RESUMEN
Using spectroscopic and thermal analysis, this study investigated drug-polymer interaction and its significance on the physical stability of drug amorphous dispersion in microparticles of an ammonio polymethacrylate copolymer (Eudragit RL) (RL) and ethylcellulose (EC) binary blend (RL/EC = 2:1 w/w) prepared for use in controlled release of poorly water-soluble drugs. Solid dispersion of the model drug, nifedipine in the microparticles could be described as an ideal amorphous mixture for drug loadings up to 11% w/w. The antiplasticizing effect of the polymer blend was indicated by a significant increase in the glass transition point from approximately 50 degrees C for the amorphous nifedipine to approximately 115 degrees C for its solid solution. Moreover, shifts in infrared vibration wavenumber of nifedipine carbonyl and amine groups suggested that the hydrogen bonds (H-bonds) originally formed among nifedipine molecules were broken and replaced by those formed between nifedipine and polymers in the microparticles. Further infrared analysis on nifedipine amorphous dispersions with a single polymer, namely RL or EC, confirmed the proposed hydrogen-bonding interactions; and their stability study results suggested that both antiplasticizing effects and hydrogen bonding of EC and RL with nifedipine might be responsible for the physical stability of the microparticles of nifedipine amorphous dispersion with a RL/EC binary blend.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Celulosa/análogos & derivados , Nanopartículas/química , Nifedipino/química , Polímeros/química , Bloqueadores de los Canales de Calcio/administración & dosificación , Rastreo Diferencial de Calorimetría , Celulosa/química , Fenómenos Químicos , Química Farmacéutica , Química Física , Cristalización , Estabilidad de Medicamentos , Enlace de Hidrógeno , Nanopartículas/administración & dosificación , Nifedipino/administración & dosificación , Tamaño de la Partícula , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
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
The objective of this study is to explore matrix-type microparticles, comprising a solid dispersion of drug with an ammonio methacrylate copolymer and ethylcellulose binary blend, for use in the controlled release of a poorly water-soluble drug, nifedipine. Microparticles consisting of an ethylcellulose N7 (N7) and Eudragit RL (RL) binary blend at different ratios were prepared using phase-separation methodology. The effects of matrix composition on microparticle properties were evaluated by polarized light microscopy, differential scanning calorimetry (DSC), FT-infrared and UV-visible spectroscopy, stability, and drug release studies. Study results indicate that the particle size distribution, particle morphology, and drug release rate from the microparticles were influenced by the ratio of RL to N7. Discrete spherical microparticles with a narrow size distribution and a controlled release profile were obtained when the ratio of RL to N7 was in the range from 1:1 to 2:1 w/w. Solid-state characterization and release kinetic studies on these microparticles confirmed that the nifedipine release from the microparticles followed the Baker and Lonsdale's matrix diffusion model (1974) for microspheres containing dissolved drug, and the nifedipine diffusion in the microparticle matrix was the rate-limiting step. As the ratio of RL to N7 was changed from 0:1 to 4:1 w/w, the effective drug diffusion coefficient in the micro-matrix increased from 5.8 x 10-10 to 8.6 x 10-9 (cm2/h). In addition, probably due to formation of a stable molecular dispersion promoted by hydrogen bonding between nifedipine and the polymers, no significant changes in the nifedipine physical form or release kinetics were observed after 1-year storage at ambient room temperature followed by 3-month accelerated stability at 40 degrees C/75% RH in a closed container.
Asunto(s)
Resinas Acrílicas , Celulosa/análogos & derivados , Portadores de Fármacos , Nifedipino/administración & dosificación , Resinas Acrílicas/química , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacocinética , Rastreo Diferencial de Calorimetría , Celulosa/química , Química Farmacéutica , Preparaciones de Acción Retardada , Difusión , Composición de Medicamentos , Estabilidad de Medicamentos , Humanos , Técnicas In Vitro , Nifedipino/farmacocinética , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
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
The purpose of this work was to determine the total amount of water contained in dry powder and wet bead samples of microcrystalline cellulose, MCC, (Avicel PH-101), taken from various stages of the extrusion/marumerization process used to make beads and to determine the kinetic rates of water release from each sample. These samples were allowed to equilibrate in controlled humidity chambers at 25 degrees C. The total amount of water in each sample, after equilibration, was determined by thermogravimetric analysis (TGA) as a function of temperature. The rates of water release from these samples were determined by using isothermal gravimetric analysis (ITGA) as a function of time. Analysis of the results for these studies suggest that water was released from these systems by several different kinetic mechanisms. The water release mechanisms for these systems include: zero order, second order, and diffusion controlled kinetics. It is believed that all three kinetic mechanisms will occur at the same time, however; only one mechanism will be prominent. The prominent mechanism was based on the amount of water present in the sample.
Asunto(s)
Celulosa/química , Química Farmacéutica , Excipientes/química , Termogravimetría , Agua/química , Difusión , Humedad , Cinética , Polvos/química , Temperatura , HumectabilidadRESUMEN
In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.
Asunto(s)
Resinas Acrílicas/química , Bloqueadores de los Canales de Calcio/química , Celulosa/análogos & derivados , Nifedipino/química , Celulosa/química , Preparaciones de Acción Retardada , Difusión , Composición de Medicamentos , Cinética , Modelos Químicos , Tamaño de la Partícula , SolubilidadRESUMEN
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.
Asunto(s)
Preparaciones Farmacéuticas/química , Química Farmacéutica/métodos , Química Física/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Tamaño de la PartículaRESUMEN
An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Algoritmos , Animales , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica , Perros , Formas de Dosificación , Esquema de Medicación , Excipientes , Predicción , Inyecciones Intravenosas , Modelos Animales , Solubilidad , Teofilina/administración & dosificación , Teofilina/sangre , Teofilina/farmacocinéticaRESUMEN
Our previous study has successfully prepared a combination of immediate release, enteric coated, and controlled release (CR) beads and mathematically modeled in vitro drug release characteristics of the combination based on the release profiles of individual beads. The objectives of the present study are to evaluate the combination and individual beads in vivo and to mathematically model in vivo drug input characteristics of the combination based on the in vivo input of individual beads. Beagle dogs were used as an animal model, and theophylline as a model drug. In vivo percent drug absorbed at different times (input function) after administration of a capsule bead dosage form was calculated using the Wagner-Nelson deconvolution method using intravenous injection of theophylline in each dog as a reference. The in vivo input functions of individual beads were each fitted to appropriate mathematical equations. The in vivo input function of the bead combination dosage form was calculated based on the individual mathematical equations (expected), and verified experimentally in vivo (experimental). The results showed that all bead dosage forms behave in vivo as defined in vitro. Enteric coated beads significantly delay the time to reach the maximum concentration of drug (tmax=4.9 h) compared to uncoated immediate release beads (2 h). The lag time of enteric coated beads is 1.1 h. CR beads showed both longer tmax (6 h) and mean residence time (MRT=9.7 h) compared to the uncoated immediate release beads (tmax=2 h and MRT=7.1 h) as designed in vitro. The in vivo input functions for the three individual beads can be fitted to equations as a function of square root of time. The combined bead dosage form showed tmax of 2.4 h and MRT of 7.9 h. The experimental and expected in vivo input profiles agreed to within +/- 12% (residues at individual data points). Our results suggest that the drug input function of a combined multi-mechanism oral dosage form can be predicted from the in vivo performance of individual formulations using the dog as an in vivo model.
Asunto(s)
Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos/métodos , Predicción , Teofilina/farmacocinética , Administración Oral , Algoritmos , Animales , Disponibilidad Biológica , Cápsulas , Perros , Esquema de Medicación , Estabilidad de Medicamentos , Gelatina , Masculino , Modelos Animales , Soluciones , Comprimidos , Teofilina/administración & dosificación , Teofilina/sangre , Factores de TiempoRESUMEN
The objective of this study was to prepare a combination of immediate release, enteric coated, and controlled release (CR) beads and to mathematically model in vitro drug release characteristics of the combination based on the release profiles of individual beads. Uncoated beads were manufactured by using extrusion/spheronization technology. Fluid-bed bottom spraying was used for coating: Eudragit-L-30D for enteric coating and Eudragit-NE-30D for CR coating. In vitro drug release profiles for uncoated and coated beads were each fitted to appropriate mathematical equations. The drug release from the bead combination dosage form was predicted from the individual mathematical models and verified experimentally in vitro. The in vitro dissolution was conducted in 0.1 N HCl for 2 hr and then in buffer (pH 6.5 phosphate, 0.05 M) to mimic in vivo conditions using USP dissolution apparatus I. The results showed that uncoated beads gave similar release profiles in water, acid, and buffer with complete release within 2 hr. The release from CR beads was about 50% at 10 hr and was independent of the dissolution medium. As expected, enteric coated beads showed drug release < 5% at 2 hr in water and acid, whereas the release in buffer was comparable to that of uncoated beads. Exposure of enteric coated beads to acid for 2 hr produced a slower release rate in buffer compared with the release from beads added directly in the buffer. The release characteristics of the three beads can be described by square root and zero-order kinetics. The release characteristics from the combination dosage form were 39%, 69%, and 81% at 1, 4, and 8 hr, respectively. The experimental and predicted profiles agreed to within +/- 6% (residuals at individual data points). Our results suggest that release from the combined multimechanism oral dosage form can be predicted from the performance of individual beads.
Asunto(s)
Formas de Dosificación , Preparaciones Farmacéuticas/administración & dosificación , Algoritmos , Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Química Farmacéutica , Preparaciones de Acción Retardada , Excipientes , Modelos Estadísticos , Ácidos Polimetacrílicos , Solubilidad , Comprimidos Recubiertos , Teofilina/administración & dosificación , Teofilina/farmacocinéticaRESUMEN
The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80 degrees C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.
Asunto(s)
Preparaciones de Acción Retardada , Comprimidos/química , Ceras/química , Química Farmacéutica , Composición de Medicamentos , Estabilidad de Medicamentos , Excipientes/química , Ácidos Grasos/química , Calefacción , Fenilpropanolamina/química , Solubilidad , Teofilina/química , Factores de TiempoRESUMEN
Oral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of cyclobenzaprine hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water inhibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150-510 microns diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.
Asunto(s)
Amitriptilina/análogos & derivados , Amitriptilina/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Excipientes/administración & dosificación , Polietilenglicoles/administración & dosificación , Administración Oral , Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Excipientes/química , Humanos , Presión Osmótica , Polietilenglicoles/química , ComprimidosRESUMEN
Osmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems. The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pin-holes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity. Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core. The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.
Asunto(s)
Amitriptilina/análogos & derivados , Amitriptilina/administración & dosificación , Tranquilizantes/administración & dosificación , Química Farmacéutica , Excipientes/química , Membranas Artificiales , Presión Osmótica , Polietilenglicoles/química , ComprimidosRESUMEN
The impact of controlled release (CR) formulations having different gel strength values (gamma) on in vivo tablet performance and the in vitro/in vivo correlation of the formulations was investigated. The CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose to produce tablets with a polymer content of 8 and 30% w/w. gamma was measured using a previously reported method. Male beagle dogs were utilized. Results showed that dissolution profiles were similar for all three polymers at the same % w/w level of polymer, irrespective of media (DI H2O, 0.1 N HCl, and pH 6.8 phosphate buffer). Mean gamma values were significantly different (p < or = 0.05) and were in order of HPMC K100MP > HPC HXF > carbomer 971P (same 30% w/w) with absolute gamma values at 30% w/w in DI H2O of 6600, 4600, and 1600 ergs/cm3, respectively. Drug profiles in plasma for the 30% HPMC K100MP tablets were consistent with in vitro dissolution profiles and gamma values. Plasma profiles for the 30% HPC HXF tablets were similar in vivo as the HPMC tablets. Plasma profiles for the 30% carbomer 971P formulation showed much higher drug concentrations (compared to HPMC and HPC) in vivo in all dogs. This findings is not consistent with the slow drug release found in the dissolution profiles but consistent with its low in vitro gamma values. Assessment of the predictability of a level A in vitro/in vivo correlation was quantified by absolute mean percent prediction error (PE). Formulations having gamma approximately 6000 ergs/cm3 have acceptable PE < 20%, and low standard deviation (sigma). Results showed that gamma values of CR hydrogel tablets in vitro will affect the in vivo performance (i.e., absorption kinetics of the drug) of the tablets and were also found to better assess (compared to in vitro dissolution profiles alone) the predictability of in vitro/in vivo correlations (level A and multiple level C).
Asunto(s)
Celulosa/análogos & derivados , Preparaciones de Acción Retardada , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Lactosa/análogos & derivados , Metilcelulosa/análogos & derivados , Teofilina/administración & dosificación , Resinas Acrílicas , Animales , Celulosa/administración & dosificación , Química Farmacéutica , Perros , Lactosa/administración & dosificación , Masculino , Metilcelulosa/administración & dosificación , Oxazinas , Polivinilos/administración & dosificación , Solubilidad , Comprimidos , Teofilina/química , Teofilina/farmacocinéticaRESUMEN
An adjusted pharmacokinetic equation that predicts in vivo plasma drug profiles for controlled release (CR) dosage forms having square root of time drug release kinetics has been derived. The CR hydrogel tablets containing hydroxypropyl methylcellulose (HPMC) were formulated with theophylline and Fast Flo lactose, to produce tablets with HPMC K100MP content of 30% w/w. Plasma profiles in vivo were determined from four male beagle dogs. Tablet gel strength (gamma) was measured as previously reported. Results show drug release in vitro follows square root of time kinetics for the formulation in all media (purified H2O, 0.1 N HCl, and pH 6.8 phosphate buffer). The gamma values were not significantly different (p > 0.05) among the tablets in different dissolution media, with absolute values in DI H2O of 6600 erg/cm3, which is above the minimum threshold value of gamma (approximately 6000 erg/cm3) needed for acceptable in vitro/in vivo correlation. Comparison of predicted and observed plasma profiles in vivo, using the adjusted square root pharmacokinetic equation, showed a better fit of the overall pattern and absolute values of the in vivo data as compared to equations that assume first- or zero-order drug release from the HPMC based tablets. The adjusted square root pharmacokinetic equation can serve as a valuable aid in the design of formulations to yield a desired plasma profile in vivo and provides supporting evidence to the mechanism of drug release in vitro.