RESUMEN
The purpose of this study was to demonstrate the usefulness and wide applicability of a taste sensor and a new disintegration testing apparatus in the development and/or evaluation of orally disintegrating tablets (ODTs). In this paper, we described methods for the effective utilization of a taste sensor in the development of a new medicine. First we predicted the taste of propiverine hydrochloride, a model drug substance whose taste is unknown, using a taste sensor. Then we screened masking agents for their ability to suppress the bitterness of propiverine hydrochloride, and manufactured ODTs of propiverine hydrochloride with various masking agents. The tastes of these ODTs were then evaluated in chronological order by combining the taste sensor with the new disintegration testing apparatus, ODT-101, to resemble the oral cavity. As a result, we were able to evaluate the taste of propiverine hydrochloride and the effectiveness of various masking agents in ODTs. The result using this combination of taste sensor and ODT-101 shows good agreement with the results of human gustatory sensation testing, thus demonstrating the usefulness and applicability of the taste sensor and disintegration testing apparatus, ODT-101, in the development of new medicine.
Asunto(s)
Bencilatos/farmacología , Química Farmacéutica/métodos , Composición de Medicamentos/instrumentación , Composición de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Gusto/efectos de los fármacos , Administración Oral , Bencilatos/administración & dosificación , Bencilatos/química , Química Farmacéutica/instrumentación , Humanos , Boca/fisiología , Valor Predictivo de las Pruebas , Saliva/química , Saliva/fisiología , Solubilidad , Edulcorantes/administración & dosificación , Edulcorantes/química , Edulcorantes/farmacología , ComprimidosRESUMEN
The preformulation, solubilization and pharmacokinetic evaluation of antalarmin, a stress inhibitor, have been conducted. Antalarmin has a poor water solubility of less than 1 microg/mL and is weakly basic with an experimentally determined pK(a) of 5.0. Multiple solubilization approaches including pH-control either alone or in combination with cosolvents, surfactants and complexing agents have been investigated. The applicability of lipid-based systems has also been explored. Four formulations, each with a targeted drug loading capacity of 100 mg/mL, show potential for oral administration. Three of these formulations are aqueous solutions (10% ethanol + 40% propylene glycol; 20% cremophor EL; 20% sulfobutylether-beta-cyclodextrin) each buffered at pH 1. The fourth formulation is a lipid-based formulation comprising of 20% oleic acid, 40% cremophor EL and 40% Labrasol. No precipitation was observed following dilution of the four formulations with water and enzyme free simulated gastric fluid. However, only the lipid-based formulation successfully resisted drug precipitation following dilution with enzyme free simulated intestinal fluid. Pharmacokinetic analysis conducted in rats revealed that the 20% cremophor EL solution formulation has a fivefold higher oral bioavailability compared to a suspension formulation. The lipid-based formulation resulted in over 12-fold higher bioavailability as compared to the suspension formulation, the highest amongst the formulations examined.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacocinética , Pirroles/química , Pirroles/farmacocinética , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Estrés Fisiológico/efectos de los fármacos , Animales , Química Farmacéutica , Masculino , Ratas , Ratas Endogámicas F344 , Receptores de Hormona Liberadora de Corticotropina/fisiología , Solubilidad , Estrés Fisiológico/fisiologíaRESUMEN
The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is found to be a more efficient solubilizer for all the drugs studied. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model is used to estimate the drug solubility in NMP-water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that it's strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log K (ow) of the drugs and the cosolvency coefficients. The correlation between log K (ow) and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes.
Asunto(s)
Preparaciones Farmacéuticas/química , Pirrolidinonas/química , Solventes/química , Etanol/química , Modelos Químicos , Polímeros/química , Glicoles de Propileno/química , Solubilidad , Tensión Superficial , Tecnología Farmacéutica/métodos , Temperatura , Agua/químicaRESUMEN
This manuscript is a study of precipitation of insoluble drug upon dilution from the pH-cosolvent solubilized formulation with simulated blood fluid. An equation is developed to estimate drug precipitation upon dilution of combined pH-cosolvent solubilized formulations. This is an extension of a previous equation used for the estimation of drug precipitation from simple pH controlled formulations. The proposed equation considers the effect of the cosolvent and its concentration on the pK(a) of the drug as well as all buffering species. According to the proposed equation and our experimental data, the addition of cosolvent on the pH solubilized formulation could increase total drug solubility in the formulation. However, the solubility after dilution became lower than the 0% ethanol formulation because of the change in both drug and buffer pK(a) values. Since this equation is based on the equilibrium condition, it is the worst case scenario for precipitation. This equation provides useful information regarding the feasibility of the successful use of pH-cosolvent combinations in drug formulation.
Asunto(s)
Química Farmacéutica , Preparaciones Farmacéuticas/química , Solventes/química , Algoritmos , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Simulación por Computador , Concentración de Iones de Hidrógeno , Fenitoína/administración & dosificación , Fenitoína/químicaRESUMEN
An equation is developed for estimating the precipitation that may occur upon diluting or injecting a (pH-)solubilized drug formulation. Since it is based on equilibrium, it is the worst case scenario for precipitation. This equation can be programmed in any commercially available spread sheet program such as Excel. According to the proposed equation, the type and the strength of the buffer species are the most significant factors that affect the pH and solubility of a drug in its microenvironment during dilution. To demonstrate the utility and robustness of the proposed equation, experimental measurements were performed using phenytoin as the model drug. The result suggests that the proposed equation can be used to indicate the possibility and the degree of precipitation that would occur upon injection. This provides a useful tool for the design of a successful pH-controlled solution formulation.
Asunto(s)
Química Farmacéutica , Preparaciones Farmacéuticas/química , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Tampones (Química) , Fenómenos Químicos , Precipitación Química , Química Física , Concentración de Iones de Hidrógeno , Fenitoína/administración & dosificación , Fenitoína/química , SolubilidadRESUMEN
The purpose of this study was to demonstrate the usefulness and broad-applicability of a simple disintegration test method for orally disintegrating tablets (ODT). Eight types of commercial famotidine 20 mg orally disintegrating tablets with different physical properties (formulation, manufacturing method, tablet weight, shape, diameter, thickness, etc.), were used. Disintegration times of these tablets were evaluated employing human sensory test, conventional disintegration test, and the new proposed disintegration test. The human sensory test was performed in 5 healthy volunteers. In the conventional disintegration test, the disintegration apparatus described in the Japanese Pharmacopeia (JP 1(st)) was used. Our proposed new test which is characterized by a rotating shaft with a low weight (10, 15 g) and rotation speed (10, 25, 50 rpm) was evaluated using tablets with and without storage under severe conditions (60 degrees C/75%RH for 1 week). The disintegration times of famotidine 20 mg orally disintegrating tablets in human sensory test varied from 9 to 32 s. In contrast, disintegration times in the conventional test were prolonged to over 300 s. Disintegration times in the new proposed test were close to those in human sensory test. Especially, when the new test was conducted with 15 or 10 g weight and 25 rpm, the slope (human sensory test vs. new proposed test) was almost 1. We were able to demonstrate that the new proposed test was useful to estimate the actual human disintegration time.
Asunto(s)
Famotidina/química , Saliva/fisiología , Comprimidos/química , Tecnología Farmacéutica/instrumentación , Administración Oral , Humanos , Tecnología Farmacéutica/métodos , Factores de TiempoRESUMEN
The aim of this study was to develop a simple and suitable disintegration method specific for rapid disintegrating tablets (RDTs). The new disintegration method that we propose employs a rotary shaft to exert mechanical pressure on the RDT. To assess our method, we manufactured several placebo RDTs and exposed them to severe storage conditions (60 degrees C/75%RH for 1 week) in order to obtain RDTs with a wide range of disintegration times. These placebo RDTs were utilized to compare the disintegration times obtained by several methods, including the proposed method. As expected, the disintegration time of the placebo RDTs in human sensory test varied widely. The disintegration times determined by the conventional disintegration test were in good correlation to those in human sensory test, but the slope was far from 1 (0.241). There was no correlation between the disintegration time of RDTs in human sensory test and those determined by the conventional dissolution test. In contrast, we acquired good correlation between the disintegration times obtained with the new method and those in human sensory test, and the slope was very close to 1 (0.858). We attribute this to the use of mechanical stress in the new method, similar to that the RDT is subject to in the oral cavity. We therefore concluded that the proposed method was suitable for the measurement of the disintegration time of RDTs. This new method might provide a valuable approach for the establishment of the official disintegration test for RDTs in the future.