Nifedipine 速溶與控釋劑型之處方研究

1. Nifedipine 速溶與控釋劑型之處方研究 • 對於難溶性藥物而言，藥物溶離的快慢為胃腸道吸收速率的決定步驟。將 • 溶解型態之難溶性藥物吸附於賦型劑之表面，使其在溶離時能維持原先之 • 溶解狀態，進而增加藥物溶離速率。本實驗選用難溶性藥物(Nifedipine) • ，添加不同量的親水性載體(PEG 400,PEG 600, PEG 6000)及界面活性劑( • SLS)，並以賦型劑微晶纖維素(MCC)吸附其液體，製成固體粉末，再以抗 • 黏劑(Aerosil)增加粉末的流動性。實驗結果顯示?隨著親水性載體及界 • 面活性劑含量的增加，能增加Nifedipine 的溶離速率。其中親水性載體 • 之助溶效果以PEG 6000較佳，而PEG 400及PEG 600無明顯差別。但在親水 • 性載體高含量(90mg)及界面活性劑含量低(1mg)時，因粉末黏所吸收之液 • 體過多而黏結反使Nifedipine的溶離速率較親水性載體含量低(80mg, • 70mg)時慢。 • 難溶性藥物固體分散系製備，添加親水性載體及界面活性劑，不但能增加 • 藥物的溶離速率同時也增加藥物的吸收速率。但傳統製備方法需多個步驟 • 才能完成，本實驗在第二部份另使用側噴式 (tangential spraying) 流 • 動床作為包覆的機器，以較簡單易行的一個步驟方法將藥物包覆於圓粒表 • 面來製備圓粒固體分散系劑型，可較一般固體分散系中的溶媒揮發法需要 • 經過多個步驟才能完成的製備簡易。經由慎選的溶媒將藥物與載體溶解後 • ，包覆於圓粒表面，進而打成錠片或充填於膠囊中。圓粒固體分散劑型中 • ，添加界面活性劑Pluronic F68 及SLS，隨著其含量的增加，皆能增加 • Nifedipine 的溶離速率。或藉由抑制Nifedipine在劑型中的結晶形成， • 使之成為無晶型(amorphous)及提高其濕潤性、分散性和溶解度作用進而 • 增加Nifedipine的溶離。利用共同界面活性劑(Plur(Plonic F68 及SLS) • 添加於處方中，較單一界面活性劑(Pluronic F68)更能提高Nifedipine固 • 體分散系之溶離。 • 圓粒劑型之多樣化設計，可符合改善藥物療效和提高安全性的目標。尤其 • 是多層包覆的圓粒劑型，可將含有不同藥物的圓粒或含有多種不同釋放速 • 率的圓粒混合在同一劑型內。本實驗以參考藥物Coracten作為多層包覆圓 • 粒控釋劑型之處方比對。將Nifedipine及其固體分散溶液以流動床包覆機 • 器黏附於糖蕊上，作為緩釋層藥物；再將乙基纖維素水性分散液( • Surelease)包覆於緩釋層藥物外，作為控釋藥物釋放之膜衣層；最後將速 • 放之Nifedipine固體分散溶液包覆於最外層，作為速溶層藥物。由實驗結 • 果顯示：緩釋層藥物和速溶層藥物比例為10/10及速溶層藥之界面活性劑 • Pluronic F68和Nifedipine比例為1/1時，與參考藥物Coracten溶離曲線 • 較相似；緩釋層藥物在5%藥物重量的Ethylcellulose進行包覆時，即有明 • 顯緩釋效果；進一步在不同酸鹼值(pH 1.2, pH 4.5,pH 6.8)及添加不同 • 量的Tween 80 溶離液下進行溶離試驗中，此處方與參考藥物Coracten其 • 溶離曲線有良好的相關。由此溶離結果可作為未來建立體內體外相關性及 • 品質控制的基礎。

2. The Formulation Studies og Nifeeipine Dosage Forms : Instant Release and Controlled-Release • Because of limited aqueous solubility in body fluids, the • dissolution rate of the poorly soluble drugs becomes the rate • limiting step in the absorption process. The adsorption of • soluble form of poorly soluble drugonto the surface of • excipients could maintain its solubilization and plays a • valuable way to enhance the drug release. In the first part of • thisstudy, soluble form of Nifedipine in the medium containing • various amountsof PEG derivatives (PEG 400, PEG 600, PEG 6000) • and SLS was compounded aand then was adsorbed on the mixture of • microcrystalline cellulose (MCC) andAerosil-200 to become powder • forms. The dissolution of Nifedipine demonstrated to be • independent of the ratios of powder mixture of MCC and • Aerosil-200.The results also showed that the amounts of water • soluble carriers and surfactants increased, the dissolution • rate of Nifedipine was increased expectedly. With sufficient • amount of surfactant, the release rate of Nifedipine from three • samples followed the order of PEG 6000 > PEG 600 = PEG 400. When • the formulations employ high concentration (90mg) of carrier but • low amount (1mg) of surfactants, the dissolution rate of • Nifedipine was slower than that containing low concentrations • (80mg, 70mg) of carriers with any amount of surfactant. • The preparation of solid dispersion of the poorly soluble drugs • with water soluble carriers and/or surfactants has been a • popular and workable mean to increase drug dissolution and • absorption rate. However, several steps were involved in the • preparation of such a dosage form. The second part of studies • was in an attempt to enhance the drug release by means of solid • dispersion. Tangential spraying fluidized-bed system was • employed to produce solid dispersions of drugs on the pellet in • one step using surfactant as dissolution enhance. It was thought • to be easier and less steps was involved than traditional • solvent evaporation method to prepare solid dispersions. By • carefulselection of solvent systems with an ability to • simultaneously dissolve both drug and water soluble carrier, the • solid dispersion of drug with carrier could be layered onto the • pellets, which would be ready for tabletting or encapsulation. • Expectedly, when the amounts of Pluronic F68 and SLS were

3. The Formulation Studies og Nifeeipine Dosage Forms : Instant Release and Controlled-Release • increased, the dissolution rate was also increased. The • combination of PluronicF68 and SLS in the solid dispersion • showed higher enhancement on dissolution rate of Nifedipine than • that with only one surfactant. The surfactants may act to • inhibit the crystal growth of Nifedipine during the formation of • solid dispersion on the pellet surface. Increasing wettability, • dispersibility and solubilization of drug to enhance dissolution • rate of Nifedipine from the soliddispersion are among the • possible reasons. • Pellet capsule dosage form has shown many advantages and • flexibility in theway of enhancing the therapeutic safety and • potency or in term of processing and formulation design. • Especially, multilayered pellet dosage forms may include many • different kinds or different release rates of drugs in the same • pellet. In this study, a multilayered pellet dosage form was • developed with reference to Cortance (SB). Basically, a • Nifedipine solid dispersion was adhered onto nu-pareil seeds in • a fluidized-bed system as the first layer. Then cellulose ether • of ethylcellulose (Surelease, 25% ethylcellulose aqueous • dispersion) was applied as a controlled release membrane to • adjust the release of Nifedipine from the first layer. Finally, • the third layer of Nifedipine also in a form of solid dispersion • was coated onto the pellet as a immediate releaselayer. The • results showed that when the ratio of Nifedipine in the • sustained release layer to that in the immediate release layer • was 10/10 and the ratios of Pluronic F68 and Nifedipine in the • solid dispersion was 1/1, the release of Nifedipine from such a • product was possibly to closely simulate the release profiles of • the reference product of Coracten. Employing an amount of • ethylcellulose equivalent to 5% w/w of total drug content in the • controlled layer was sufficient enough to comply with the • sustenance of the Nifedipine release from Coracten. Moreover, • the closeness of release profiles between the sample and • thereference was further confirmed by testing them in different • pH media with the addition of various amounts of a nonionic • surfactant of Tween 80. These profiles could also be a basis to • set up any useful in vitro/in vivo correlation for the quality • control in the future.