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。
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
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.
