【摘要】：龍血竭是由百合科植物劍葉龍血樹Dracaena cochinchinensis (Lour.) S. C. Chen的樹脂經(jīng)加工制成,含有黃酮、揮發(fā)油等成分,具有活血散淤、定痛止血和斂瘡生肌的功能,龍血竭在水中溶解度小,難以吸收,生物利用度低。因此,如能制備出水溶性好的新劑型,將有助于提高其生物利用度,為其廣泛應(yīng)用創(chuàng)造條件。納米給藥系統(tǒng)(nanoparticle drug delivery system, NDDS)是指藥物或藥物與藥用材料一起形成的粒徑為1-1000nm的納米級藥物輸送系統(tǒng),為近年來藥劑學(xué)領(lǐng)域頗為活躍的一系列超微小給藥系統(tǒng)的統(tǒng)稱。由于納米粒比人體內(nèi)最小的毛細(xì)管內(nèi)徑(4000nnm)和紅血球(6000nm-9000nm)小得多,它可以在血中自由運(yùn)動到達(dá)人體的各部位。藥劑學(xué)中的納米�？煞譃閮深悾杭{米載體藥物和納米藥物。納米載體藥物為藥物與藥用材料一起形成的納米給藥系統(tǒng),可通過載體提高藥物的吸收,并可使其具有細(xì)胞親和性、藥物緩釋性、靶向性,具有提高藥物療效、降低毒副作用的特征；納米藥物則是指直接將原料藥加工成納米粒,難溶性藥物制備成納米粒后,可有效提高藥物的吸收,提高生物利用度,且和納米載體相比,藥物含量更高。根據(jù)脂質(zhì)納米載體藥物較強(qiáng)細(xì)胞轉(zhuǎn)運(yùn)的特點(diǎn),首先開展了龍血竭脂質(zhì)納米粒的研究。以硬脂酸為脂質(zhì)材料,采用水性溶劑擴(kuò)散法制備龍血竭脂質(zhì)納米粒；微粒粒度及表面電位儀測定其粒徑和表面電位；透射電鏡觀察其形態(tài)；以龍血素A為指標(biāo),建立HPLC測定龍血竭脂質(zhì)納米粒中龍血竭含量的方法學(xué)；計(jì)算龍血竭脂質(zhì)納米粒的包封率和載藥量。結(jié)果表明,本研究所制備的1 mg·ml-1龍血竭脂質(zhì)納米粒(藥物與納米載體比例為1：1)呈球形,數(shù)均粒徑為29.4nm,電位為-20.2+1.9Mv；龍血素A于0.135-5.4μg·ml-1濃度范圍內(nèi)有良好線性關(guān)系,標(biāo)準(zhǔn)曲線方程為Y=33.694X+1.5898(r=0.9999)。所制備的1 mg·ml-1龍血竭脂質(zhì)納米粒中龍血素A的濃度為1.43μg·ml-1,平均包封率為89.59%。由于龍血竭中其有效成分龍血素A的含量較低,而一般脂質(zhì)納米粒的載藥量僅為5%左右,所以我們針對龍血竭這類中藥,開展了藥物納米粒研究,以提高納米粒中的主藥含量。采用水性溶劑擴(kuò)散法制備龍血竭納米粒；微粒粒度及表面電位儀測定其粒徑和表面電位；透射電鏡觀察其形態(tài)；以龍血素A為指標(biāo),建立HPLC測定龍血竭納米粒中龍血竭含量的方法學(xué)；計(jì)算龍血竭納米粒載藥量；以透析袋法對龍血竭納米粒體進(jìn)行外釋放行為的研究。結(jié)果表明,本研究所制備的1 mg·ml-1龍血竭納米粒呈球形,數(shù)均粒徑為101.7nm,電位為-19.9±1.6mV；龍血素A于0.135.5.4μgvml-1濃度范圍內(nèi)有良好線性關(guān)系,標(biāo)準(zhǔn)曲線方程為Y=33.694X+1.589 8(r=0.9999),所制備的1 mg·ml-1龍血竭納米粒中龍血素A的濃度為2.87μg·ml-1;體外釋放行為的研究結(jié)果表明,與龍血竭原料藥粉混懸液相比,龍血竭納米粒分散液在72h中藥物釋放了約68%,而龍血竭原料藥粉混懸液僅釋放了約40%,促進(jìn)釋放的效果明顯。在以上研究的基礎(chǔ)上,我們進(jìn)一步制備以龍血竭為主藥的外用凝膠。以1%卡波姆為凝膠基質(zhì),制備龍血竭納米粒凝膠、龍血竭粉凝膠、龍血竭醇溶液凝膠；考察其流動性,粘性及外觀性能；以透析袋法對其進(jìn)行體外釋放行為的研究。結(jié)果表明,龍血竭納米粒凝膠、龍血竭粉凝膠流動性小、粘性大,龍血竭醇溶液凝膠流動性小、粘性��；體外釋放行為的研究中,相比較龍血竭粉所制備的凝膠,龍血竭納米粒凝膠72h中藥物釋放可達(dá)約83%,而龍血竭粉所制備的凝膠72h中藥物釋放約為52%,龍血竭納米粒凝膠促進(jìn)釋放的效果明顯；而相比較龍血竭醇溶液制備的凝膠,龍血竭納米粒凝膠在4h中藥物釋放了約55%,龍血竭醇溶液凝膠在4h中藥物釋放了約76%,龍血竭納米粒凝膠則表現(xiàn)出緩釋的效果。以大鼠背部剃毛區(qū)開方形全層皮膚切除創(chuàng)面的方法,建立動物皮膚損傷模型,以云南白藥粉制備的凝膠為對照,通過肉眼觀察、拍照、測量傷口大小,電子顯微鏡觀察新生皮膚HE染色切片的方法,考察龍血竭納米粒凝膠對皮膚損傷模型的促進(jìn)愈合作用。結(jié)果表明,三種龍血竭凝膠制劑均能縮短愈合時間,其中龍血竭納米粒凝膠促進(jìn)促進(jìn)皮膚愈合效果最顯著。在實(shí)驗(yàn)初期(3d,6d),龍血竭醇溶液凝膠組愈合率較其他組顯著高；但到實(shí)驗(yàn)后期(14d,20d),大鼠創(chuàng)面愈合速度進(jìn)入減慢階段后,龍血竭納米粒凝膠組優(yōu)勢明顯,20d時只有龍血竭納米粒凝膠組創(chuàng)面完全愈合。創(chuàng)面新生皮膚切片經(jīng)HE染色后觀察,可見4組皮膚內(nèi)均有豐富的毛細(xì)血管,說明新生皮膚為有組織活性的皮膚。
[Abstract]:Dracaena cochinchinensis (Lour.) S. C. Chen is a Liliaceous plant Dracaena cochinchinensis (Lour.) S. C. Chen resin processed, containing flavonoids, volatile oils and other components, has the function of activating blood circulation and dispersing stasis, relieving pain and stopping bleeding, astringent sores and muscle formation, Dracaena cochinchinensis (Lour.) Dracaena Nanoparticle drug delivery system (NDDS) is a kind of nanoparticle drug delivery system with a diameter of 1-1000 nm formed by drugs or drugs together with medicinal materials. It is an active series of ultramicro-particles in the field of pharmaceutics in recent years. Because nanoparticles are much smaller than the smallest capillary diameter (4000nnm) and red blood cells (6000nm-9000nm) in the body, they can move freely in the blood to various parts of the body. Pharmaceutical nanoparticles can be divided into two categories: nanocarrier drugs and nanodrugs. Nanocarrier drugs are drugs and medicinal materials together. The nano-drug delivery system can enhance the absorption of drugs through carriers, and make them have cell affinity, drug sustained release, targeting, with the characteristics of improving drug efficacy and reducing side effects; nano-drug refers to the direct processing of raw materials into nanoparticles, insoluble drugs into nanoparticles, can effectively improve the drug Lipid nanoparticles of Dragon's Blood were prepared by water-based solvent diffusion method with stearic acid as lipid material. The particle size and surface potential of Dragon's Blood Lipid Nanoparticles were determined; the morphology of Dragon's Blood Lipid Nanoparticles was observed by transmission electron microscopy; the content of Dragon's Blood Lipid Nanoparticles in Dragon's Blood Lipid Nanoparticles was determined by HPLC; the entrapment efficiency and drug loading of Dragon's Blood Lipid Nanoparticles were calculated. The carrier ratio was 1:1) spherical, the number average diameter was 29.4 nm, and the potential was - 20.2 + 1.9 Mv. There was a good linear relationship between the concentration of Loureirin A and the concentration of Loureirin A in the range of 0.135 - 5.4 ug. ML - 1. The standard curve equation was Y = 33.694 x + 1.5898 (r = 0.9999). The concentration of Loureirin A in the prepared nanoparticles was 1.43 ugh. ML - 1, and the average entrapment rate was 89.5 ugh. 9%. Because the content of Dragon's Blood Active Component Dragon's Blood A is low, and the drug loading capacity of the general lipid nanoparticles is only about 5%, we have carried out the research on the drug nanoparticles to improve the content of the main drug in the nanoparticles. The particle size and surface potential of Dragon's blood nanoparticles were measured by potentiometer; the morphology was observed by transmission electron microscopy; the content of Dragon's blood nanoparticles was determined by HPLC with Dragon's blood A as the index; the drug loading of Dragon's blood nanoparticles was calculated; the release behavior of Dragon's blood nanoparticles was studied by dialysis bag method. Dragon's blood A nanoparticles were spherical with an average diameter of 101.7 nm and a potential of - 19.9 (- 1.6 mV); there was a good linear relationship between the concentration of Dragon's blood A and the concentration of Dragon's blood A in the range of 0.135.5.4 ugvml-1. The standard curve equation was Y = 33.694 X + 1.589 8 (r = 0.9999), and the concentration of Dragon's blood A in the prepared nanoparticles was 2.87 UG (- ml-1); the release behavior in vitro was studied. The results showed that compared with the suspension of Dragon's blood powder, the drug release rate of Dragon's blood nanoparticles was about 68% at 72 h, while the suspension of Dragon's blood powder only released about 40% and the effect of promoting release was obvious. Dragon's blood nanoparticle gel, Dragon's blood powder gel and Dragon's blood alcohol solution gel were prepared with M as gel matrix, and their fluidity, viscosity and appearance properties were investigated. Compared with the gel prepared by dragon's blood powder, the drug release rate of dragon's blood nanoparticle gel reached about 83% after 72 hours, while that of dragon's blood powder gel reached about 52% after 72 hours, and the effect of dragon's blood nanoparticle gel on promoting drug release was obvious. The prepared gel, Dragon's blood nanoparticle gel and Dragon's blood alcohol solution gel were released about 55% and 76% respectively in 4 h and 4 h. Dragon's blood nanoparticle gel showed sustained release effect. The effect of dragon's blood nanoparticles gel on the healing of skin injury model was investigated by means of naked eye observation, photography, measurement of wound size and electron microscopy. The results showed that the three kinds of dragon's blood nanoparticles gel could shorten the healing time, and dragon's blood nanoparticles gel could promote the healing of skin injury model. At the beginning of the experiment (3d, 6d), the healing rate of Dragon's Blood Solution Gel group was significantly higher than that of other groups, but at the end of the experiment (14d, 20d), the healing rate of the wound in the Dragon's Blood Nanoparticle Gel group was slowed down. At the 20th day, only Dragon's Blood Nanoparticle Gel group healed completely. Skin sections stained with HE showed that there were abundant capillaries in the skin of the four groups, indicating that the newly formed skin was an organized and active skin.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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