罗红霉素注射液的初步研制
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摘要
罗红霉素是一种半合成的大环内酯类抗生素，对常见的革兰氏阳性菌、部分革兰氏阴性菌、支原体和部分厌氧菌等都有良好的抗菌活性，临床上主要用于各种组织和器官感染的治疗，是目前呼吸道感染，特别是小儿呼吸道感染的首选约。近年米，随着大环内酯类抗生素的药理作用的新发现及其在非抗感染领域的新应用，也使得罗红霉素的应用范围不断扩大。为了适应临床应用的需要，以及给医护人员、患者提供更多的选择，用羟丙基-β-环糊精与罗红霉素进行包合，然后，用此包合物制备成罗红霉素注射液，弥补了罗红霉素注射液剂型空缺。本论文对罗红霉素注射液进行了相关研究。
通过对罗红霉素注射液的热稳定性、体外抑菌活性和在山羊体内的药代动力学及相对生物利用度测定，以及运用药代动力学／药效学(PK／PD)参数和抗生素后效应(PAE)，对罗红霉素注射液治疗山羊葡萄球菌感染的给药方案进行了探讨，证明罗红霉素注射液是一个具有开发前景的新剂型。
首先，为了考察经羟丙基-β-环糊精和γ-环糊精包合罗红霉素制备的注射液Ⅰ和Ⅱ的热稳定性，初步筛选出适合临床应用的罗红霉素注射液，用研磨法制备了包合物，HPLC测定罗红霉素注射液Ⅰ和Ⅱ经不同温度处理后的含量，以初均速法预测其有效期，结果罗红霉素注射液It_(0.9)~(25℃)=1.8a；罗红霉素注射液Ⅱt_(0.9)~(25℃)=0.87a，即由羟丙基-β-环糊精包合罗红霉素所制备的注射液，有效期可达1.8年，基本可以满足生产、储存、运输及临床使用的需要。
其次，测定了罗红霉素注射液的体外抗菌活性。按照新药临床指导原则的要求，采用二倍稀释法测定了罗红霉素注射液对4株革兰氏阳性菌和5株革兰氏阴性菌的的最低抑菌浓度(MIC)，结果罗红霉素注射液对猪丹毒杆菌、猪链球菌、李氏单核胞浆菌、金黄色葡萄球菌、猪巴氏杆菌、禽巴氏杆菌、猪人肠杆菌、禽人肠杆菌、禽沙门氏菌的MIC分别为0.195、0.025、0.098、0.098、12.500、12.500. 50.000 25.000、100.000ug／mL，表明罗红霉素注射液仍保持了罗红霉素的体外抑菌活性，其对革兰氏阳性菌和部分革兰氏阴性菌有明显的抑菌作用。
再者，为了考察罗红霉素注射液肌内注射给药后，山羊血药浓度随时间变化趋势和药代动力学参数，并与口服罗红霉素分散片进行比较，评价罗红霉素注射液药动学特性及相对生
Roxithromycin (RXM) is a semisynthetic macrolides antibiotic with a broad and essentially bateriostatic action against many Gram-positive and some Gram-negative bacteria,as well as some anaerobes.Roxithromycin has been widely used clinically to treat a variety of tissues and organs infection,especially as the first picked medicine to therapy pediatric respiratory tract infection. Late years, go with the new found of Pharmacological Action and the new use in non-infection about macrolide antibiotics, enlarge continually clinical uses of roxithromycin. In order to adapt to the demand of clinical uses,and offer multi-choice to medical staff and patients,inclusion compound of roxithromycin can be prepared by reaction with hydroxypropyl-β-cyclodextrin, roxithromycin injection prepared from the inclusion compound may fill up the vacancy that roxithromycin was not injection preparation.The thesis carried out investigate to roxithromycin injection.
Through these studies of thermal stability 、 in vitro antibacterial activities、 pharmacokinetics and relative bioavailability in goats,probing of dosage regimen to go by pharmacokinetics /pharmacodynamics(PK/PD) parameters and postantibiotic effect(PAE) in that roxithromycin injection was treat the infection caused by Staphylococcus in goats.Information available suggests that roxithromycin injection is a new dosage form possessing develop prospect extremely.
Above all, roxithromycin injection suitable for clinical apply was selected by assessing the thermal stability of roxithromycin injection I and roxithromycin injection II ,which were respectively wraped by hydroxypropyl- β -cyclodextrin and γ -cyclodextrin. The inclusion compounds were prepared by trituration method. A reversed-phase HPLC method was developed for the determination of contents in RXM injection I and RXM injection II at different temperture and time.Initial equal-speed method was adopted to predict the period of validity.Results,expiry date of roxithromycin injection I is t_(0.9)~(25℃)=1.8a ,and t_(0.9)~(25℃)=0.87a for roxithromycin injection II .It showed roxithromycin injection I wraped by hydroxypropyl- β -cyclodextrin could be stored for 1 .8 year at room temperature .It is suitable for clinical circumstances demand.
Secondly,to study bacteriostatic activity of the roxithromycin injection in vitro. As was demanded by the practicing principles of clinical new medicines, liquid doubling dilution method was used to detect the MIC of roxithromycin injection on tested strain: four Gram-positive bacteria and five Gram-negative bacteria. Results ,the MIC of roxithromycin injection to swine erysipelas、 swine streptococcus、 Listeria monocytogenes、 staphylococcus aureus、 swine pasteurella、 avian pasteurella、 swine coleocele、 avian coleocele、 avian salmonella were 0.098、 0.025、 0.098、 0.195、
通过对罗红霉素注射液的热稳定性、体外抑菌活性和在山羊体内的药代动力学及相对生物利用度测定，以及运用药代动力学／药效学(PK／PD)参数和抗生素后效应(PAE)，对罗红霉素注射液治疗山羊葡萄球菌感染的给药方案进行了探讨，证明罗红霉素注射液是一个具有开发前景的新剂型。
首先，为了考察经羟丙基-β-环糊精和γ-环糊精包合罗红霉素制备的注射液Ⅰ和Ⅱ的热稳定性，初步筛选出适合临床应用的罗红霉素注射液，用研磨法制备了包合物，HPLC测定罗红霉素注射液Ⅰ和Ⅱ经不同温度处理后的含量，以初均速法预测其有效期，结果罗红霉素注射液It_(0.9)~(25℃)=1.8a；罗红霉素注射液Ⅱt_(0.9)~(25℃)=0.87a，即由羟丙基-β-环糊精包合罗红霉素所制备的注射液，有效期可达1.8年，基本可以满足生产、储存、运输及临床使用的需要。
其次，测定了罗红霉素注射液的体外抗菌活性。按照新药临床指导原则的要求，采用二倍稀释法测定了罗红霉素注射液对4株革兰氏阳性菌和5株革兰氏阴性菌的的最低抑菌浓度(MIC)，结果罗红霉素注射液对猪丹毒杆菌、猪链球菌、李氏单核胞浆菌、金黄色葡萄球菌、猪巴氏杆菌、禽巴氏杆菌、猪人肠杆菌、禽人肠杆菌、禽沙门氏菌的MIC分别为0.195、0.025、0.098、0.098、12.500、12.500. 50.000 25.000、100.000ug／mL，表明罗红霉素注射液仍保持了罗红霉素的体外抑菌活性，其对革兰氏阳性菌和部分革兰氏阴性菌有明显的抑菌作用。
再者，为了考察罗红霉素注射液肌内注射给药后，山羊血药浓度随时间变化趋势和药代动力学参数，并与口服罗红霉素分散片进行比较，评价罗红霉素注射液药动学特性及相对生
Roxithromycin (RXM) is a semisynthetic macrolides antibiotic with a broad and essentially bateriostatic action against many Gram-positive and some Gram-negative bacteria,as well as some anaerobes.Roxithromycin has been widely used clinically to treat a variety of tissues and organs infection,especially as the first picked medicine to therapy pediatric respiratory tract infection. Late years, go with the new found of Pharmacological Action and the new use in non-infection about macrolide antibiotics, enlarge continually clinical uses of roxithromycin. In order to adapt to the demand of clinical uses,and offer multi-choice to medical staff and patients,inclusion compound of roxithromycin can be prepared by reaction with hydroxypropyl-β-cyclodextrin, roxithromycin injection prepared from the inclusion compound may fill up the vacancy that roxithromycin was not injection preparation.The thesis carried out investigate to roxithromycin injection.
Through these studies of thermal stability 、 in vitro antibacterial activities、 pharmacokinetics and relative bioavailability in goats,probing of dosage regimen to go by pharmacokinetics /pharmacodynamics(PK/PD) parameters and postantibiotic effect(PAE) in that roxithromycin injection was treat the infection caused by Staphylococcus in goats.Information available suggests that roxithromycin injection is a new dosage form possessing develop prospect extremely.
Above all, roxithromycin injection suitable for clinical apply was selected by assessing the thermal stability of roxithromycin injection I and roxithromycin injection II ,which were respectively wraped by hydroxypropyl- β -cyclodextrin and γ -cyclodextrin. The inclusion compounds were prepared by trituration method. A reversed-phase HPLC method was developed for the determination of contents in RXM injection I and RXM injection II at different temperture and time.Initial equal-speed method was adopted to predict the period of validity.Results,expiry date of roxithromycin injection I is t_(0.9)~(25℃)=1.8a ,and t_(0.9)~(25℃)=0.87a for roxithromycin injection II .It showed roxithromycin injection I wraped by hydroxypropyl- β -cyclodextrin could be stored for 1 .8 year at room temperature .It is suitable for clinical circumstances demand.
Secondly,to study bacteriostatic activity of the roxithromycin injection in vitro. As was demanded by the practicing principles of clinical new medicines, liquid doubling dilution method was used to detect the MIC of roxithromycin injection on tested strain: four Gram-positive bacteria and five Gram-negative bacteria. Results ,the MIC of roxithromycin injection to swine erysipelas、 swine streptococcus、 Listeria monocytogenes、 staphylococcus aureus、 swine pasteurella、 avian pasteurella、 swine coleocele、 avian coleocele、 avian salmonella were 0.098、 0.025、 0.098、 0.195、
引文
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