可溶性微针用于水难溶性利多卡因的递送研究
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摘要
目的选择利多卡因作为水难溶性模型化合物,以Gantrez S-97(methyl vinyl ether/maleic anhydride copolymer)和PVPk30(polyvinylpyrrolidone)作为复合基质材料制备可溶性微针来加快水难溶性药物的递送。本实验分别研究可溶性微针的制备、外观性能、机械性能、皮内溶解性能、药效及所加载药物在微针中的结晶行为。方法以聚二甲氧基硅氧烷(PDMS)为阴模,采用倒模法制备微针。用扫描电镜(SEM)观察微针的外观形态;结合物性分析仪和组织学切片考察微针的机械性能;用皮内溶解和药效实验表征利多卡因的成功递送;用差示扫描量热法(DSC)表征利多卡因的结晶行为。结果利多卡因可溶性微针针型良好,具有足够的机械强度刺入皮肤,微针可在皮内于3 min内溶解并起局麻药效,药物在微针中以无定形存在。结论共溶剂法制备可溶性微针对于促进水难溶性药物的递送具有一定的潜力。
OBJECTIVE To prepare dissolving microneedles using Gantrez S-97 and PVPk30 as composite matrix materials to accelerate the delivery of poorly water soluble drugs and study the preparation,appearance,mechanical properties,intradermal solubility,drug efficacy and crystallization behavior of dissolving microneedles. METHODS Using polydimethylsiloxane( PDMS) as the negative mode,microneedles were prepared by the reverse casting method. SEM was used to observe the morphological appearance of the microneedles. The mechanical properties of the microneedles were investigated by texture analyzer and histological sections. Delivery of lidocaine was characterized by intradermal dissolution and pharmacodynamics. Crystallization behavior of lidocaine was characterized by DSC. RESULTS Lidocaine dissolving microneedles had good needle shape and possessed sufficient mechanical strength to penetrate into the skin. The microneedles could dissolve in the dermis within 3 min and retain anesthetic effect,and the drug existed in amorphous form in the microneedles. CONCLUSION Cosolvent preparation of dissolving microneedles has potential for promoting the delivery of poorly water soluble drugs.
OBJECTIVE To prepare dissolving microneedles using Gantrez S-97 and PVPk30 as composite matrix materials to accelerate the delivery of poorly water soluble drugs and study the preparation,appearance,mechanical properties,intradermal solubility,drug efficacy and crystallization behavior of dissolving microneedles. METHODS Using polydimethylsiloxane( PDMS) as the negative mode,microneedles were prepared by the reverse casting method. SEM was used to observe the morphological appearance of the microneedles. The mechanical properties of the microneedles were investigated by texture analyzer and histological sections. Delivery of lidocaine was characterized by intradermal dissolution and pharmacodynamics. Crystallization behavior of lidocaine was characterized by DSC. RESULTS Lidocaine dissolving microneedles had good needle shape and possessed sufficient mechanical strength to penetrate into the skin. The microneedles could dissolve in the dermis within 3 min and retain anesthetic effect,and the drug existed in amorphous form in the microneedles. CONCLUSION Cosolvent preparation of dissolving microneedles has potential for promoting the delivery of poorly water soluble drugs.
引文
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[25] ZHANG J,MA F S,ZHAN H H. Matrix materials and their composites for dissolvable microneedle construction:a review[J].Mat Rev(材料导报),2017,31(19):129-134.
[26] DAVIS S P,LANDIS B J,ADAMS Z H,et al. Insertion of microneedles into skin:measurement and prediction of insertion force and needle fracture force[J]. J Biomech,2004,37(8):1155-1163.
[27] UMEDA Y,FUKAMI T,FURUISHI T,et al. Molecular complex consisting of two typical external medicines:intermolecular interaction between indomethacin and lidocaine[J]. Chem Pharm Bull,2007,55(5):832-836.
[28] LI J Y,HE Z G,WANG Q F. The effect of glimepiride crystal inhibitor on its solid dispersions[J]. J Shenyang Pharm Univ(沈阳药科大学学报),2017,34(6):451-460.
[2] LEE D S,LI C G,IHM C,et al. A three-dimensional and bevel-angled ultrahigh aspect ratio microneedle for minimally invasive and painless blood sampling[J]. Sens Actuators B Chem,2018,255:384-390.
[3] HWA K Y,CHANG V H S,CHENG Y Y,et al. Analyzing polymeric matrix for fabrication of a biodegradable microneedle array to enhance transdermal delivery[J]. Biomed Microdev,2017,19(4):84.
[4] HUANG Y C,MA F S,ZHAN H H. Microneedle array used for transdermal delivery of biomacromolecules[J]. Pro Biochem Biophys(生物化学与生物物理进展),2017,44(9):757-768.
[5] HIROBE S,OTSUKA R,IIOKA H,et al. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo[J]. Life Sci,2017,168:24-27.
[6] YAO G,QUAN G,LIN S,et al. Novel dissolving microneedles for enhanced transdermal delivery of levonorgestrel:in vitro and in vivo characterization[J]. Int J Pharm,2017,534(1-2):378-386.
[7] GRIFFIN P,ELLIOTT S,KRAUER K,et al. Safety,acceptability and tolerability of uncoated and excipient-coated high density silicon micro-projection array patches in human subjects[J].Vaccine,2017,35(48):6676-6684.
[8] MA S,XIA Y,WANG Y,et al. Fabrication and characterization of a tungsten microneedle array based on deep reactive ion etching technology[J]. J Vac Sci Technol B Nanotechnol Microelectron,2016,34(5):052002.
[9] WENDORF J R,GHARTEY-TAGOE E B,WILLIAMS S C,et al.Transdermal delivery of macromolecules using solid-state biodegradable microstructures[J]. Pharm Res,2011,28(1):22-30.
[10] BERGSTRM C A S,LUTHMAN K,ARTURSSON P. Accuracy of calculated p H-dependent aqueous drug solubility[J]. Eur J Pharm Sci,2004,22(5):387-398.
[11] LEE U,CHOI Y J,CHOI G J,et al. Intravenous lidocaine for effective pain relief after bimaxillary surgery[J]. Clin Oral Investig,2017,21(9):1-8.
[12] ZHOU W,LIU C,LU M J. The impact of filling endotracheal tube cuff with lidocaine carbonate on postoperative sore throat in general anaesthesia[J]. J Clin Anesthesiol(临床麻醉学杂志),2013,29(11):1051-1053.
[13] ZHONG C,WANG L P. Preemptive analgesia of lidocaine-prilocaine cream on hypertrophic scars injection with low pressure needle free syringe[J]. Chin J Nurs(中华护理杂志),2017,52(2):190-192.
[14] KREILGAARD M,KEMME M J B,BURGGRAAF J,et al. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics[J]. Pharm Res,2001,18(5):593-599.
[15] VAN HAL D A,JEREMIASSE E,DE VRINGER T,et al.Encapsulation of lidocaine base and hydrochloride into non-ionic surfactant vesicles(NSVs)and diffusion through human stratum corneum in vitro[J]. Eur J Pharm Sci,1996,4(3):147-157.
[16] REPKA M A,GUTTA K,PRODDUTURI S,et al. Characterization of cellulosic hot-melt extruded films containing lidocaine[J].Eur J Pharm Biopharm,2005,59(1):189-196.
[17] KOCHHAR J S,LIM W X S,ZOU S,et al. Microneedle integrated transdermal patch for fast onset and sustained delivery of lidocaine[J]. Mol Pharm,2013,10(11):4272-4280.
[18] ZHANG Y,BROWN K,SIEBENALER K,et al. Development of lidocaine-coated microneedle product for rapid,safe,and prolonged local analgesic action[J]. Pharm Res,2012,29(1):170-177.
[19] KIM M Y,JUNG B,PARK J H. Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin[J]. Biomaterials,2012,33(2):668-678.
[20] FRIEDMANN A,CISMAK A,TAUTORAT C,et al. FIB Preparation and SEM investigations for three-dimensional analysis of cell cultures on microneedle arrays[J]. Scanning,2012,34(4):221-229.
[21] LARRAETA E,MOORE J,VICENTE-PREZ E M,et al. A proposed model membrane and test method for microneedle insertion studies[J]. Int J Pharm,2014,472(1):65-73.
[22] LI H M. Pharmcodynamics in analgesics of ketoprofen injectable in situ forming gel and pharmcokinetics in dogs[D]. Nanjing:Nanjing Forestry University,2015.
[23] LUTTON R E M,LARRAETA E,KEARNEY M C,et al. A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays[J]. Int J Pharm,2015,494(1):417-429.
[24] ZHENG J M. Polymer Science in Pharmaceutics(药用高分子材料学)[M]. Beijing:China Medical Science Press,2000:147.
[25] ZHANG J,MA F S,ZHAN H H. Matrix materials and their composites for dissolvable microneedle construction:a review[J].Mat Rev(材料导报),2017,31(19):129-134.
[26] DAVIS S P,LANDIS B J,ADAMS Z H,et al. Insertion of microneedles into skin:measurement and prediction of insertion force and needle fracture force[J]. J Biomech,2004,37(8):1155-1163.
[27] UMEDA Y,FUKAMI T,FURUISHI T,et al. Molecular complex consisting of two typical external medicines:intermolecular interaction between indomethacin and lidocaine[J]. Chem Pharm Bull,2007,55(5):832-836.
[28] LI J Y,HE Z G,WANG Q F. The effect of glimepiride crystal inhibitor on its solid dispersions[J]. J Shenyang Pharm Univ(沈阳药科大学学报),2017,34(6):451-460.