RESUMEN
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 solubility enhancement of 11 poorly soluble drugs by complexation using nicotinamide has been studied. The solubilization efficiency of nicotinamide has been compared to that of hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin. Solubility enhancements as high as 4000-fold are observed in 20% (w/v) nicotinamide solution. Furthermore, nicotinamide is more effective than cyclodextrins for solubilizing some of the drugs. The mechanism of drug solubilization by nicotinamide is investigated by studying the effects of nicotinamide concentration on the surface tension and the conductivity of water. A slight break in both, the surface tension and conductivity is noticed at around 10% (w/v), suggesting self-association at higher concentrations. Corresponding breaks in the solubility profiles of estrone and griseofulvin at similar concentrations support self-association. Based on this observation it appears that at low concentrations, one molecule of nicotinamide undergoes complexation with one drug molecule to form a 1:1 complex. At higher concentrations, two molecules of nicotinamide undergo complexation with one drug molecule forming a 1:2 complex. The complexation constants have been calculated for all the drugs and the data are well described by this model. Expectedly, increasing the temperature reduces the complexation constants.