(s)

Enfermedades Transmisibles/etiología , Enfermedades Transmisibles/inmunología , Inmunosupresores/efectos adversos , Inmunosupresores/inmunología , Útero/efectos de los fármacos , Útero/inmunología , Adulto , Estudios de Cohortes , Femenino , Francia , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Riesgo

RESUMEN

Glucocorticoids are widely used for the management of inflammatory bowel disease, albeit with known limitations for long-term use and relevant adverse effects. In turn, they have harmful effects in experimental colitis. We aimed to explore the mechanism and possible implications of this phenomenon. Regular and microbiota depleted C57BL/6 mice were exposed to dextran sulfate sodium (DSS) to induce colitis and treated with budesonide. Colonic inflammation and animal status were compared. In vitro epithelial models of wound healing were used to confirm the effects of glucocorticoids. Budesonide was also tested in lymphocyte transfer colitis. Budesonide (1-60µg/day) exerted substantial colonic antiinflammatory effects in DSS colitis. At the same time, it aggravated body weight loss, increased rectal bleeding, and induced general deterioration of animal status, bacterial translocation and endotoxemia. As a result, there was an associated increase in parameters of sepsis, such as plasma NOx, IL-1ß, IL-6, lung myeloperoxidase and iNOS, as well as significant hypothermia. Budesonide also enhanced DSS induced colonic damage in microbiota depleted mice. These effects were correlated with antiproliferative effects at the epithelial level, which are expected to impair wound healing. In contrast, budesonide had significant but greatly diminished deleterious effects in noncolitic mice or in mice with lymphocyte transfer colitis. We conclude that budesonide weakens mucosal barrier function by interfering with epithelial dynamics and dampening the immune response in the context of significant mucosal injury, causing sepsis. This may be a contributing factor, at least in part, limiting clinical usefulness of corticoids in inflammatory bowel disease.

Asunto(s)

Antiinflamatorios/uso terapéutico , Budesonida/uso terapéutico , Modelos Animales de Enfermedad , Fármacos Gastrointestinales/uso terapéutico , Glucocorticoides/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Traslocación Bacteriana/efectos de los fármacos , Biomarcadores/sangre , Budesonida/administración & dosificación , Budesonida/efectos adversos , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Colon/patología , Sulfato de Dextran , Relación Dosis-Respuesta a Droga , Disbiosis/inducido químicamente , Disbiosis/etiología , Disbiosis/prevención & control , Endotoxemia/inducido químicamente , Endotoxemia/etiología , Endotoxemia/prevención & control , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/fisiopatología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Organismos Libres de Patógenos Específicos , Pérdida de Peso/efectos de los fármacos

RESUMEN

In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water). The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p0 until 0.5 p/p0) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content. In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8bar, 1-3 grinding cycles), respectively.

Asunto(s)

Preparaciones Farmacéuticas/química , Tecnología Farmacéutica/métodos , Absorción Fisicoquímica , Química Farmacéutica , Cristalización , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Preparaciones Farmacéuticas/normas , Tecnología Farmacéutica/normas , Volatilización , Agua/química

RESUMEN

Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTß) as well as inhibition of hepatocellular BS uptake through basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTß and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/genética , Colestasis/genética , Proteínas de Transporte de Membrana/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Ácidos y Sales Biliares/metabolismo , Transporte Biológico , Colestasis/patología , Colestasis/terapia , Regulación de la Expresión Génica , Humanos , Proteínas de Transporte de Membrana/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/genética , Simportadores/metabolismo , Activación Transcripcional/genética

RESUMEN

The aim of this study was to investigate the stability of four corticosteroids in the presence of human colonic bacteria to understand better their luminal behaviour when delivered orally in the treatment of inflammatory bowel disease. The stability of prednisolone, budesonide, beclometasone (17, 21) dipropionate (BDP) and its active metabolite, beclometasone-17-monopropionate (17-BMP), were investigated at three different concentrations following incubation in a mixed faecal inoculum (simulated human colonic fluid) under anaerobic conditions. Prednisolone, at all three concentrations, was completely degraded within 3 h. The degradation of budesonide progressed at a slower rate, with complete degradation occurring within 7h; the degradation of the S epimer of budesonide was faster than the R epimer. BDP degraded completely within 2 h while its active metabolite 17-BMP was comparatively stable. In contrast to the results in the faecal inoculum, all molecules were stable in the simulated colonic fluid in the absence of human faeces (control). This study demonstrates that prednisolone, BDP and budesonide are completely metabolized in simulated human colonic fluid and confirms the role of colonic bacteria in the metabolism of corticosteroids.

Asunto(s)

Bacterias/metabolismo , Beclometasona/metabolismo , Budesonida/metabolismo , Colon/microbiología , Prednisolona/metabolismo , Beclometasona/análogos & derivados , Heces/microbiología , Humanos