| In this paper, tetramethylpyrazine hydrochloride (TMPH), which is used for angina pectoris clinically, was selected as a water-soluble model drug to prepare timed release pellets. According to the fact that angina pectoris usually happens in the early morning, the TMPH timed release pellet is devised to be administered at night and reaches its plasma concentration climax in the next early morning.Ultraviolet spectrophotometry (UV) was developed for in vitro assay of drug content and release of pellets. High-performance liquid chromatography (HPLC) detection was applied to quantify the drug plasma concentration of dogs. The extraction recovery of TMPH was 83.20% and the detective concentration limit is 25ng/ml.Free films of two aqueous ethyl cellulose dispersions (Aquacoat ECD-30 and Surelease E-7-19010) and its ethanol solutions were prepared by a casting method. The tensile strength and permeability of drug and vapors through the film were studied. Effects of film thickness, plasticizer type and its amount, drying temperature and time, as well as dipping and diffusion conditions were studied on the properties of films produced using Aquacoat. The results indicated that the type of dispersions or solutions, plasticizer type and amount, as well as drying temperature had significant influence on these properties. While the film thickness, drying time and dipping conditions had relatively little effects on them. For example, films prepared from ethyl cellulose dispersions resulted in weak and brittle films when compared to the ethyl cellulose ethanol solution, and the permeability of the former to drug and vapor is higher than thatof the latter. Furthermore, with the increase of the plasticizer amount and the drying temperature, the elongation of films increases, while the permeability to drug and vapor decreases correspondingly. Finally, wet Aquacoat films plasticized with water insoluble plasticizer were significantly more flexible than the corresponding wet films plasticized with water soluble plasticizer.The timed release pellets consist of three laminar layers from the center to the outside: the core, the swelling agent layer and the controlled layer. The core pellets, which contained the drug, were prepared by extrusion-spheronization and then coated on a mini-fluidized bed spray coater by using swelling agent as the inner layer and water insoluble material as the outer layer respectively. The factors which affect the lag time and drug release behavior were investigated, such as the type and thickness of the inner and outer layers, the type and amount of the plasticizer, etc. The results showed that the swelling agent layer played an indispensable role in the formulation since the drug release is triggered by the destruction of the outer membrane. The lag time is shortened in some degree with the increase of the thickness of the inner layer and prolonged with the increase of the outer layer or the amount of the plasticizer. According to these results, croscarmellose sodium (CCNa) was selected as the swelling agent layer, Aquacoat as the controlled release layer, and triethyl citrate (TEC) as the plasticizer. Furthermore, full experiment design was chosen to optimize the formulations and the optimum formulation is as follows: a 25% CCNa coating level, 24% Aquacoat coating level and 30% TEC as well. The prepared pellets released the drug after a lag time of about 4 hours and the accumulative release percent arrived 80% within the following 2.5 hours. At last, the quality of the pellets was investigated, and the pellets were sensitive to high temperature and high humidity.The investigation on the drug release mechanisms indicated that drug release exhibited a lag period followed afterwards by instantaneous release. The relationship between the lag time and the square of the amount of Aquacoat layer appeared to be linear as predicted in Crank equation. In addition, the model of logarithmic normal distribution (LND) was adopted to describe the sigmoid release profiles and the correlation-ship was si... |
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