RESUMEN
Hot-melt coating process (HMCP) was applied to develop a lipid based oral controlled release matrix system (tablet) to deliver highly aqueous soluble drugs using paracetamol as a model drug. Granules prepared from paracetamol and particular filler were coated with different levels of lipid and then compressed into tablets to get controlled/sustained delivery of the drug over an optimum period. Process parameters were optimized with particular focus on fluidization pattern during HMCP proposing a 'design space' with 'Quality by Design' (QbD) concept in mind. The results demonstrated that the granule composition influenced the drug release pattern, and the rate of release could be manipulated by varying the amount of lipid in the formulation. The in vitro release profile of the drug was pH-independent and the most promising release profile was obtained from tablets prepared from granules with the water-soluble filler, lactose, and coated at 9% (w/w) level with a lipid, glyceryl behanate. In vivo plasma profiles of the drug were predicted from the in vitro release profile data by convolution analysis which confirmed that the lactose based formulation with 9% (w/w) lipid coating on the granules would be suitable for controlled delivery of the drug over a period of 12 h making the formulation suitable for highly water soluble drug candidates like paracetamol with twice daily dose regimen. Moreover, the dissolution data adequately fitted into Higuchi model suggesting that the drug release occurred predominantly by diffusion.
Asunto(s)
Portadores de Fármacos/química , Diseño de Fármacos , Lípidos , Agua/química , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos/métodos , Calor , Cinética , Lípidos/química , Microscopía Electrónica de Rastreo , Solubilidad , Propiedades de SuperficieRESUMEN
The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.
Asunto(s)
Medicamentos Genéricos/clasificación , Sulfonamidas/clasificación , United States Food and Drug Administration/normas , Área Bajo la Curva , Disponibilidad Biológica , Cristalización , Aprobación de Drogas , Medicamentos Genéricos/química , Medicamentos Genéricos/farmacocinética , Guías como Asunto/normas , Humanos , Concentración de Iones de Hidrógeno , Estructura Molecular , Estándares de Referencia , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/química , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/clasificación , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacocinética , Solubilidad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Comprimidos , Equivalencia Terapéutica , Torasemida , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
The objective of this study was to identify the factors controlling the arrival of amlodipine into the systemic circulation after oral administration in the fasting state. Dissolution data were collected with the rotating paddle and the flow-through apparatus. Caco-2 cell lines were used to assess the intestinal permeability characteristics. Actual in-vivo data were collected in 24 fasted healthy subjects after single-dose administration of the same amlodipine besylate tablet formulation used in the in-vitro dissolution studies. Regardless of the hydrodynamics, dissolution of amlodipine besylate tablets was rapid and complete in media simulating the contents of the upper gastrointestinal tract in the fasting state. Permeability of amlodipine through Caco-2 cell lines was lower than propranolol's and higher than ranitidine's, indicating that transport through the intestinal mucosa may be one process that limits the arrival into the systemic circulation. Indeed, the de-convoluted profile indicated that arrival into portal blood occurs at rates much slower than gastric emptying or dissolution rates. However, prediction of amlodipine's mean plasma profile after oral administration became possible only after additionally assuming excretion of amlodipine into the bile and a reasonable gastrointestinal residence time. Interestingly, in-vitro permeability data collected in this or in previous studies were inappropriate for simulating the mean actual plasma profile.
Asunto(s)
Amlodipino/farmacocinética , Bilis/metabolismo , Bloqueadores de los Canales de Calcio/farmacocinética , Mucosa Intestinal/metabolismo , Administración Oral , Adulto , Amlodipino/administración & dosificación , Humanos , Concentración de Iones de Hidrógeno , Membranas Artificiales , Permeabilidad , SolubilidadRESUMEN
Loratadine was studied both in vitro and in vivo (in healthy humans) to classify it according to the Biopharmaceutics Classification System (BCS) in order to gain more understanding of the reasons for its highly variable nature with respect to plasma time profiles, and to determine the most appropriate dissolution test conditions for in vitro assessment of the release profile of the drug from solid dose forms. Based on the solubility of loratadine determined under various pH conditions and its permeability through Caco-2 monolayers, loratadine was classified as a Class II drug. Plasma profiles were predicted by convolution analysis using dissolution profiles obtained under various pH and hydrodynamic conditions as the input function and plasma time data obtained from a syrup formulation as the weighting function. The predicted profiles based on dissolution studies done at gastric pH values were in reasonable agreement with the mean bio-data suggesting dissolution testing should be done at gastric pH values. However, the bio-data were highly variable and it is suggested this may be due, at least in part, to high individual gastric pH variability and dissolution occurring in the intestine on some occasions, and therefore, dissolution testing should also be done in simulated intestinal fluid.