首页 > 最新文献

AAPS PharmSci最新文献

英文 中文
Preparation, characterization, and biodistribution study of technetium-99m -labeled leuprolide acetate-loaded liposomes in Ehrlich ascites tumor-bearing mice. 锝-99m标记醋酸左连翘酯脂质体在埃利希腹水荷瘤小鼠体内的制备、表征及生物分布研究。
Pub Date : 2004-02-06 DOI: 10.1208/ps060105
N Arulsudar, N Subramanian, P Mishra, K Chuttani, R K Sharma, R S R Murthy

The purpose of this study was to prepare conventional and sterically stabilized liposomes containing leuprolide acetate in an attempt to prolong the biological half life of the drug, to reduce the uptake by reticuloendothelial system (RES), and to reduce the injection frequency of intravenously administered peptide drugs. The conventional and sterically stabilized liposomes containing leuprolide acetate were prepared by reverse phase evaporation method and characterized for entrapment efficiency and particle size. Radiolabeling of leuprolide acetate and its liposomes was performed by direct labeling with reduced technetium-99m. Its biodistribution and imaging characteristics were studied in ehrlich ascites tumor (EAT)-bearing mice after labeling with technetium-99m. The systemic pharmacokinetic studies were performed in rabbits. A high uptake by tumor was observed by sterically stabilized liposome containing leuprolide acetate compared with free drug and conventional liposomes. The liver/tumor uptake ratio of free drug, conventional (LL), and sterically stabilized liposomes (SLL5000 and SLL2000) was found to be 20, 7.99, 1.63, and 1.23, respectively, which showed the increased accumulation of sterically stabilized liposomes in tumor compared with the free drug and conventional liposomes at 24 hours postinjection. Liver uptake of sterically stabilized liposomes was still 7-fold less than the conventional liposomes. The marked accumulation of liposomes in the tumor-bearing mice was also documented by gamma scintigraphic studies. The findings demonstrate the distribution of these liposomes within solid tumor and prove that the sterically stabilized liposomes experience increased tumor uptake and prolonged circulation half life. Hence these findings will be relevant for the optimal design of long circulating liposomes for the peptide drugs and for targeting of liposomes toward tumor.

本研究的目的是制备含有醋酸leuprolide的常规和空间稳定脂质体,试图延长药物的生物半衰期,减少网状内皮系统(RES)的摄取,减少静脉给药多肽药物的注射频率。采用反相蒸发法制备了醋酸leuprolide常规脂质体和空间稳定脂质体,并对其包封效率和粒径进行了表征。用还原锝-99m直接标记醋酸leuprolide及其脂质体。用锝-99m标记后,研究其在携带埃利希腹水瘤(EAT)小鼠体内的生物分布和影像学特征。在家兔体内进行了全身药代动力学研究。与游离药物和常规脂质体相比,含有醋酸leuprolide的空间稳定脂质体具有较高的肿瘤吸收率。游离脂质体、常规脂质体(LL)和空间稳定脂质体(SLL5000和SLL2000)的肝脏/肿瘤摄取比分别为20、7.99、1.63和1.23,表明在注射后24小时,与游离脂质体和常规脂质体相比,空间稳定脂质体在肿瘤中的蓄积增加。肝脏对空间稳定脂质体的摄取仍比常规脂质体少7倍。脂质体在荷瘤小鼠体内的显著积累也被伽玛显像研究证实。研究结果证明了这些脂质体在实体瘤中的分布,并证明了空间稳定脂质体增加了肿瘤的吸收和延长了循环半衰期。因此,这些发现将对多肽药物长循环脂质体的优化设计和脂质体靶向肿瘤具有重要意义。
{"title":"Preparation, characterization, and biodistribution study of technetium-99m -labeled leuprolide acetate-loaded liposomes in Ehrlich ascites tumor-bearing mice.","authors":"N Arulsudar,&nbsp;N Subramanian,&nbsp;P Mishra,&nbsp;K Chuttani,&nbsp;R K Sharma,&nbsp;R S R Murthy","doi":"10.1208/ps060105","DOIUrl":"https://doi.org/10.1208/ps060105","url":null,"abstract":"<p><p>The purpose of this study was to prepare conventional and sterically stabilized liposomes containing leuprolide acetate in an attempt to prolong the biological half life of the drug, to reduce the uptake by reticuloendothelial system (RES), and to reduce the injection frequency of intravenously administered peptide drugs. The conventional and sterically stabilized liposomes containing leuprolide acetate were prepared by reverse phase evaporation method and characterized for entrapment efficiency and particle size. Radiolabeling of leuprolide acetate and its liposomes was performed by direct labeling with reduced technetium-99m. Its biodistribution and imaging characteristics were studied in ehrlich ascites tumor (EAT)-bearing mice after labeling with technetium-99m. The systemic pharmacokinetic studies were performed in rabbits. A high uptake by tumor was observed by sterically stabilized liposome containing leuprolide acetate compared with free drug and conventional liposomes. The liver/tumor uptake ratio of free drug, conventional (LL), and sterically stabilized liposomes (SLL5000 and SLL2000) was found to be 20, 7.99, 1.63, and 1.23, respectively, which showed the increased accumulation of sterically stabilized liposomes in tumor compared with the free drug and conventional liposomes at 24 hours postinjection. Liver uptake of sterically stabilized liposomes was still 7-fold less than the conventional liposomes. The marked accumulation of liposomes in the tumor-bearing mice was also documented by gamma scintigraphic studies. The findings demonstrate the distribution of these liposomes within solid tumor and prove that the sterically stabilized liposomes experience increased tumor uptake and prolonged circulation half life. Hence these findings will be relevant for the optimal design of long circulating liposomes for the peptide drugs and for targeting of liposomes toward tumor.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"6 1","pages":"E5"},"PeriodicalIF":0.0,"publicationDate":"2004-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps060105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 37
Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid. 布洛芬与乙酰水杨酸的溶剂化和水化特性。
Pub Date : 2004-01-26 DOI: 10.1208/ps060103
German L Perlovich, Sergey V Kurkov, Andrey N Kinchin, Annette Bauer-Brandl

Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, DeltaH(0) (sub), as well as the entropies of sublimation, DeltaS(0) (sub), and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, DeltaG(Oct) (solv), and the transfer Gibbs energy from water to octanol, DeltaG(0) (tr). Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.

采用热分析方法:升华量热法、溶液量热法和溶解度法对布洛芬和乙酰水杨酸进行了研究。通过测量饱和蒸汽压的温度依赖性,计算出升华焓δ δ(0)(次)和升华熵δ δ(0)(次)及其在整个过程中的相对分量。研究了脂肪醇的吉布斯溶剂化能及其焓和熵分数,并与模型物质和其他非甾体类抗炎药(苯甲酸、双氟尼拉、氟比洛芬、酮洛芬和萘普生)的各自性质进行了比较。在所有情况下,发现焓是溶剂化过程的驱动力。得到了辛醇溶剂化的吉布斯能DeltaG(Oct) (solv)与水向辛醇转移的吉布斯能DeltaG(0) (tr)之间的相关关系。讨论了辛醇和水的相互溶解度对分划驱动力的影响。在辛醇中观察到焓-熵-补偿效应,并讨论了偏离一般趋势的后果。
{"title":"Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid.","authors":"German L Perlovich,&nbsp;Sergey V Kurkov,&nbsp;Andrey N Kinchin,&nbsp;Annette Bauer-Brandl","doi":"10.1208/ps060103","DOIUrl":"https://doi.org/10.1208/ps060103","url":null,"abstract":"<p><p>Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, DeltaH(0) (sub), as well as the entropies of sublimation, DeltaS(0) (sub), and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, DeltaG(Oct) (solv), and the transfer Gibbs energy from water to octanol, DeltaG(0) (tr). Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"6 1","pages":"E3"},"PeriodicalIF":0.0,"publicationDate":"2004-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps060103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 27
Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: development of a novel process for obtaining a dry, stable powder. 聚乙二醇诱导沉淀干扰素α-2a,然后真空干燥:开发一种获得干燥稳定粉末的新工艺。
Pub Date : 2004-01-26 DOI: 10.1208/ps060104
Vikas K Sharma, Devendra S Kalonia

Feasibility studies were performed on the development of a novel process based on polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum drying in the presence of sugars to obtain dry protein powders. Apparent solubility of interferon alpha-2a (IFNalpha2a) was determined in the presence of various PEGs and the effect of solution pH, ionic strength, and temperature was investigated. IFNalpha2a precipitate was dried at a shelf temperature of 25 degrees C at 100 mTorr either as it is or in the presence of mannitol and/or trehalose. The dried IFNalpha2a formulations were subjected to accelerated stability studies at 40 degrees C (3 months), and the stability was compared with that of a similar lyophilized formulation. The results indicated that more than 90% of the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted in the formation of insoluble aggregates of IFNalpha2a; however, this was prevented by the addition of either mannitol or trehalose. The addition of excess mannitol resulted in low residual moisture content and better handling of the final dried product. Accelerated storage stability did not show any aggregation and showed less than 5% formation of oxidized IFNalpha2a in the dried formulation containing IFNalpha2a:trehalose:mannitol in a 1:10:100 wt/wt ratio upon storage at 40 degrees C for 3 months. The stability of this vacuum dried formulation was comparable with that of a similar lyophilized formulation.

对基于聚乙二醇(PEG)诱导蛋白质沉淀,然后在有糖存在的情况下进行真空干燥以获得干蛋白粉的新型工艺的开发进行了可行性研究。测定了干扰素α-2a(IFNalpha2a)在各种 PEG 存在下的表观溶解度,并研究了溶液 pH 值、离子强度和温度的影响。IFNalpha2a 沉淀在 25 摄氏度、100 毫托的保存温度下按原样或在甘露醇和/或曲哈糖存在下进行干燥。干燥后的 IFNalpha2a 制剂在 40 摄氏度(3 个月)下进行了加速稳定性研究,并将其稳定性与类似的冻干制剂进行了比较。结果表明,在 pH 值为 6.5、溶液离子强度为 71 mM 的条件下,使用 10% wt/vol PEG 1450 可以沉淀 90% 以上的蛋白质。对沉淀物进行真空干燥只会导致 IFNalpha2a 形成不溶性的聚集体;然而,加入甘露醇或曲海洛糖可防止这种情况的发生。添加过量的甘露醇可降低残余水分含量,使最终干燥产品的处理效果更好。在 40 摄氏度下贮存 3 个月后,在含有 IFNalpha2a:曲哈洛糖:甘露醇(重量比为 1:10:100)的干燥制剂中,加速贮存稳定性未显示任何聚集现象,氧化 IFNalpha2a 的形成率低于 5%。这种真空干燥制剂的稳定性与类似的冻干制剂相当。
{"title":"Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: development of a novel process for obtaining a dry, stable powder.","authors":"Vikas K Sharma, Devendra S Kalonia","doi":"10.1208/ps060104","DOIUrl":"10.1208/ps060104","url":null,"abstract":"<p><p>Feasibility studies were performed on the development of a novel process based on polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum drying in the presence of sugars to obtain dry protein powders. Apparent solubility of interferon alpha-2a (IFNalpha2a) was determined in the presence of various PEGs and the effect of solution pH, ionic strength, and temperature was investigated. IFNalpha2a precipitate was dried at a shelf temperature of 25 degrees C at 100 mTorr either as it is or in the presence of mannitol and/or trehalose. The dried IFNalpha2a formulations were subjected to accelerated stability studies at 40 degrees C (3 months), and the stability was compared with that of a similar lyophilized formulation. The results indicated that more than 90% of the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted in the formation of insoluble aggregates of IFNalpha2a; however, this was prevented by the addition of either mannitol or trehalose. The addition of excess mannitol resulted in low residual moisture content and better handling of the final dried product. Accelerated storage stability did not show any aggregation and showed less than 5% formation of oxidized IFNalpha2a in the dried formulation containing IFNalpha2a:trehalose:mannitol in a 1:10:100 wt/wt ratio upon storage at 40 degrees C for 3 months. The stability of this vacuum dried formulation was comparable with that of a similar lyophilized formulation.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"6 1","pages":"E4"},"PeriodicalIF":0.0,"publicationDate":"2004-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750939/pdf/12248_2008_Article_61031.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Formulations for natural and peptide nucleic acids based on cationic polymeric submicron particles. 基于阳离子聚合亚微米粒子的天然核酸和多肽核酸配方。
Pub Date : 2004-01-20 DOI: 10.1208/pt060102
Rita Cortesi, Carlo Mischiati, Monica Borgatti, Laura Breda, Alessandra Romanelli, Michele Saviano, Carlo Pedone, Roberto Gambari, Claudio Nastruzzi

This article describes the production and characterization of cationic submicron particles constituted with Eudragit RS 100, plus different cationic surfactants, such as dioctadecyl-dimethyl-ammonium bromide (DDAB18) and diisobutylphenoxyethyl-dimethylbenzyl ammonium chloride (DEBDA), as a transport and delivery system for DNA/DNA and DNA/peptide nucleic acid (PNA) hybrids and PNA-DNA chimeras. Submicron particles could offer advantages over other delivery systems because they maintain unaltered physicochemical properties for long time periods, allowing long-term storage, and are suitable for industrial production. Submicron particles were characterized in terms of size, size distribution, morphology, and zeta potential. Moreover, the in vitro activity and ability of submicron particles to complex different types of nucleic acids were described. Finally, the ability of submicron particles to deliver functional genes to cells cultured in vitro was determined by a luciferase activity assay, demonstrating that submicron particles possess superior transfection efficiency with respect to commercially available, liposome-based transfection kits.

本文介绍了以乌拉木RS 100为原料,与不同阳离子表面活性剂,如二十二烷基二甲基溴化铵(DDAB18)和二异丁基苯氧乙基二甲基氯化铵(DEBDA)组成的阳离子亚微米颗粒的制备和表征,作为DNA/DNA和DNA/肽核酸(PNA)杂种和PNA-DNA嵌合体的运输和递送系统。亚微米颗粒比其他输送系统更有优势,因为它们在很长一段时间内保持不变的物理化学性质,允许长期储存,并且适合工业生产。亚微米颗粒在尺寸、尺寸分布、形貌和zeta电位方面进行了表征。此外,还描述了亚微米颗粒对复杂不同类型核酸的体外活性和能力。最后,通过荧光素酶活性测定确定了亚微米颗粒向体外培养的细胞传递功能基因的能力,表明亚微米颗粒相对于市售的基于脂质体的转染试剂盒具有更高的转染效率。
{"title":"Formulations for natural and peptide nucleic acids based on cationic polymeric submicron particles.","authors":"Rita Cortesi,&nbsp;Carlo Mischiati,&nbsp;Monica Borgatti,&nbsp;Laura Breda,&nbsp;Alessandra Romanelli,&nbsp;Michele Saviano,&nbsp;Carlo Pedone,&nbsp;Roberto Gambari,&nbsp;Claudio Nastruzzi","doi":"10.1208/pt060102","DOIUrl":"https://doi.org/10.1208/pt060102","url":null,"abstract":"<p><p>This article describes the production and characterization of cationic submicron particles constituted with Eudragit RS 100, plus different cationic surfactants, such as dioctadecyl-dimethyl-ammonium bromide (DDAB18) and diisobutylphenoxyethyl-dimethylbenzyl ammonium chloride (DEBDA), as a transport and delivery system for DNA/DNA and DNA/peptide nucleic acid (PNA) hybrids and PNA-DNA chimeras. Submicron particles could offer advantages over other delivery systems because they maintain unaltered physicochemical properties for long time periods, allowing long-term storage, and are suitable for industrial production. Submicron particles were characterized in terms of size, size distribution, morphology, and zeta potential. Moreover, the in vitro activity and ability of submicron particles to complex different types of nucleic acids were described. Finally, the ability of submicron particles to deliver functional genes to cells cultured in vitro was determined by a luciferase activity assay, demonstrating that submicron particles possess superior transfection efficiency with respect to commercially available, liposome-based transfection kits.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"6 1","pages":"E2"},"PeriodicalIF":0.0,"publicationDate":"2004-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats. 全反式维甲酸在大鼠体内时间依赖性消除的药代动力学。
Pub Date : 2004-01-09 DOI: 10.1208/ps060101
Anas Saadeddin, Francisca Torres-Molina, Jaime Cárcel-Trullols, Amparo Araico, José-Esteban Peris

The time-dependent elimination kinetics of all-trans-retinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of time-dependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg(-1) and 0.40 mg kg(-1)), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg(-1)), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h(-1) kg(-1) of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg(-1)) was approximately 8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.

全反式维甲酸(ATRA)的时间依赖性消除动力学与其代谢的自身诱导有关,并导致了一种假设,即ATRA获得性临床耐药性的快速发展可能通过联合使用代谢抑制剂来预防。本研究在大鼠中研究ATRA的药代动力学和时间依赖性消除的开始时间,目的是建立一个适合于抑制ATRA代谢的化合物的体内临床前研究的动物模型。单剂量ATRA (1.60 mg kg(-1)和0.40 mg kg(-1))静脉注射后,血浆浓度-时间曲线在给药后180分钟呈加速下降趋势。第二次静脉给药(1.60 mg kg(-1))后180分钟的血浆清除率(Cl)高于单次给药后的Cl,这表明在第一次给药后180分钟存在可检测到的时间依赖性消除过程。通过在10小时内静脉等速输注0.48 mg h(-1) kg(-1) ATRA,证实了这种时间依赖性消除。血浆ATRA浓度在180分钟达到峰值,此后血浆浓度下降,在420分钟达到更低的表观稳态药物浓度。口服第二次ATRA剂量(1.60 mg kg(-1))后获得的血浆浓度-时间曲线下面积(AUC)约为单次口服剂量后获得的AUC的8%;与IV给药后观察到的ATRA消除的时间依赖性增加一致。
{"title":"Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats.","authors":"Anas Saadeddin,&nbsp;Francisca Torres-Molina,&nbsp;Jaime Cárcel-Trullols,&nbsp;Amparo Araico,&nbsp;José-Esteban Peris","doi":"10.1208/ps060101","DOIUrl":"https://doi.org/10.1208/ps060101","url":null,"abstract":"<p><p>The time-dependent elimination kinetics of all-trans-retinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of time-dependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg(-1) and 0.40 mg kg(-1)), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg(-1)), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h(-1) kg(-1) of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg(-1)) was approximately 8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"6 1","pages":"E1"},"PeriodicalIF":0.0,"publicationDate":"2004-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps060101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 50
A photo-crosslinked poly(vinyl alcohol) hydrogel growth factor release vehicle for wound healing applications. 用于伤口愈合的光交联聚乙烯醇水凝胶生长因子释放载体。
Pub Date : 2003-12-04 DOI: 10.1208/ps050433
Sharon L Bourke, Mohammad Al-Khalili, Tonye Briggs, Bozena B Michniak, Joachim Kohn, Laura A Poole-Warren

The objective of this study was to develop and evaluate a hydrogel vehicle for sustained release of growth factors for wound healing applications. Hydrogels were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI permeability was altered by changing the solids content of the gel and by adding hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase in model drug release was achieved by incorporating hydrophilic PVA fillers into the hydrogel. As filler molecular weight increased, TI flux increased. The mechanism for this is most likely an alteration in protein/gel interactions and transient variations in water content. The percent protein released was also altered by varying protein loading concentration. Release studies conducted using growth factor in vehicles with hydrophilic filler showed sustained release of platelet-derived growth factor (PDGF-beta,beta) for up to 3 days compared with less than 24 hours in the controls. In vitro bioactivity was demonstrated by doubling of normal human dermal fibroblast numbers when exposed to growth factor-loaded vehicle compared to control. The release vehicle developed in this study uses a rapid and simple fabrication method, and protein release can be tailored by modifying solid content, incorporating biocompatible hydrophilic fillers, and varying protein loading concentration.

本研究旨在开发和评估一种用于伤口愈合的生长因子持续释放的水凝胶载体。水凝胶是通过紫外线光交联丙烯酰胺功能化的不可降解聚乙烯醇(PVA)制成的。蛋白质渗透性最初使用胰蛋白酶抑制剂(TI)(一种 21 000 MW 的蛋白质模型药物)进行评估。通过改变凝胶的固体含量和添加亲水性 PVA 填充物来改变 TI 的渗透性。随着 PVA 含量从 10% 增加到 20%,蛋白质通量下降,20% 的 PVA 水凝胶中没有 TI 渗透。通过在水凝胶中加入亲水性 PVA 填充剂,进一步增加了模型药物释放量。随着填料分子量的增加,TI 通量也随之增加。其机制很可能是蛋白质/凝胶相互作用的改变和含水量的瞬时变化。蛋白质释放的百分比也会随着蛋白质负载浓度的变化而改变。使用亲水性填充物载体中的生长因子进行的释放研究表明,血小板衍生生长因子(PDGF-beta,beta)的持续释放时间长达 3 天,而对照组的释放时间不到 24 小时。体外生物活性的证明是,与对照组相比,正常人真皮成纤维细胞暴露于含有生长因子的载体时,其数量增加了一倍。本研究中开发的释放载体采用了快速、简单的制造方法,可通过改变固体含量、加入生物相容性亲水填料和改变蛋白质负载浓度来定制蛋白质释放。
{"title":"A photo-crosslinked poly(vinyl alcohol) hydrogel growth factor release vehicle for wound healing applications.","authors":"Sharon L Bourke, Mohammad Al-Khalili, Tonye Briggs, Bozena B Michniak, Joachim Kohn, Laura A Poole-Warren","doi":"10.1208/ps050433","DOIUrl":"10.1208/ps050433","url":null,"abstract":"<p><p>The objective of this study was to develop and evaluate a hydrogel vehicle for sustained release of growth factors for wound healing applications. Hydrogels were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI permeability was altered by changing the solids content of the gel and by adding hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase in model drug release was achieved by incorporating hydrophilic PVA fillers into the hydrogel. As filler molecular weight increased, TI flux increased. The mechanism for this is most likely an alteration in protein/gel interactions and transient variations in water content. The percent protein released was also altered by varying protein loading concentration. Release studies conducted using growth factor in vehicles with hydrophilic filler showed sustained release of platelet-derived growth factor (PDGF-beta,beta) for up to 3 days compared with less than 24 hours in the controls. In vitro bioactivity was demonstrated by doubling of normal human dermal fibroblast numbers when exposed to growth factor-loaded vehicle compared to control. The release vehicle developed in this study uses a rapid and simple fabrication method, and protein release can be tailored by modifying solid content, incorporating biocompatible hydrophilic fillers, and varying protein loading concentration.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"5 4","pages":"E33"},"PeriodicalIF":0.0,"publicationDate":"2003-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750995/pdf/12248_2008_Article_54101.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacokinetics of paclitaxel-containing liposomes in rats. 含紫杉醇脂质体在大鼠体内的药动学。
Pub Date : 2003-11-21 DOI: 10.1208/ps050432
Gerald J Fetterly, Robert M Straubinger

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1 +/- 3.32 microg-h/mL; Cre-pac: 34.5 +/- 0.994 microg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K(p)) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K(p) was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.

在动物模型中,与临床制剂紫杉醇相比,紫杉醇脂质体制剂具有较低的毒性和相同的抗肿瘤功效。本研究的目的是确定大鼠体内紫杉醇药代动力学的配方依赖性,以验证改变紫杉醇生物分布改变关键正常组织暴露的假设。紫杉醇被静脉注射到由磷脂酰甘油/磷脂酰胆碱(L-pac)组成的多层(MLV)脂质体中,或用于紫杉醇制剂(Cremophor EL/乙醇)的载体中。剂量为40 mg/kg,滴注时间8 ~ 9分钟。在不同时间处死动物,从紫杉醇的血液和组织分布中测定药代动力学参数。两种制剂的血药浓度-时间曲线下面积(AUC)相似(L-pac: 38.1 +/- 3.32 μ g-h/mL;Cre-pac: 34.5 +/- 0.994 μ g-h/mL),但不同组织的AUC与制剂相关。对于骨髓、皮肤、肾脏、大脑、脂肪和肌肉组织,crec -pac的AUC在统计学上更高。脾脏是网状内皮系统的一个组织,对脂质体的清除很重要,L-pac的AUC在统计学上更高。计算组织表观分配系数(K(p))。对于骨髓,一个紫杉醇具有显著毒性的组织,Cre-pac中紫杉醇的K(p)高5倍。这些数据与紫杉醇从循环脂质体中释放一致,但外排延迟到足以使药物在更大程度上保留在中央(血液)室,并减少渗透到周围组织。这些作用可能有助于降低紫杉醇脂质体制剂的毒性。
{"title":"Pharmacokinetics of paclitaxel-containing liposomes in rats.","authors":"Gerald J Fetterly,&nbsp;Robert M Straubinger","doi":"10.1208/ps050432","DOIUrl":"https://doi.org/10.1208/ps050432","url":null,"abstract":"<p><p>In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1 +/- 3.32 microg-h/mL; Cre-pac: 34.5 +/- 0.994 microg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K(p)) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K(p) was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"5 4","pages":"E32"},"PeriodicalIF":0.0,"publicationDate":"2003-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps050432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 103
Properties of microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier transform Raman spectroscopy and environmental scanning electron microscopy. 用傅里叶变换拉曼光谱和环境扫描电镜研究了挤出/滚圆后微晶纤维素和粉末纤维素的性质。
Pub Date : 2003-11-19 DOI: 10.1208/ps050431
Petra M Fechner, Siegfried Wartewig, Manfred Füting, Andreas Heilmann, Reinhard H H Neubert, Peter Kleinebudde

In this study, the effect of powder cellulose (PC) and 2 types of microcrystalline cellulose (MCC 101 and MCC 301) on pellet properties produced by an extrusion/spheronization process was investigated. The different investigated types of cellulose displayed different behavior during the extrusion/spheronization process. Pure PC was unsuitable for extrusion, because too much water was required and the added water was partly squeezed during the extrusion process. In contrast, MCC 101 and MCC 301 were extrudable at a wide range of water content, but the quality of the resulting products varied. In the extrusion/spheronization process, MCC 101 was the best substance, with easy handling and acceptable product properties. The properties of the extrudates and pellets were determined by Fourier transform (FT) Raman spectroscopy and environmental scanning electron microscopy (ESEM). FT-Raman spectroscopy was able to distinguish between the original substances and also between the wet and dried extrudates. The particle sizes of the raw material and of the extrudates were determined by ESEM without additional preparation. For MCC, the size of the resulting particles within the extrudate or pellet was smaller. However, in the extrudates of PC, changes in particle size could not be observed.

本文研究了粉末纤维素(PC)和2种微晶纤维素(MCC 101和MCC 301)对挤压/滚圆法制备球团性能的影响。不同类型的纤维素在挤压/滚圆过程中表现出不同的行为。纯PC不适合挤压,因为需要太多的水,在挤压过程中加入的水被部分挤压。相比之下,mcc101和mcc301在很宽的含水量范围内都是可挤压的,但最终产品的质量却有所不同。在挤压/球化工艺中,mcc101是最佳材料,易于操作,产品性能可接受。采用傅里叶变换(FT)拉曼光谱和环境扫描电子显微镜(ESEM)对挤出物和球团的性能进行了测定。ft -拉曼光谱能够区分原始物质,也可以区分湿挤出物和干挤出物。原料和挤出物的颗粒大小由ESEM测定,无需额外的制备。对于MCC,在挤出物或球团中产生的颗粒尺寸较小。然而,在PC的挤出物中,没有观察到颗粒大小的变化。
{"title":"Properties of microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier transform Raman spectroscopy and environmental scanning electron microscopy.","authors":"Petra M Fechner,&nbsp;Siegfried Wartewig,&nbsp;Manfred Füting,&nbsp;Andreas Heilmann,&nbsp;Reinhard H H Neubert,&nbsp;Peter Kleinebudde","doi":"10.1208/ps050431","DOIUrl":"https://doi.org/10.1208/ps050431","url":null,"abstract":"<p><p>In this study, the effect of powder cellulose (PC) and 2 types of microcrystalline cellulose (MCC 101 and MCC 301) on pellet properties produced by an extrusion/spheronization process was investigated. The different investigated types of cellulose displayed different behavior during the extrusion/spheronization process. Pure PC was unsuitable for extrusion, because too much water was required and the added water was partly squeezed during the extrusion process. In contrast, MCC 101 and MCC 301 were extrudable at a wide range of water content, but the quality of the resulting products varied. In the extrusion/spheronization process, MCC 101 was the best substance, with easy handling and acceptable product properties. The properties of the extrudates and pellets were determined by Fourier transform (FT) Raman spectroscopy and environmental scanning electron microscopy (ESEM). FT-Raman spectroscopy was able to distinguish between the original substances and also between the wet and dried extrudates. The particle sizes of the raw material and of the extrudates were determined by ESEM without additional preparation. For MCC, the size of the resulting particles within the extrudate or pellet was smaller. However, in the extrudates of PC, changes in particle size could not be observed.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"5 4","pages":"E31"},"PeriodicalIF":0.0,"publicationDate":"2003-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps050431","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 32
Lipid-based supramolecular systems for topical application: a preformulatory study. 局部应用的脂基超分子系统:配方前研究。
Pub Date : 2003-11-18 DOI: 10.1208/ps050430
Elisabetta Esposito, Nadia Eblovi, Silvia Rasi, Markus Drechsler, Giordano M Di Gregorio, Enea Menegatti, Rita Cortesi

This article describes the production and characterization of monoglyceride-based supramolecular systems by a simple processing technique, avoiding time-consuming procedures, high energy input, and the use of organic solvents. A preformulatory study was performed to study the influence of the experimental parameters on the production of monoglyceride-based disperse systems. In particular the effects of (1) stirring speed, (2) type and concentration of monoglyceride mixture, and (3) type and concentration of surfactant were investigated on the recovery, fraction of larger particles, mean diameter, and shape of smaller particles (so called nanosomes). Dispersions were first characterized by optical microscopy and freeze-fracture electron microscopy. The mean diameter of standard nanosomes, analyzed by photon correlation spectroscopy (PCS) after elimination of larger particles by filtration, was 193.5 nm. Cryotransmission electron microscopy studies, conducted in order to investigate the structure of dispersions, showed the coexistence of vesicles and particles characterized by a cubic organization. X-ray diffraction data revealed the coexistence of 2 different cubic phases, the first being a bicontinuous cubic phase of spatial symmetry Im3m (Q229) and the second belonging to the Pn3m spatial symmetry. A study on the stability of monoglyceride-based dispersions based on macroscopical analysis of organoleptic properties and dimensional analysis by time was performed after elimination of larger particles by filtration. Organoleptic and morphological features do not change by time, appearing free from phase-separation phenomena for almost 1 year from production. PCS studies showed that nanosomes undergo an initial increase in mean diameter within the first month following production; afterwards they generally maintain their dimensions for the next 4 months.

本文介绍了单甘油酯基超分子体系的生产和表征,通过一种简单的加工技术,避免了耗时的程序,高能量输入,并使用有机溶剂。进行了配方前研究,研究了实验参数对单甘油酯分散体系生产的影响。特别研究了(1)搅拌速度、(2)单甘油酯混合物类型和浓度、(3)表面活性剂类型和浓度对回收率、大颗粒分数、平均直径和小颗粒(即纳米体)形状的影响。分散体首先通过光学显微镜和冷冻断裂电镜进行表征。通过光子相关光谱(PCS)分析,滤除较大颗粒后,标准纳米体的平均直径为193.5 nm。为了研究分散体的结构,进行了低温透射电镜研究,显示了以立方组织为特征的囊泡和颗粒共存。x射线衍射数据显示,两种不同的立方相共存,第一种是空间对称的双连续立方相Im3m (Q229),第二种属于Pn3m空间对称。通过过滤去除大颗粒后的宏观感官分析和时间量纲分析,对单甘油酯基分散体的稳定性进行了研究。感官和形态特征不随时间变化,生产后近1年没有相分离现象。PCS研究表明,纳米体在生产后的第一个月内平均直径初始增加;之后,他们通常会在接下来的4个月里保持他们的尺寸。
{"title":"Lipid-based supramolecular systems for topical application: a preformulatory study.","authors":"Elisabetta Esposito,&nbsp;Nadia Eblovi,&nbsp;Silvia Rasi,&nbsp;Markus Drechsler,&nbsp;Giordano M Di Gregorio,&nbsp;Enea Menegatti,&nbsp;Rita Cortesi","doi":"10.1208/ps050430","DOIUrl":"https://doi.org/10.1208/ps050430","url":null,"abstract":"<p><p>This article describes the production and characterization of monoglyceride-based supramolecular systems by a simple processing technique, avoiding time-consuming procedures, high energy input, and the use of organic solvents. A preformulatory study was performed to study the influence of the experimental parameters on the production of monoglyceride-based disperse systems. In particular the effects of (1) stirring speed, (2) type and concentration of monoglyceride mixture, and (3) type and concentration of surfactant were investigated on the recovery, fraction of larger particles, mean diameter, and shape of smaller particles (so called nanosomes). Dispersions were first characterized by optical microscopy and freeze-fracture electron microscopy. The mean diameter of standard nanosomes, analyzed by photon correlation spectroscopy (PCS) after elimination of larger particles by filtration, was 193.5 nm. Cryotransmission electron microscopy studies, conducted in order to investigate the structure of dispersions, showed the coexistence of vesicles and particles characterized by a cubic organization. X-ray diffraction data revealed the coexistence of 2 different cubic phases, the first being a bicontinuous cubic phase of spatial symmetry Im3m (Q229) and the second belonging to the Pn3m spatial symmetry. A study on the stability of monoglyceride-based dispersions based on macroscopical analysis of organoleptic properties and dimensional analysis by time was performed after elimination of larger particles by filtration. Organoleptic and morphological features do not change by time, appearing free from phase-separation phenomena for almost 1 year from production. PCS studies showed that nanosomes undergo an initial increase in mean diameter within the first month following production; afterwards they generally maintain their dimensions for the next 4 months.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"5 4","pages":"E30"},"PeriodicalIF":0.0,"publicationDate":"2003-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps050430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 113
Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model. 羟嗪从局部磷脂脂质体制剂:评估外周抗组胺活性和全身吸收的兔模型。
Pub Date : 2003-11-05 DOI: 10.1208/ps050428
Abeer A W Elzainy, Xiaochen Gu, F Estelle R Simons, Keith J Simons

Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50, 1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.

羟嗪是一种有效但具有镇静作用的h1 -抗组胺药,用于口服治疗过敏性皮肤病。本研究旨在评估外周H(1)-抗组胺活性和皮肤脂质体对羟嗪的全身吸收程度。以l - α -磷脂酰胆碱(PC)为原料,制备了含羟嗪的单层小囊泡(suv)和多层小囊泡(MLVs)。以玻璃碱羟嗪(GB)为对照。采用随机交叉设计,每个配方含有10 mg羟嗪,应用于6只兔子(3.08 +/- 0.05 kg)剃光的背部。组胺诱导的轮试验和血液取样在指定的时间间隔内进行,最长可达24小时。与基线相比,所有配方的羟嗪在长达24小时内显著抑制组胺诱导的轮状形成75%至95%。2 ~ 6小时的平均最大抑制率为85% ~ 94%,各剂型间无差异。PC-SUV和PC-MLV处理的24 h血浆羟嗪浓度曲线下面积(aus)分别为80.1 +/- 20.8和78.4 +/- 33.9 ng/mL/h,低于GB处理的492 +/- 141 ng/mL/h (P < or = 0.05)。体内西替利嗪作为羟嗪的活性代谢物,在PC-SUV、PC-MLV和GB中产生的血浆浓度与AUCs相似,分别为765 +/- 50、1035 +/- 202和957 +/- 227 ng/mL/h (P < or = 0.05)。24小时后,只有0.02%至0.06%的初始羟嗪剂量留在皮肤上。在该模型中,来自SUV和MLV的羟嗪具有优异的局部h1抗组胺活性,并且发生最小的全身暴露。体内形成的西替利嗪有助于部分h1抗组胺活性。
{"title":"Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.","authors":"Abeer A W Elzainy,&nbsp;Xiaochen Gu,&nbsp;F Estelle R Simons,&nbsp;Keith J Simons","doi":"10.1208/ps050428","DOIUrl":"https://doi.org/10.1208/ps050428","url":null,"abstract":"<p><p>Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50, 1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"5 4","pages":"E28"},"PeriodicalIF":0.0,"publicationDate":"2003-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps050428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24566599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 24
期刊
AAPS PharmSci
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1