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Controlled release microspheres based on Eudragit L100 for the oral administration of erythromycin. 红霉素口服控释微球的研制。
Pub Date : 1991-07-01
I Morishita, M Morishita, Y Machida, T Nagai

The use of Eudragit L100, a copolymer based on methacrylic acid and methacrylic acid methyl ester, in preparing erythromycin microspheres is described. The microspheres were simply prepared in liquid paraffin by solidifying an Eudragit L100 in ethanol solution. When gelatin was incorporated in the solidifying solution, the resultant microspheres were more spherical and had a smooth surface. The size of the microspheres could be controlled by varying the Eudragit L100 concentration in ethanol, and erythromycin was incorporated with 60-70% efficiency. The degradation of erythromycin by acid was markedly protected when the erythromycin microspheres were coated with the polymer. The in vitro release rate of erythromycin from the microspheres was also modified by the coating process. The feasibility of preparing formulations of erythromycin for oral administration, which release the drug at a controlled rate, and protect the drug from gastric acid, is thus demonstrated.

介绍了以甲基丙烯酸和甲基丙烯酸甲酯为基料的共聚物乌德拉吉L100在红霉素微球制备中的应用。将Eudragit L100在乙醇溶液中固化,在液体石蜡中制备微球。当明胶加入到固化溶液中时,得到的微球更圆,表面光滑。通过改变乌龙茶L100在乙醇中的浓度可以控制微球的大小,红霉素的掺入效率为60-70%。高分子聚合物包被红霉素微球后,红霉素被酸降解的过程明显受到保护。包被工艺对红霉素微球的体外释放速度也有影响。因此,证明了制备口服红霉素制剂的可行性,该制剂以可控的速度释放药物,并保护药物免受胃酸的侵害。
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引用次数: 0
Conjugate of N4-(4-carboxybutyryl)-ara-C and ethylenediamine-introduced dextran. Drug release profiles and further in vivo study of its antitumor effects. N4-(4-羧基丁基)-ara- c与乙二胺引入的葡聚糖的缀合物。药物释放谱及其抗肿瘤作用的进一步体内研究。
Pub Date : 1991-04-01
H Onishi, Y Seno, P Pithayanukul, T Nagai

In vitro and further in vivo work with a conjugate formed from the cytotoxic drug 1-beta-arabinofuranosylcytosine (ara-C) and dextran 2000 are described. In the preparation of this conjugate, functionalisation of ara-C was via N4-(4-carboxybutyryl)-ara-C (glu-ara-C), permitting conjugation with amino groups introduced by prior reaction of the oxidised dextran with ethylenediamine; by varying the proportions of the reaction components, 5.4 to 7.7% w/w loadings of ara-C were obtained. At physiological pH, in vitro, drug release from a 5.4% loaded conjugate was gradual and was dominantly ara-C; at lysosomal pH (pH 5) the release rate was much slower and more ara-U was formed. Antitumour effects were evaluated in L1210 leukaemic mice following single (1 day after inoculation) or double (2 and 6 days after inoculation) intraperitoneal injection of ara-C, glu-ara-C, or a 7.7% loaded conjugate at three dose levels. In all cases, the increase in lifespan was greatest following use of the conjugate, but the differences in the effects of ara-C and the conjugate were only significant at the lowest dose level. Glu-ara-C was virtually inactive under all conditions.

本文描述了细胞毒性药物1- β -阿拉伯糖醛基胞嘧啶(ara-C)和葡聚糖2000形成的缀合物在体外和体内的进一步工作。在该缀合物的制备中,ara-C的功能化是通过N4-(4-羧基丁基)-ara-C(葡萄糖-ara-C)进行的,允许与氧化右旋糖酐与乙二胺预先反应引入的氨基结合;通过改变反应组分的比例,可以获得5.4 ~ 7.7% w/w的ara-C负荷。在生理pH下,5.4%负载的缀合物的体外药物释放是渐进的,主要是ara-C;在溶酶体pH (pH 5)时,释放速度较慢,形成更多的ara-U。在L1210白血病小鼠中,单次(接种后1天)或两次(接种后2天和6天)腹腔注射ara-C、glu-ara-C或负载7.7%的缀合物,以三个剂量水平评估其抗肿瘤作用。在所有情况下,使用缀合物后寿命的增加最大,但ara-C和缀合物的效果差异仅在最低剂量水平下显着。在所有条件下,Glu-ara-C几乎都没有活性。
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引用次数: 0
Nonleast-squares jackknife regression in drug design. 药物设计中的非最小二乘折刀回归。
Pub Date : 1991-04-01
P P Mager

Nonleast-squares jackknife regression was applied to model a quantitative structure-activity relationship (QSAR) analysis of butyrophenones. Dependent physicochemical and dependent psychopharmacological parameters were correlated, and the robustness of the model was confirmed by resampling.

采用非最小二乘折刀回归对丁苯酮进行了定量构效关系分析。依赖的物理化学参数和依赖的精神药理学参数相互关联,并通过重新采样证实了模型的稳健性。
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引用次数: 0
New approaches to drug design and delivery based on drug-membrane interactions. 基于药物-膜相互作用的药物设计和递送新方法。
Pub Date : 1991-04-01
L G Herbette, D G Rhodes, R P Mason

In this review, the complex physical and chemical interactions of drugs with model and biological membranes under normal and pathological conditions are examined at the molecular level. The results of our own published and unpublished structural studies are discussed and correlated with kinetic binding studies to assess the potential role of nonspecific drug interaction with the membrane bilayer in the overall receptor binding mechanism for membrane-bound receptors in heart and brain.

本文从分子水平研究了正常和病理条件下药物与模型膜和生物膜之间复杂的物理和化学相互作用。我们对已发表和未发表的结构研究结果进行了讨论,并将其与动力学结合研究相关联,以评估非特异性药物与膜双分子层相互作用在心脏和大脑膜结合受体的整体受体结合机制中的潜在作用。
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引用次数: 0
Enhanced skin permeation of papaverine by a medium chain glyceride. 中链甘油酯增强罂粟碱的皮肤渗透性。
Pub Date : 1991-04-01
M Okumura, Y Nakamori, K Sugibayashi, Y Morimoto

The mode and mechanism of action of Sefsol-318, a medium chain glyceride and a potent percutaneous absorption enhancer, on the in vitro permeation of papaverine hydrochloride through hairless rat skin were investigated and compared with those of laurocapram (Azone). The total amount of the drug delivered through excised skin over 28 h from aqueous solutions of the drug in which 5% S-318 or Azone was suspended was about 820 or 420 times higher, respectively, than from the solution alone. Experiments using liposomes as models, indicated that both the enhancers markedly increased the fluidity of lipid membranes. Skin conductance measurements in hairless rats indicated that they both also increased in vivo skin moisturizing and water holding capacity. These results suggest that the mechanism of action of Sefsol-318 and Azone in enhancing skin permeation are similar. But following in vitro pretreatment of the excised skin with 5% Sefsol-318 and aqueous emulsion for 2 h, skin permeation of papaverine hydrochloride through the pretreated skin was much lower than through non-treated skin in the presence of Sefsol-318. In contrast, the enhancing effect of Azone on the pretreated skin was similar to that of Azone on the in vitro non-treated skin. We found that, unlike Azone, Sefsol-318 disappeared from skin completely one day after 24 h-in vivo pretreatment of skin with aqueous gels containing each agent. In agreement, drug permeation through skin excised one day after the in vivo pretreatment with Sefsol-318 was almost the same as in non-pretreated controls without Sefsol-318. This difference in the mode of action of Sefsol-318 and Azone may arise from the difference in the residence times of these enhancers in skin.

研究了中链甘油酯和强效透皮吸收促进剂Sefsol-318对盐酸罂粟碱体外通过无毛大鼠皮肤的作用模式和机制,并与laurocapram (Azone)进行了比较。在28小时内,从含有5% S-318或偶氮酮的药物水溶液中通过切除皮肤递送的药物总量分别比单独从溶液中递送的药物总量高820倍或420倍。以脂质体为模型的实验表明,两种增强剂均能显著提高脂质膜的流动性。无毛大鼠的皮肤电导测量表明,它们也增加了体内皮肤的保湿和保水能力。这些结果表明,Sefsol-318与Azone在促进皮肤渗透方面的作用机制相似。但在用5%的Sefsol-318和水乳液对切除皮肤进行体外预处理2小时后,在Sefsol-318存在的情况下,盐酸罂粟碱通过预处理皮肤的皮肤渗透性远低于未经处理的皮肤。相比之下,氮酮对预处理皮肤的增强作用与氮酮对体外未处理皮肤的增强作用相似。我们发现,与氮酮不同的是,Sefsol-318在体内用含有每种药物的水凝胶预处理皮肤24小时后1天从皮肤中完全消失。与此一致的是,用Sefsol-318进行体内预处理后1天切除皮肤的药物渗透与不使用Sefsol-318的未预处理对照组几乎相同。Sefsol-318和Azone在作用方式上的差异可能是由于这些增强剂在皮肤中停留时间的不同。
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引用次数: 0
Quantitative structure-activity relationship studies of inhibitors of gastric (H+/K+)-ATPase. 胃(H+/K+)- atp酶抑制剂的定量构效关系研究。
Pub Date : 1991-04-01
P Singh, R C Sharma, T N Ojha

The (H+/K+)-ATPase enzyme inhibitory activity of omeprazole analogues (Figure 1) and 1-aryl-4-methyl-2,3-dihydropyrrolo[3,2-c]quinolines (Figure 2) was found to be significantly correlated with electronic (sigma) or pKa parameter that governs the basicity of the molecules. The former compounds are representative of irreversible blockers, and the latter of reversible blockers. Inclusion of hydrophobic (pi) and/or steric (Es) parameters sometimes led to improvement in the correlations, suggesting that these parameters may play a role in the formation of a cyclic intermediate. The derived significant correlation equations strongly support a mechanism of action, first proposed by Lindberg et al., involving such a cyclic intermediate.

发现奥美拉唑类似物(图1)和1-芳基-4-甲基-2,3-二氢吡罗[3,2-c]喹啉(图2)的(H+/K+)- atp酶抑制活性与控制分子碱度的电子(sigma)或pKa参数显著相关。前者是不可逆阻滞剂的代表,后者是可逆阻滞剂的代表。包含疏水(pi)和/或位阻(Es)参数有时会导致相关性的改善,这表明这些参数可能在环状中间体的形成中起作用。推导出的显著相关方程有力地支持了Lindberg等人首先提出的涉及这种循环中间体的作用机制。
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引用次数: 0
Thermo-responsive hydrogels based on acryloyl-L-proline methyl ester and their use as long-acting testosterone delivery systems. 基于丙烯酰- l-脯氨酸甲酯的热反应性水凝胶及其作为长效睾酮输送系统的应用。
Pub Date : 1991-04-01
M Yoshida, M Asano, M Kumakura, R Kataki, T Mashimo, H Yuasa, H Yamanaka

New thermo-responsive hydrogels were synthesized by copolymerizing acryloyl-L-proline methyl ester (A-ProOMe) with minor amounts of 2-hydroxypropyl methacrylate (HPMA) or polyethylene glycol 600 dimethacrylate (14G), using gamma-rays from a 60Co source. In water, extensive swelling of the hydrogels occurred at 10 degrees C, but there was marked deswelling as the temperature was raised to 37 degrees C. The poly(A-ProOMe-co-HPMA) hydrogel was characterized by an initial rapid shrinkage at the surface in the deswollen state; this shrinkage arose because of the formation of a rigid membrane barrier devoid of micropores. The system is therefore 'surface regulated'. In contrast, no such a barrier formed in the deswollen poly(A-ProOMe-co-14G) hydrogel. The whole matrix shrunk without the disappearance of micropores, and it is therefore a 'matrix pumping' system. Testosterone was incorporated into both these types of hydrogels, and the drug-loaded hydrogels were implanted subcutaneously into the backs of castrated rats. The daily dose of testosterone released in vivo from the poly(A-ProOMe-co-HPMA) hydrogel was constant at approximately 30 micrograms/day throughout an experimental period of 54 weeks. In contrast, drug release from the poly(A-ProOME-co-14G) hydrogel reached a maximum after one week and then decreased linearly with time down to the 7th week, when it was undetectable. These conclusions were supported by the changes in weight of the ventral prostates and right-side seminal vesicles of the rats, which were restored to normal when delivery of the testosterone was sustained.

利用60Co源的伽马射线,将丙烯酰- l-脯氨酸甲酯(a- proome)与少量2-羟丙基甲基丙烯酸酯(HPMA)或聚乙二醇600二甲基丙烯酸酯(14G)共聚,合成了新型热响应性水凝胶。在水中,水凝胶在10℃时发生了广泛的溶胀,但当温度升高到37℃时,出现了明显的溶胀。聚(A-ProOMe-co-HPMA)水凝胶在溶胀状态下,表面开始迅速收缩;这种收缩是由于形成了一个没有微孔的刚性膜屏障。因此,该系统是“表面调节的”。相反,在溶胀的聚(a - proome -co- 14g)水凝胶中没有形成这样的屏障。整个基质收缩而没有微孔消失,因此它是一个“基质泵送”系统。将睾酮掺入这两种类型的水凝胶中,并将载药水凝胶皮下植入去势大鼠的背部。在54周的实验期间,聚(A-ProOMe-co-HPMA)水凝胶在体内释放的睾酮日剂量恒定在约30微克/天。而poly(a - proome -co- 14g)水凝胶的药物释放量在1周后达到最大值,然后随着时间的推移呈线性下降,直到第7周无法检测到。这些结论得到了大鼠腹侧前列腺和右侧精囊重量变化的支持,当持续给予睾酮时,它们恢复正常。
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引用次数: 0
Linear free energy-related and quantitative structure-activity relationships of inhibitors of thymidylate synthetase. 胸苷酸合成酶抑制剂的线性自由能相关和定量构效关系。
Pub Date : 1991-01-01
P P Mager

Thirteen previously described 5-(p-substituted-phenyl)-2'-deoxyuridines were synthesized, and the NMR and IR spectra of their 2,4-dioxopyrimidine (2,4-DP) rings were correlated against linear free energy-related and extrathermodynamic parameters. We conclude that the 5-phenyl ring is probably oriented over the plane of the 2,4-DP ring (sandwich structure, Figure 6). The main component of the spectroscopic data is largely determined by the stereoelectronic nature of the para-groups in the 5-phenyl ring, while a second component is largely determined by apolar forces. The inhibitory activity of the compounds against thymidylate synthetase is enhanced by the presence of apolar groups with a positive inductive effect, provided these groups do not extend the plane of the 2,4-DP ring.

合成了13个先前描述的5-(p-取代苯基)-2'-脱氧尿嘧啶,它们的2,4-二氧嘧啶(2,4- dp)环的NMR和IR光谱与线性自由能相关参数和热力学外参数相关。我们得出结论,5-苯基环可能在2,4- dp环的平面上取向(三明治结构,图6)。光谱数据的主要组成部分主要由5-苯基环中对基的立体电子性质决定,而第二部分主要由极性力决定。当极性基团不延伸2,4- dp环平面时,具有正向诱导作用的极性基团的存在增强了化合物对胸苷酸合成酶的抑制活性。
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引用次数: 0
5-HT3 receptor antagonists. 5-HT3受体拮抗剂。
Pub Date : 1991-01-01
M B Tyers
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引用次数: 0
5-HT3 receptor antagonists. 5-HT3受体拮抗剂。
Pub Date : 1991-01-01 DOI: 10.1016/b0-44-451005-2/00569-6
M. Tyers
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引用次数: 1
期刊
Drug design and delivery
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