【摘要】：塞來(lái)昔布是COX-2酶選擇性抑制劑,有很強(qiáng)的特異性。塞來(lái)昔布目前用于治療關(guān)節(jié)炎、風(fēng)濕性關(guān)節(jié)炎等,具有廣闊的市場(chǎng)前景。塞來(lái)昔布的水溶性差,在使用過(guò)程中存在釋放不均勻的現(xiàn)象,溶出是其體內(nèi)吸收的限速步驟,進(jìn)而導(dǎo)致藥物生物利用度低且吸收差異較大。因此本論文希望通過(guò)改變劑型來(lái)改變?nèi)麃?lái)昔布在體內(nèi)的生物利用度。微丸制劑丸心徑較小,不受胃腸道轉(zhuǎn)運(yùn)規(guī)律及消化道消化規(guī)律運(yùn)輸節(jié)律的影響,給藥系統(tǒng)在體內(nèi)吸收的個(gè)體間差異性小,吸收動(dòng)力學(xué)重現(xiàn)性好,生物利用度高,所以微丸制劑為代表的多單元型給藥系統(tǒng)(multiple-unit drug delivery system)以其特有的優(yōu)越性,逐漸成為目前緩控釋制劑的研究熱點(diǎn)之一,也成為本篇論文所研究的主要內(nèi)容。本論文研究了塞來(lái)昔布速釋及緩釋膜控微丸處方以及包衣鍋造粒法制備塞來(lái)昔布速釋、緩釋微丸的制備工藝。最終確定塞來(lái)昔布速釋微丸以羥丙甲基纖維素(HPMC)為速釋包衣膜,塞來(lái)昔布緩釋膜控微丸以丙烯酸樹(shù)脂為緩釋包衣材料。通過(guò)考察表面活性劑的濃度、溶出介質(zhì)的pH、以及攪槳速度對(duì)塞來(lái)昔布速釋、緩釋微丸的釋放度的影響,確定塞來(lái)昔布速釋、緩釋微丸的最佳溶出條件為0.5%十二烷基硫酸鈉的水溶液,攪槳速度為50轉(zhuǎn)。其中緩釋微丸的釋放機(jī)制符合Higuchi方程,為擴(kuò)散與骨架溶蝕雙重機(jī)制,且以擴(kuò)散為主。除此之外還對(duì)塞來(lái)昔布速釋及緩釋微丸的穩(wěn)定性進(jìn)行了初步的研究,實(shí)驗(yàn)結(jié)果表明:塞來(lái)昔布速釋、緩釋微丸在強(qiáng)光照、高溫、高濕下均穩(wěn)定;加速試驗(yàn)結(jié)果表明樣品在6個(gè)月內(nèi)未發(fā)生明顯變化。通過(guò)塞來(lái)昔布速釋、緩釋微丸的藥動(dòng)學(xué)的初步研究,確定速釋、緩釋微丸的藥動(dòng)學(xué)參數(shù)。速釋微丸:t1/2為6h左右;Tmax為3h左右;Cmax為0.7mg/L(100mg/kg)、1.4mg/L(200mg/kg)、2.8mg/L(400mg/kg),緩釋微丸:t1/2為4h左右;Tmax為8h左右;Cmax為1.4mg/L(100mg/kg)、2.8mg/L(200mg/kg)、5.6mg/L(400mg/kg)。繪制了藥時(shí)曲線(xiàn)。
[Abstract]:Celecoxib is a selective inhibitor of COX-2 and has strong specificity. Celecoxib is currently used in the treatment of arthritis, rheumatoid arthritis and so on, with broad market prospects. The water solubility of celecoxib is poor, and there is a phenomenon of uneven release in the process of use. Dissolution is the speed limiting step of its absorption in vivo, which leads to low bioavailability and great difference in absorption. Therefore, we hope to change the bioavailability of celecoxib in vivo by changing the dosage form. The heart diameter of pellets was small and not affected by the laws of gastrointestinal tract transport and digestive tract digestion. The drug delivery system had little difference in individual absorption in vivo, good reproducibility of absorption kinetics and high bioavailability. Therefore, the multi-unit drug delivery system (multiple-unit drug delivery system) represented by pellets has gradually become one of the research hotspots of slow and controlled release preparations, and has become the main content of this paper. In this paper, the formulation of celecoxib rapid release and sustained-release film controlled pellets and the preparation of celecoxib rapid release pellets and sustained-release pellets were studied. Finally, it was determined that celecoxib rapid release pellets were coated with hydroxypropylcellulose (HPMC) and celecoxib sustained-release film controlled pellets with acrylic resin as the coating material. The effects of the concentration of surfactant, the pH, of dissolution medium and the speed of paddle on the release of celecoxib and sustained-release pellets were investigated to determine the rapid release of celecoxib. The optimum dissolution conditions of the pellets were 0.5% sodium dodecyl sulfate aqueous solution and 50 rotations of agitating speed. The release mechanism of sustained-release pellets accords with the Higuchi equation, which is the dual mechanism of diffusion and skeleton dissolution, and diffusion is the main mechanism. In addition, the stability of celecoxib rapid release and sustained release pellets was studied. The results showed that celecoxib rapid release and sustained release pellets were stable under strong light, high temperature and high humidity. The accelerated test results showed that the sample did not change significantly within 6 months. The pharmacokinetic parameters of celecoxib and sustained-release pellets were determined by the preliminary study of pharmacokinetics of Celecoxib and sustained-release pellets. Rapid release pellets: t 1 / 2 is about 6 h, Tmax is about 3 h, Cmax is 0.7mg/L (100mg/kg), 1.4mg/L (200mg/kg), 2.8mg/L (400mg/kg), sustained release pellets: t 1 / 2 is about 4 h, Tmax is about 8 h; Cmax is 1.4mg/L (100mg/kg), 2.8mg/L (200mg/kg), 5.6mg/L (400mg/kg). The drug time curve was drawn.
【學(xué)位授予單位】：遼寧大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R943

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本文編號(hào)：2310744