（I）姜黄素半互穿式羟丙甲纤维素—明胶微球给药系统的研究（II）OX26-NGF-融合蛋白的基因克隆及其表达纯化
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摘要
近年来,姜黄素在抗氧化、消炎、抗肿瘤、等疾病领域具有良好的药理活性,已经成为了药物研发的热点之一。虽然如此,姜黄素却具有稳定性差、水溶性差、生物利用度低等缺点,极大地限制了其开发成药。针对这一问题,诸如微乳制剂、包合物技术等很多手段被提出,但是利用凝胶微球给药系统却尚未见报道。本文试图提出一种新的由高吸水性材料羟丙甲纤维素(HPMC, Hydroxypropyl methylcellulose)和天然高分子材料明胶(Gelatin)所构成的半互穿式高分子网络凝胶微球(Semi-IPN gel microsphere,Semi-interpenetrating polymer network gel microsphere)作为给药系统,来解决姜黄素稳定性差、溶出度低和生物利用度低的问题。
文章首先采用紫外分光光度法建立了姜黄素体外分析方法,发现姜黄素在421nm处有最大吸收波长,且线性浓度范围为0~10μg/mL;该方法符合药典规定。对于稳定性的研究表明光强越强、温度越高、酸性或者碱性越强,姜黄素稳定性越差。而对于溶解度的研究则表明,在水和环己烷中姜黄素溶解度极低,在HPMC溶液中则溶解度大大增加(达到1027μg/mL),因此利用这一特点,制备HPMC-Gelatin半互穿式凝胶微球,以解决其溶出度低的问题。
其次,通过实验确定了搅拌转速为500rpm、相比为3:1和分散剂选用单硬酸甘油酯(用量为0.6g/30mL环己烷)的反向悬浮聚合工艺。采用这一工艺,成功制备出了9个处方的微球。用傅立叶变换红外光谱表征了半互穿网络结构的形成;采用扫描电镜、光学显微镜和激光粒度分布仪观察微球,结果表明微球呈球形、表面光滑、平均粒径为201μm,粒径分布窄。另外实验结果表明表明随着交联剂用量的增加和HPMC含量的减少,平衡吸水倍率和吸水速率在逐渐减小,机械强度在不断增加。空白微球的制备,为制备载药微球奠定基础。
第三,采用反相悬浮的手段,在不同交联剂和HPMC/Gelatin比例条件下,成功制备了包载有姜黄素的载药微球,并进行了如下表征:扫描电镜和光学显微镜观察微球的形貌;激光粒度扫描仪分析其平均粒径;傅立叶红外光谱仪表征药物包载入球后是否保持原型;X-RD和DSC表征药物在微球中的存在形式。结果表明载药微球呈球形,表面光滑,平均粒径为216μm,药物以原型形式被包载进入到微球中,有晶体形式存在。另外还通过稳定性试验,表明与原料药相比,微球中的姜黄素稳定性有所提高,因此凝胶微球可以增加姜黄素的稳定性。
第四,文章还考察了HPMC/Gelatin比例和交联剂用量对姜黄素载药微球包封率和体外释放的影响。结果表明随着HPMC含量的增加和交联剂的减少,包封率有所降低,姜黄素溶出度在增加。对于体外溶出行为,采用Higuchi’s模型对有效扩散系数D进行拟合。结果表明,随着HPMC/Gelatin比例的增加和交联剂用量的减少,有效扩散系数在增加。
第五,采用高效液相色谱法建立了姜黄素体内分析方法,计算了药动学参数和生物利用度。结果表明该方法符合《中国药典》的规定,该微球制剂在体内的吸收呈单室模型,其相对于原料药的生物利用度提高了4.863±1.185倍。通过以上研究,姜黄素借助于半互穿式HPMC-Gelatin凝胶微球这一新型的给药系统后,溶出度、稳定性和生物利用度得到了很大提高。同时,这一给药系统也为提高其它难溶性药物溶出,增加生物利用度提供了提供了可供借鉴的参考。
第二部分
针对NGF无法透过血脑屏障这一问题,本文拟通过基因工程的手段,将NGF与OX26抗体进行融合,构建一个既能透血脑屏障又能够治疗神经疾病的融合蛋白。为此,通过PCR的方法,扩增了NGF-β基因,并将其亚克隆至pXA6载体上。将pXA6-NGF-β质粒,转染入COS-1细胞,瞬时表达融合蛋白并收集上清。采用Protein A亲和层析的方法从其中纯化出了融合蛋白OX26- NGF-β。采用FcELISA的方法测定含量,SDS-PAGE确定纯度,并结合Western Blot的分析确认融合蛋白构建成功。
In recent years, extensive attention has been paied to a very promising drugcandidate, curcumin, in anti-oxidant, anti-inflammatory, antitumor areas. Nonetheless,its drug development is limited for its poor stability, poor water-solubility and lowbioavailability. Therefore, many technologies such as micro-emulsion, cyclodextrininclusion, have been put forward. But using gel microspheres drug delivery systemhas not been reported. So a new DDS, Semi-IPN gel microsphere composed ofHPMC and Gelatin, has been raised to solve the problem.
Firstly, curcumin analytical method in vitro has been established by UV withmax absorption wavelength of 421nm and linear absorption from 0-10ug. Thisanalytical method was confirmed to meet C.P. For curcumin, higher light intensity,temperature and strong acidic or alkaline condition leds to poor stabilty. Solubilitytests results show that the solubility in water and cyclohexane are low, but increasegreatlyin HPMC solution, reaching to 1027μg/mL.
Secondly, the reverse suspension polymerization process of preparation wasdetermined, namely GSM is selected as dispersant (0.6g/30mL cyclohexane), stirringspeed equals to 500rpm and O/Wratio is 3:1. Nine formulations were successfulpreparaed. Semi-IPN structure formation was confirmed using FT-IR. The appearanceresults show that the microspheres are spherical with smooth surface, and averageparticle size is 201um with narrow distribution. Additionally results show that withthe increase of crosslinking agent and decrease of the content of HPMC, balancebibulous magnification and bibulous rate decline while mechanical strength increases.
Thirdly, curcumin loaded microsphere was prepared. By using scanning electronmicroscope and optical microscope, the microspheres are spherical with smoothsurface, and average particle size is 216um.Characterized by FT-IR, the drug issuccessfully incroprated into microspheres. Stability test results show that, thestability of curcumin in microsphere is improved compared with the raw curcumin.Amorphous form mainly of curcumin in microsphere was observed through the X-rayRD and DSC, but the crystals also exist.
Fourth,the effect of HPMC/gelatin ratio and crosslinking agent dosage oncurcumin release in vitro was also investigated. Results show that with the dosageincrease of HPMC and decrease of crosslinking reagent, encapsulating ratio decreases and solubility increases. The effective diffusion coefficient D was fitted usingHiguchi's mode and with the increase of HPMC and decrease of crosslinking agent,,effective diffusion coefficients rise.
Finally, analytical method in vivo has been established by HPLC. Results showthat methodological verify complies with the CP. The drug loaded microsphere wasoral administration and blood was taken by angulus oculi medialis. PK parameterswere calculated. Results show that the absorption behavior is one compartment model.Bioavailability relative to raw curcumin is improved by4.863±1.185 times.
To sum up, by HPMC-Gelatin semi-interpenetrating gel microspheres,curcumin’s solubility, stability and bioavailability are improved and this newformulation will probably contribute to other poorly-soluble drugs to solve theseproblems.
(Part II)
In order to solve the problem of transferring NGF through blood brain barrier,the fusion protein composed of NGF and OX26 antibody was constructed by meansof genetic engineering. NGF-? gene was amplified and subcloned into pXA6 by PCRmethod, then the plasmid was transfected into COS-1 cells, and the fusion protein wastransient expressed following collecting the supernatant. OX26-NGF-? waspurified byProtein A affinity chromatography. Concentration was determined by the method ofFc ELISA, purity was dtermined by SDS-PAGE, at last it was confirmed that thefusion protein was constructed successfully combined with Western Blot analysis.
文章首先采用紫外分光光度法建立了姜黄素体外分析方法,发现姜黄素在421nm处有最大吸收波长,且线性浓度范围为0~10μg/mL;该方法符合药典规定。对于稳定性的研究表明光强越强、温度越高、酸性或者碱性越强,姜黄素稳定性越差。而对于溶解度的研究则表明,在水和环己烷中姜黄素溶解度极低,在HPMC溶液中则溶解度大大增加(达到1027μg/mL),因此利用这一特点,制备HPMC-Gelatin半互穿式凝胶微球,以解决其溶出度低的问题。
其次,通过实验确定了搅拌转速为500rpm、相比为3:1和分散剂选用单硬酸甘油酯(用量为0.6g/30mL环己烷)的反向悬浮聚合工艺。采用这一工艺,成功制备出了9个处方的微球。用傅立叶变换红外光谱表征了半互穿网络结构的形成;采用扫描电镜、光学显微镜和激光粒度分布仪观察微球,结果表明微球呈球形、表面光滑、平均粒径为201μm,粒径分布窄。另外实验结果表明表明随着交联剂用量的增加和HPMC含量的减少,平衡吸水倍率和吸水速率在逐渐减小,机械强度在不断增加。空白微球的制备,为制备载药微球奠定基础。
第三,采用反相悬浮的手段,在不同交联剂和HPMC/Gelatin比例条件下,成功制备了包载有姜黄素的载药微球,并进行了如下表征:扫描电镜和光学显微镜观察微球的形貌;激光粒度扫描仪分析其平均粒径;傅立叶红外光谱仪表征药物包载入球后是否保持原型;X-RD和DSC表征药物在微球中的存在形式。结果表明载药微球呈球形,表面光滑,平均粒径为216μm,药物以原型形式被包载进入到微球中,有晶体形式存在。另外还通过稳定性试验,表明与原料药相比,微球中的姜黄素稳定性有所提高,因此凝胶微球可以增加姜黄素的稳定性。
第四,文章还考察了HPMC/Gelatin比例和交联剂用量对姜黄素载药微球包封率和体外释放的影响。结果表明随着HPMC含量的增加和交联剂的减少,包封率有所降低,姜黄素溶出度在增加。对于体外溶出行为,采用Higuchi’s模型对有效扩散系数D进行拟合。结果表明,随着HPMC/Gelatin比例的增加和交联剂用量的减少,有效扩散系数在增加。
第五,采用高效液相色谱法建立了姜黄素体内分析方法,计算了药动学参数和生物利用度。结果表明该方法符合《中国药典》的规定,该微球制剂在体内的吸收呈单室模型,其相对于原料药的生物利用度提高了4.863±1.185倍。通过以上研究,姜黄素借助于半互穿式HPMC-Gelatin凝胶微球这一新型的给药系统后,溶出度、稳定性和生物利用度得到了很大提高。同时,这一给药系统也为提高其它难溶性药物溶出,增加生物利用度提供了提供了可供借鉴的参考。
第二部分
针对NGF无法透过血脑屏障这一问题,本文拟通过基因工程的手段,将NGF与OX26抗体进行融合,构建一个既能透血脑屏障又能够治疗神经疾病的融合蛋白。为此,通过PCR的方法,扩增了NGF-β基因,并将其亚克隆至pXA6载体上。将pXA6-NGF-β质粒,转染入COS-1细胞,瞬时表达融合蛋白并收集上清。采用Protein A亲和层析的方法从其中纯化出了融合蛋白OX26- NGF-β。采用FcELISA的方法测定含量,SDS-PAGE确定纯度,并结合Western Blot的分析确认融合蛋白构建成功。
In recent years, extensive attention has been paied to a very promising drugcandidate, curcumin, in anti-oxidant, anti-inflammatory, antitumor areas. Nonetheless,its drug development is limited for its poor stability, poor water-solubility and lowbioavailability. Therefore, many technologies such as micro-emulsion, cyclodextrininclusion, have been put forward. But using gel microspheres drug delivery systemhas not been reported. So a new DDS, Semi-IPN gel microsphere composed ofHPMC and Gelatin, has been raised to solve the problem.
Firstly, curcumin analytical method in vitro has been established by UV withmax absorption wavelength of 421nm and linear absorption from 0-10ug. Thisanalytical method was confirmed to meet C.P. For curcumin, higher light intensity,temperature and strong acidic or alkaline condition leds to poor stabilty. Solubilitytests results show that the solubility in water and cyclohexane are low, but increasegreatlyin HPMC solution, reaching to 1027μg/mL.
Secondly, the reverse suspension polymerization process of preparation wasdetermined, namely GSM is selected as dispersant (0.6g/30mL cyclohexane), stirringspeed equals to 500rpm and O/Wratio is 3:1. Nine formulations were successfulpreparaed. Semi-IPN structure formation was confirmed using FT-IR. The appearanceresults show that the microspheres are spherical with smooth surface, and averageparticle size is 201um with narrow distribution. Additionally results show that withthe increase of crosslinking agent and decrease of the content of HPMC, balancebibulous magnification and bibulous rate decline while mechanical strength increases.
Thirdly, curcumin loaded microsphere was prepared. By using scanning electronmicroscope and optical microscope, the microspheres are spherical with smoothsurface, and average particle size is 216um.Characterized by FT-IR, the drug issuccessfully incroprated into microspheres. Stability test results show that, thestability of curcumin in microsphere is improved compared with the raw curcumin.Amorphous form mainly of curcumin in microsphere was observed through the X-rayRD and DSC, but the crystals also exist.
Fourth,the effect of HPMC/gelatin ratio and crosslinking agent dosage oncurcumin release in vitro was also investigated. Results show that with the dosageincrease of HPMC and decrease of crosslinking reagent, encapsulating ratio decreases and solubility increases. The effective diffusion coefficient D was fitted usingHiguchi's mode and with the increase of HPMC and decrease of crosslinking agent,,effective diffusion coefficients rise.
Finally, analytical method in vivo has been established by HPLC. Results showthat methodological verify complies with the CP. The drug loaded microsphere wasoral administration and blood was taken by angulus oculi medialis. PK parameterswere calculated. Results show that the absorption behavior is one compartment model.Bioavailability relative to raw curcumin is improved by4.863±1.185 times.
To sum up, by HPMC-Gelatin semi-interpenetrating gel microspheres,curcumin’s solubility, stability and bioavailability are improved and this newformulation will probably contribute to other poorly-soluble drugs to solve theseproblems.
(Part II)
In order to solve the problem of transferring NGF through blood brain barrier,the fusion protein composed of NGF and OX26 antibody was constructed by meansof genetic engineering. NGF-? gene was amplified and subcloned into pXA6 by PCRmethod, then the plasmid was transfected into COS-1 cells, and the fusion protein wastransient expressed following collecting the supernatant. OX26-NGF-? waspurified byProtein A affinity chromatography. Concentration was determined by the method ofFc ELISA, purity was dtermined by SDS-PAGE, at last it was confirmed that thefusion protein was constructed successfully combined with Western Blot analysis.
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