RESUMEN
Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.
Asunto(s)
Diltiazem/farmacocinética , Ácidos Polimetacrílicos/química , Compuestos de Amonio Cuaternario/química , Disponibilidad Biológica , Tampones (Química) , Carbohidratos/química , Celulosa/química , Preparaciones de Acción Retardada , Diltiazem/administración & dosificación , Diltiazem/química , Excipientes/química , Ácido Clorhídrico/química , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Vasodilatadores/administración & dosificación , Vasodilatadores/química , Vasodilatadores/farmacocinéticaRESUMEN
A cationic polymethacrylate coated multiparticulate diltiazem formulation exhibited sigmoidal drug release. Lag time prior to drug release was influenced by dissolution media, coat thickness, and by the nature of additives included in the formulation. Incorporation of up to 5% w/w sodium lauryl sulfate (SLS) in the coating membrane resulted in substantial increases in lag times in acidic and neutral media. The extent of drug release in acid was 100%, whereas in phosphate buffer, the extent of release was dependent on the level of SLS. Substituting SLS for various compounds was used to assess the functionality of the SLS molecule responsible for these behaviors. The ability to ion-pair with the polymer and the presence of a hydrophobic moiety were both important functionalities.
Asunto(s)
Resinas Acrílicas/química , Diltiazem/química , Excipientes/química , Polímeros/química , Tensoactivos/química , Química Farmacéutica , Citratos/química , Concentración de Iones de Hidrógeno , Dodecil Sulfato de Sodio/química , SolubilidadRESUMEN
Drug release from single pellets was measured on an easily assembled flow-through system. Despite heterogeneity between pellets, the sum of the individual results resembled drug release from an ensemble. A typical pellet displayed a long lag followed by rapid release. Heterogeneity appeared to result from substrate properties rather than coating uniformity. Swelling behavior in acid and buffer was measured by dynamic image analysis and related to drug release. Drug release was sensitive to dissolution temperature but swelling was not. A description of the drug release process was proposed.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Diltiazem/química , Ácidos Polimetacrílicos/química , Compuestos de Amonio Cuaternario/química , Implantes de Medicamentos , Tamaño de la Partícula , Factores de TiempoRESUMEN
Dynamic image analysis (DIA) was used to measure particle diameter (D50) of in-process samples removed during fluid bed coating. A single, rapid measurement gave D50 to within 4 mum. Samples removed at intervals of 2% weight gain were readily distinguishable by DIA and by their drug release profiles. Drug release was related to D50. DIA was assessed as a surrogate dissolution test with considerable potential. Current limitations of the approach were presented.
Asunto(s)
Materiales Biocompatibles Revestidos/análisis , Procesamiento de Imagen Asistido por Computador/métodos , Tamaño de la Partícula , FarmacocinéticaRESUMEN
Drugs layering experiments were performed in a fluid bed fitted with a rotor granulator insert using diltiazem as a model drug. The drug was applied in various quantities to sugar spheres of different mesh sizes to give a series of drug-layered sugar spheres (cores) of different potency, size, and weight per particle. The drug presence lowered the bulk density of the cores in proportion to the quantity of added drug. Polymer coating of each core lot was performed in a fluid bed fitted with a Wurster insert. A series of polymer-coated cores (pellets) was removed from each coating experiment. The mean diameter of each core and each pellet sample was determined by image analysis. The rate of change of diameter on polymer addition was determined for each starting size of core and compared to calculated values. The core diameter was displaced from the line of best fit through the pellet diameter data. Cores of different potency with the same size distribution were made by layering increasing quantities of drug onto sugar spheres of decreasing mesh size. Equal quantities of polymer were applied to the same-sized core lots and coat thickness was measured. Weight/weight calculations predict equal coat thickness under these conditions, but measurable differences were found. Simple corrections to core charge weight in the Wurster insert were successfully used to manufacture pellets having the same coat thickness. The sensitivity of the image analysis technique in measuring particle size distributions (PSDs) was demonstrated by measuring a displacement in PSD after addition of 0.5% w/w talc to a pellet sample.
Asunto(s)
Química Farmacéutica/métodos , Comprimidos Recubiertos/química , Formas de Dosificación , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Image analysis was used to measure particle size distributions (PSDs) of ensembles of 425 to 1400 microm-size materials. Repeatability of a measurement, suitable sample sizes, and methods of sampling were assessed. Two lots of inert spheres were compared prior to drug layering in a Glatt GPCG-5 rotor. The differences in PSD in the starting materials were reflected in the rotor-granulated products. Such detailed information was not available from sieving with U.S. standard wire mesh sieves. The products from the rotor process were polymer-coated in a Wurster process in a Glatt GPCG-3, 4-in. Wurster. The resolution of the technique was sufficient to measure differences in diameter equating to 4-microm coat thickness, which resulted from applying 2% polymer coat weight. The utility of the technique for monitoring commercial scale processes was demonstrated by measuring diameter after layering drug onto nonpareils in a Glatt RG-150 rotor, and by measuring the diameter after application of a polymer solution in a Glatt 46-in. Wurster coating process. The similarity of samples removed from the sample port in situ and samples from the batch suggested that processes in the fluid bed are intensively mixed and inherently random.