键合型直链淀粉手性固定相分离5种质子泵抑制剂对映体

目的使用HPLC手性固定相法实现5种质子泵抑制剂对映体的分离。方法考察手性固定相种类,流动相中有机改性剂的种类和比例,缓冲盐的种类和浓度,碱性添加剂,流速及柱温等因素对分离的影响。结果通过不断优化色谱分离条件,最终确定5种药物的分离条件:色谱柱为Chiralpak ID柱(250 mm×4.6 mm,5μm),柱温为25℃,流速为0.6 mL·min~(-1),分离泮托拉唑、雷贝拉唑对映体的流动相为水-乙腈(60∶40,v/v),分离奥美拉唑对映体的流动相为水-乙醇(20∶80,v/v),分离兰索拉唑对映体的流动相为5 mmol·L~(-1)醋酸铵水溶液-乙腈(60∶40,v/v),分离艾普拉唑对映体的流动相为20 mmol·L~(-1)碳酸氢铵水溶液-乙腈(55∶45,v/v)。在上述条件下,5种质子泵抑制剂对映体均达到完全分离。结论键合型直链淀粉手性固定相对5种质子泵抑制剂对映体均实现完全分离。     

阿昔洛韦眼用凝胶在兔离体角膜中的渗透释药行为研究

目的:研究阿昔洛韦眼用凝胶在兔离体角膜中的渗透释药行为。方法:以谷胱甘肽缓冲液作为释放介质,采用高效液相色谱法测定阿昔洛韦眼用凝胶及阿昔洛韦滴眼液在兔离体角膜中的累积渗透释药量,并绘制曲线。结果:阿昔洛韦眼用凝胶的渗透释药曲线符合一级释药方程;0·25h时阿昔洛韦滴眼液的累积渗透释药量高于阿昔洛韦眼用凝胶,0·25h以后则相反。结论:在给药后很短时间内(0·25h),阿昔洛韦滴眼液的房水药物浓度要高于阿昔洛韦眼用凝胶,但凝胶在眼部滞留时间较长,且角膜有一定的药物储库作用。     

盐酸地匹福林眼用凝胶剂的研究

目的：研制盐酸地匹福林眼用凝胶剂。方法：建立HPLC法测定制剂的含量及体外释药量，采用透析膜扩散法进行处方的体外释药实验，应用离体角膜进行体外渗透实验。结果：亲水凝胶材料含量越小，盐酸地匹福林从凝胶基质中释放越快，凝胶体外释药符合一级释放动力学方程，离体角膜渗透行为符合一级释放规律。结论：盐酸地匹福林眼用凝胶达到了延迟释放的目的。     

反相HPLC法测定油剂中的睾酮酯类

睾酮酯的测定通常采用分光光度法,但该法对油性注射剂专一性不强,由于抑菌剂苯甲醇氧化后生成的苯甲醛及油剂本身均产生干扰,因此作者研究了HPLC法测定油剂中的睾酮酯类.HPLC条件:层析柱为Lichrosorb RP-8(250×4mm,id),流动相A为甲醇-四氢呋喃-水(82∶3∶15v/v),用于苯丙酸诺龙,以联苯作内标;流动相B为甲醇-四氢呋喃-水(90∶2∶8v/v),用于睾酮癸酸酯     

冰片对黄芩苷角膜透过性的影响

目的研究冰片对黄芩苷通过离体角膜的影响,考察其与黄芩苷联合用药的可行性。方法采用改良的立式Franz扩散池,以林格氏液为扩散介质考察在不同浓度冰片的促进渗透下黄芩苷的离体兔角膜通透性。结果质量分数0.01%、0.03%、0.05%、0.08%和0.1%冰片分别使黄芩苷的渗透增强比为3.86、11.0、14.27、21.27和36.55,与黄芩苷对照组比较呈显著性差异(P<0.01)且质量分数0.1%冰片渗透效果最佳。结论冰片对黄芩苷通过离体角膜有显著的促进作用,具有良好的开发应用前景。     

氟啶酸眼用缓释凝胶的制备及释药研究

目的制备氟啶酸眼用缓释凝胶并研究其释放机理.方法建立UV测定制剂的含量及体外释药量,建立HPLC测定制剂离体角膜渗透量,采用溶出度法进行处方的体外释药试验,应用离体角膜进行体外渗透试验.结果亲水凝胶材料含量越小,氟啶酸从凝胶基质中释放越快,体外释药符合一级释放动力学方程;亲水凝胶含量高,体外释放符合Higuchi方程.结论氟啶酸眼用凝胶达到了缓慢释放的目的.     

氟啶酸眼用缓释凝胶的制备及释药研究

目的制备氟啶酸眼用缓释凝胶并研究其释放机理。方法建立UV测定制剂的含量及体外释药量，建立HPLC测定制剂离体角膜渗透量，采用溶出度法进行处方的体外释药试验，应用离体角膜进行体外渗透试验。结果亲水凝胶材料含量越小,氟啶酸从凝胶基质中释放越快，体外释药符合一级释放动力学方程；亲水凝胶含量高，体外释放符合Higuchi方程。结论氟啶酸眼用凝胶达到了缓慢释放的目的。     

氟啶酸眼用缓释凝胶的制备及释药研究

目的制备氟啶酸眼用缓释凝胶并研究其释放机理。方法建立UV测定制剂的含量及体外释药量,建立HPLC测定制剂离体角膜渗透量,采用溶出度法进行处方的体外释药试验,应用离体角膜进行体外渗透试验。结果亲水凝胶材料含量越小,氟啶酸从凝胶基质中释放越快,体外释药符合一级释放动力学方程;亲水凝胶含量高,体外释放符合H iguch i方程。结论氟啶酸眼用凝胶达到了缓慢释放的目的。     

阿昔洛韦眼用pH敏感原位凝胶剂的制备和评价

目的：制备并评价阿昔洛韦眼用pH敏感原位凝胶剂。方法：用旋转粘度计测定不同pH值、不同温度下制剂 的粘度,考察制剂的流变学特征;用荧光示踪法测定凝胶剂的眼部滞留时间;采用同体自身对照法考察凝胶剂的眼部刺 激性;采用Franz扩散池法考察了制剂的离体角膜渗透性能,采用HPLC法测定渗透药量。结果：所制备的阿昔洛韦原位 凝胶剂为假塑性流体,对兔眼无刺激;该原位凝胶剂的眼部滞留时间为（22.4±1.4）min,比阿昔洛韦滴眼液增加4.6 倍;兔离体角膜渗透实验结果表明,该原位凝胶剂在给药0.25 h以后各时间点的累积透过量均高于阿昔洛韦滴眼液,角 膜有一定的贮库作用。 结论：阿昔洛韦原位凝胶剂的刺激性低,眼部滞留时间长,具有一定的缓释效果。     

阿昔洛韦眼用pH敏感原位凝胶剂的制备和评价

目的：制备并评价阿昔洛韦眼用pH敏感原位凝胶剂。方法：用旋转粘度计测定不同pH值、不同温度下制剂 的粘度，考察制剂的流变学特征；用荧光示踪法测定凝胶剂的眼部滞留时间；采用同体自身对照法考察凝胶剂的眼部刺 激性；采用Franz扩散池法考察了制剂的离体角膜渗透性能，采用HPLC法测定渗透药量。结果：所制备的阿昔洛韦原位 凝胶剂为假塑性流体，对兔眼无刺激；该原位凝胶剂的眼部滞留时间为（22.4±1.4）min，比阿昔洛韦滴眼液增加4.6 倍；兔离体角膜渗透实验结果表明，该原位凝胶剂在给药0.25 h以后各时间点的累积透过量均高于阿昔洛韦滴眼液，角 膜有一定的贮库作用。 结论：阿昔洛韦原位凝胶剂的刺激性低，眼部滞留时间长，具有一定的缓释效果。     

复方两性霉素B眼用凝胶在兔眼的药代动力学

目的 观察兔眼局部应用复方两性霉素B眼用凝胶的眼内通透性和药代动力学特征.方法 将30只新西兰大白兔分为10组,每组3只（6只眼）,分别于30只兔双眼点复方两性霉素B眼用凝胶50μl后,5、15、30、45、60、90、120、180、240和360 min时取泪液,并迅速处死后取角膜和房水,测定两性霉素B和利福平的含量,计算药代动力学参数.结果 利福平有良好的眼内通透性,但房水中检测不到两性霉素B;两性霉素B和利福平在兔角膜中的达峰时间为20.96和7.57 min、达峰浓度为3.32和25.37μg/g、消除半衰期为45.34和31.69 min、浓度-时间曲线下面积为299.44和1368.91（min·mg）/g.结论 复方两性霉素B眼用凝胶可用于治疗外眼真菌感染性疾病,但其能否用于内眼真菌感染,仍需进一步研究.     

Ocular Absorption of Pz-Peptide and Its Effect on the Ocular and Systemic Pharmacokinetics of Topically Applied Drugs in the Rabbit

Purpose. To determine the corneal and conjunctival penetration of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (Pz-peptide) and to evaluate its effect on the corneal and conjunctival penetration of hydrophilic solutes as well as on the ocular and systemic absorption of topically applied atenolol and propranolol in the rabbit. The hydrophilic solutes were mannitol, fluorescein, FITC-dextran 4,000, and FITC-dextran 10,000. Methods. Drug penetration across the rabbit cornea and conjunctiva was evaluated using the modified Ussing chamber. Ocular and systemic absorption of topically applied atenolol and propranolol was evaluated by analyzing the drug concentration in various anterior segment tissues at 45 min and in the blood over 240 min, respectively, following topical instillation of 25 l of 20 mM atenolol or propranolol solution to the rabbit eye. Results. The conjunctiva was 29 times more permeable than the cornea to 3 mM Pz-peptide. Conjunctival Pz-peptide transport was 1.7 times more extensive in the mucosal-to-serosal than in the opposite direction, whereas corneal Pz-peptide transport showed no directionality. The apparent permeability coefficient of Pz-peptide across the cornea and the conjunctiva increased over the 1–5 mM range, suggesting that Pz-peptide enhanced its own transport across both epithelial tissues. The cornea appeared to be more sensitive than the conjunctiva to the penetration enhancement effect of Pz-peptide. Thus, whereas Pz-peptide elevated the corneal transport of mannitol, fluorescein, and FD4 by 50%, 57%, and 106%, respectively, it did not affect the conjunctival transport of mannitol and fluorescein, while enhancing FD4 transport by only 46%. Moreover, while Pz-peptide enhanced the ocular absorption of topically applied hydrophilic atenolol, it did not affect the ocular absorption of lipophilic propranolol. Interestingly, Pz-peptide did not affect the systemic absorption of either beta adrenergic antagonist. Conclusions. Pz-peptide appears to facilitate its own penetration across the cornea and the conjunctiva. Pz-peptide appears to increase the ocular absorption of topically applied hydrophilic but not lipophilic drugs, while not affecting the systemic absorption of either type of drugs.     

利奈唑胺滴眼液在兔眼角膜内的药动学

目的探讨利奈唑胺滴眼液单次滴兔眼后在角膜中的药动学特征。方法 40只新西兰大白兔,局部滴入利奈唑胺滴眼液50μL,采用高效液相色谱法测定兔眼角膜中利奈唑胺的药物浓度,用DAS 2.1.1软件计算药动学参数。结果给药后0～120 h,利奈唑胺在兔眼角膜中的最高浓度为(58.62±15.48)μg.g 1,消除半衰期t1/2为(38.09±11.59)h,药时曲线下面积AUC0 t为(2 459.02±508.95)μg.h.g 1,AUC0∞为(2 834.13±578.96)μg.h.g 1。结论利奈唑胺滴眼液单次滴兔眼后在角膜中具有良好的药代动力学特征和组织通透性。     

盐酸地匹福林眼用凝胶剂的研究

目的：研制了盐酸地匹福林眼用凝胶剂,进行了体外释放、体外渗透以及眼部刺激性实验。方法：建立了高效液相色谱法测定制剂的含量及体外释药量的方法,采用透析膜扩散法进行处方的体外释药实验,采用离体角膜进行体外渗透实验。结果：亲水凝胶材料含量越小,盐酸地匹福林从凝胶基质中释放越快,凝胶剂体外释药符合一级释放动力学方程。凝胶剂离体角膜渗透行为符合一级释放规律。盐酸地匹福林凝胶剂具有较低的眼部刺激性。结论：盐酸地匹福林眼用凝胶剂有较好的缓释行为,可以明显降低眼部刺激。     

Formulation Influence on Conjunctival Penetration of Four Beta Blockers in the Pigmented Rabbit: A Comparison with Corneal Penetration

The objective of this study was to compare the influence of pH, tonicity, benzalkonium chloride, and EDTA on the conjunctival and corneal penetration of four beta blockers—atenolol, timolol, levobunolol, and betaxolol. Drug penetration was evaluated using the isolated pigmented rabbit conjunctiva and cornea in the modified Ussing chamber. The conjunctiva was more permeable than the cornea to all four beta blockers. Formulation changes caused larger changes in corneal than in conjunctival drug penetration, especially for the hydrophilic beta blockers, atenolol and timolol. Raising the solution pH to 8.4 caused the largest increase in corneal penetration for all drugs except atenolol. This increase was greater than that obtained by removing the corneal epithelium. The same formulation also increased conjunctival drug penetration, although to a lesser extent. In the case of timolol, the formulation changes evaluated brought about similar changes in its ocular and systemic absorption with good in vitro–in vivo correlations. The above findings indicate that in making formulation changes to maximize corneal drug penetration, it is necessary to evaluate possible changes in conjunctival drug penetration, hence systemic absorption. Moreover, because the conjunctiva plays an active role in the noncorneal route of ocular drug absorption, the relative contribution of the noncorneal to the corneal routes to ocular drug absorption may also be altered by formulation changes.     

家兔房水及角膜中妥布霉素的测定

目的:建立妥布霉素-地塞米松滴眼液在不同时间点时家兔眼房水及角膜中妥布霉素的HPLC-ELSD法测定。方法:家兔给予妥布霉素-地塞米松滴眼液后分别于5,10,20,30,60,90,120min时抽取家兔眼房水,取出角膜,经处理后采用HPLC-ELSD法检测房水及角膜内的妥布霉素质量。结果:妥布霉素在62.50～800.00μg/mL或0.062.5～8.00mg/g范围内,峰面积响应值(A)的对数与质量浓度(μg/mL)的对数呈现良好的线性关系,在房水及角膜中相关系数(r)分别为0.9994和0.9991,平均回收率分别为100.48%(RSD=1.81%,n=5),102.13%(RSD=1.58%,n=5);给药20min左右兔房水及角膜中的药物浓度峰值分别为291.70μg/mL和2.842mg/g。结论:本法灵敏、准确,适用于测定兔眼房水、角膜中妥布霉素的质量浓度的测定。     

Mechanistic studies on transcorneal permeation of pilocarpine.

The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.     

Permeability of chemical delivery systems across rabbit corneal (SIRC) cell line and isolated corneas: a comparative study

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.     

Dodecyl N,N-Dimethylamino Acetate and Azone Enhance Drug Penetration Across Human,Snake, and Rabbit Skin

The effectiveness of the penetration enhancers, dodecyl N, N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit human > or < snake.     

Permeability of Chemical Delivery Systems Across Rabbit Corneal (SIRC) Cell Line and Isolated Corneas: A Comparative Study

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.