格尔德霉素滴眼液在离体兔眼角膜的吸收与扩散

目的制备格尔德霉素 ( geldanamycin)滴眼液 ,进行离体兔眼角膜实验 ,检测角膜及人工房水中药物量。方法采用二室渗透池法 ,在不同时间点取人工房水及角膜 ,分别测定药物在角膜吸收量及角膜中药物扩散进入人工房水量 ,对累积数据进行方程模拟。结果药物易被角膜吸收 ,但不易渗透进入房水 ,药物在角膜中不同时间的吸收累积曲线符合Higuchi方程 ,吸收速率常数为10 2 1 9ng/h。角膜中的药物扩散进入人工房水符合零级方程 ,药物在角膜和人工房水中达到平衡的时间分别为 2h和 4h ,药物从角膜扩散进入人工房水有 2h时滞。结论格尔德霉素滴眼液易被兔眼角膜吸收 ,且在角膜中达到较高浓度 ,在治疗单纯疱疹性病毒性角膜炎方面具有良好的前景     

雷帕霉素纳米粒滴眼液兔眼部药物分布研究

目的:比较雷帕霉素纳米粒滴眼液及其一般滴眼液滴眼后,在兔眼房水及角膜组织中药物分布。方法:将健康无眼疾新西兰白兔随机分为试验组与对照组,分别每眼结膜囊内单次给雷帕霉素纳米粒滴眼液及其一般滴眼液50μL。于滴眼后15、30、60、360和720min取材,采用高效液相色谱法(HPLC)测定兔眼不同时间房水及角膜组织中雷帕霉素浓度。结果:在用药后15～720min内实验组各时间点房水和角膜组织中的药物浓度均明显高于对照组。实验组内30～720min各时间点房水和角膜组织中的药物浓度比较无统计学差异。结论:雷帕霉素纳米粒滴眼液同一般滴眼液相比明显延长药物在眼部的停留时间,增加房水和角膜组织中的药物浓度,且能够维持组织中药物浓度的平稳。     

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。     

吗替麦考酚酯纳米混悬剂的制备及其兔眼内生物学性质研究

目的：研究吗替麦考酚酯纳米混悬剂在兔眼角膜黏附性、泪液和房水药物动力学特性。方法：以薄膜分散．高压乳匀法制备纳米混悬剂,测定其理化性质。HPLC法检测角膜黏附、泪液和房水中的吗替麦考酚酯和麦考酚酸的含量。结果：混悬剂滴眼液呈米黄色乳液状,纳米混悬剂药物粒子呈圆球状,粒径均一,纳米混悬剂平均粒径592nm,多分散系数Pdl为0．114,Zeta电位为-29．6mV。与普通混悬剂滴眼液相比,纳米混悬剂的角膜黏附性、泪液和房水中药物浓度明显提高。结论：纳米混悬剂可以促进和提高吗替麦考酚酯眼局部给药后角膜黏附和药物吸收。     

阿奇霉素原位凝胶滴眼液眼部滞留性和刺激性研究

摘要目的考察阿奇霉素原位凝胶滴眼液在家兔眼部的滞留性和刺激性。方法采用γ 闪烁扫描示踪技术,以放射强度为指标,评价制剂在眼部的滞留时间,应用Draize评分标准法考察阿奇霉素原位凝胶滴眼液单次给药和多次给药后对家兔眼部的刺激性。结果与普通滴眼液相比,阿奇霉素原位凝胶滴眼液的眼部滞留时间延长了约2.5倍,角膜刺激性评价实验表明制剂眼部相容性良好。结论阿奇霉素原位凝胶滴眼液眼部刺激性小,滞留时间长,具有广阔的研究开发前景。     

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。     

阿昔洛韦原位胶化滴眼液的眼内药物动力学研究

目的：考察阿昔洛韦原位胶化滴眼液滴入眼睛后在眼房水中的药物代谢动力学，并与市售阿昔洛韦滴眼液进行比较。方法：两种制剂滴眼后，采用反相高效液相色谱法测定不同时间点的兔眼房水中阿昔洛韦的浓度。结果：原位胶化滴眼液和市售滴眼液滴眼后，除0.25h时间点外，其余各时间点阿昔洛韦原位胶化滴眼液治疗组的房水药物浓度较市售阿昔洛韦滴眼液治疗组明显增高（P＜0．05）。原位胶化滴眼液的生物利用度是滴眼液的2．67倍。用胶化滴眼液后6.5h，房水中仍可测出阿昔洛韦的浓度，而用滴眼液后5.5h，房水中已测不出阿昔洛韦的浓度。结论：阿昔洛韦原位胶化滴眼液能提高药物的生物利用度，增强疗效，并减少给药频率。     

N-三甲基壳聚糖包覆司帕沙星纳米脂质体兔眼房水及角膜药动学研究

摘要：目的:对N-三甲基壳聚糖（TMC60）包覆司帕沙星（SL）纳米脂质体兔眼房水及角膜的药动学进行研究。方法:采用数字法将78只健康家兔随机分为3组:SL滴眼液组、SL纳米脂质体组和TMC60包覆SL纳米脂质体组,每组26只,双眼单次各给药100μl（SL滴入量为600μg）。在预设的时间点各组处死2只家兔,取房水及角膜,检测其中SL含量,DAS 2.0软件计算药动学参数,并绘制药-时曲线。结果:兔眼单次给药后,SL在房水及角膜中的药动学均符合二室模型。与SL滴眼液组相比,SL纳米脂质体组和TMC60包覆SL纳米脂质体组在房水及角膜中的达峰时间(Tmax)滞后,血药浓度时间曲线下面积(AUC0～t)明显增加（P<0.05）。与SL纳米脂质体组相比,TMC60包覆SL纳米脂质体组AUC0～t明显增加（P<0.05）。结论:TMC60包覆纳米脂质体可显著促进SL在眼部的滞留及吸收,呈现明显的缓释性及长效性。     

新型载药蒙脱石复合微球滴眼剂的刺激性及角膜前滞留时间的荧光示踪法考察

目的： 将阳离子型药物盐酸倍他洛尔（BH）,与具有离子交换性能的蒙脱石及聚丙烯酸树脂联合使用制备新型盐酸倍他洛尔／蒙脱石聚丙烯酸树脂微球（Mt-BH-MP）新型眼用微纳米混悬剂,考察其刺激性及眼前端滞留能力。方法： 采用油包油乳化-溶剂挥发法制备微球,以BH水溶液和市售贝特舒为对照,分别采用永生化人角膜上皮细胞（iHCECs）构筑角膜前滞留的细胞模型和荧光示踪法评价Mt-BH-MP在细胞模型及兔眼眼表的滞留能力;以MTT法、兔眼眨眼实验及角膜荧光损失来共同评价该新型给药系统的刺激性。结果： iHCECs细胞模型角膜前滞留实验结果表明,Mt-BH-MP的眼部滞留能力明显优于贝特舒组和BH水溶液组;Mt-BH-MP兔眼在体角膜前荧光可维持（46±1） min,亦明显长于BH水溶液和贝特舒滴眼液组（P<0.05）,上述二项实验结果一致。MTT实验结果显示,iHCECs与各制剂接触2 h后,细胞存活率大小顺序为：空白微球>Mt-BH-MP> BH水溶液>贝特舒;兔眼眨眼刺激性及荧光角膜损伤实验结果表明,Mt-BH-MP给药后并无明显异物感及角膜机械损伤。结论： 制备的新型微球眼部递药系统具有良好的眼部滞留能力且刺激性相对较小,具有良好的眼部递药应用前景。     

吗替麦考酚酯纳米混悬剂的制备及其在兔眼内药动学研究

目的：研究普通吗替麦考酚酯纳米混悬剂及经壳聚糖修饰的吗替麦考酚酯纳米混悬剂在免眼角膜粘附性、泪液和房水药物动力学特性。方法：以薄膜分散一高压乳匀法制备纳米混悬剂,并进一步选用壳聚糖修饰纳米药物粒子制得具有粘附作用、带正电荷的壳聚糖修饰型纳米混悬剂。HPLC法检测角膜粘附、泪液和房水中的吗替麦考酚酯和霉酚酸的含量。结果：混悬剂滴眼液呈米黄色乳液状．纳米混悬剂和壳聚糖修饰型纳米混悬剂药物粒子呈圆球状,粒径均一,纳米混悬剂平均粒径59213111,多分散系数（Pdl）为0．114,Zeta为-29．6mV,壳聚糖修饰型纳米混悬剂平均粒径442hill,Pdl为0．096,Zeta为＋45mV。与普通混悬剂滴眼液相比,纳米混悬剂的角膜粘附性、泪液和房水中药物浓度明显提高,而壳聚糖修饰型纳米混悬剂则可进一步提高角膜粘附性和泪液、房水中药物浓度。结论：纳米混悬剂可以促进和提高吗替麦考酚酯眼局部给药后角膜粘附和药物吸收,而壳聚糖修饰型纳米混悬剂可进一步促进和提高药物的角膜粘附和吸收。     

Ocular pharmacokinetics of thiamphenicol in rabbits.

The ocular pharmacokinetics of thiamphenicol (TAP, CAS 15318-45-3) was studied in rabbits by means of the assessment of its ocular and systemic absorption, and urinary excretion after instillation of 0.5% TAP eye drops. TAP concentrations in aqueous humor, plasma and urine were evaluated by a coupled LC/GC method (detection limit = 0.1 ng/ml), because the necessity to have a technique much more sensitive than the traditional chromatographic ones available in order to quantify the very low drug concentrations in biological fluids produced by the ocular treatment, and generally by a topical administration. The intravenous route was chosen as reference and allowed the absolute bioavailability to be estimated. TAP proved to be well absorbed through the cornea with the peak aqueous humor concentration of 110 ng/ml at 45 min following the instillation. The good ocular absorption of TAP was confirmed by the plasma concentrations observed after instillation of 0.5% eye drops. In any case, these concentrations were more than 1000 times lower than those observed after the intravenous treatment at the dose normally used for infectious diseases, allowing to exclude any systemic toxicity of TAP eye drops. The absolute ocular bioavailability was 16.2% when estimated from the AUC values and 34.0% from the cumulative urinary excretion values.     

麝香滴眼液对急性角膜炎的抗炎作用研究

目的:探讨麝香滴眼液对急性角膜炎的抗炎作用。方法:建立家兔手术损伤后的急性角膜炎模型,随机分为麝香滴眼液高、中、低剂量治疗组(0.3%、0.15%、0.05%)、0.5%醋酸可的松滴眼液组与生理盐水(0.9%NS)对照组。在用药24、48、72h时通过2%荧光素染色观察角膜上皮生长情况,测定房水中蛋白含量、钙离子(Ca2+)、白介素1-β(IL-1β)浓度,称量角膜重量,取角膜组织进行病理组织学检查,探讨麝香滴眼液对损伤引起的急性角膜炎的抗炎作用。结果:麝香滴眼液各组均能够减轻角膜水肿,抑制中性粒细胞的游走,抑制房水蛋白和IL-1β浓度的升高,改变房水中Ca2+的水平,促进角膜上皮的生长。结论:麝香滴眼液对急性角膜炎有明显的抗炎作用。     

Delay in ICR/f rat lens opacification by the instillation of eye drops containing disulfiram and hydroxypropyl-beta-cyclodextrin inclusion complex

In this study, we attempted to enhance disulfiram (DSF) solubility using a 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and hydroxypropylmethylcellulose (HPMC). We also investigated the effect of an HPbetaCD solution containing DSF and HPMC (DSF eye drops) on cataract development in ICR/f rat. The solubility of DSF increased with increasing HPbetaCD concentration, and the solubility of DSF in HPbetaCD solution containing 0.1% HPMC was approximately 20% greater than that of DSF in HPbetaCD solution without HPMC. In in vivo transcorneal penetration experiments using rabbits, only diethyldithiocarbamate (DDC) was detected (DSF was not detected) in the aqueous humor. This DSF-DDC conversion in the cornea was inhibited by treatment with a sulfhydryl (SH) inhibitor, p-mercuribenzoate and N-ethylmaleimide, in in vitro transcorneal penetration experiments using rabbit corneas. On the other hand, the instillation of 0.25% and 0.5% DSF eye drops delayed cataract development in ICR/f rats, a recessive-type hereditary cataractous strain. The present study demonstrates that DSF in HPbetaCD solution with HPMC is converted to DDC by the catalysis of proteins containing SH residues in the cornea, and this DDC may cause the delay in cataract development in ICR/f rats.     

Ocular absorption behavior of palmitoyl tilisolol, an amphiphilic prodrug of tilisolol, for ocular drug delivery.

The objective of this study was to examine the ocular absorption behavior of an amphiphilic prodrug after instillation onto the cornea of rabbits. A micellar solution of O-palmitoyl tilisolol (PalTL), an amphiphilic prodrug, was prepared. After instillation of tilisolol (TL) and PalTL, the drug concentrations in the tear fluid, cornea, aqueous humor, iris-ciliary body, vitreous body, and blood were measured. In addition, in situ ocular absorption behavior was also evaluated. After instillation of TL, the concentration of TL in the tear fluid quickly decreased. After instillation of PalTL, prolonged retention and high concentrations of PalTL in tear fluid and the cornea were observed. In addition, more prolonged retention of the TL concentration after instillation of PalTL than after instillation of TL was observed in the cornea, aqueous humor, and iris-ciliary body. In situ experiments demonstrated that PalTL was mainly absorbed by the corneal route and the improvement effects of PalTL under in vivo conditions was due to an enhanced transit time of PalTL in ocular tissues. PalTL, an amphiphilic prodrug, exhibited increased retention in the precorneal area compared with the parent drug, TL, resulted in improved ocular absorption of the parent drug.     

双氯酚酸钠脂质体的制备及其眼部药代动力学

目的研究双氯酚酸钠脂质体的制备方法并考察其在家兔眼部的药代动力学特征。方法采用逆相蒸发法制备双氯酚酸钠正电荷脂质体。脂质体和滴眼液滴眼后家兔采用高效液相色谱法测定角膜前、角膜和房水中药物浓度。结果制得的脂质体平均粒径为226.5 nm，多分散度为0.214，ζ电位为+18.1 mV，经均匀设计优化处方，包封率可达到63%。0.1%双氯酚酸钠脂质体和滴眼液两种制剂家兔局部滴眼后的药代动力学研究显示，脂质体可延缓药物在角膜前的清除，增加角膜中药物的浓度，药物在房水中半衰期延长，以滴眼液为参比制剂，相对生物利用度为211%。结论双氯酚酸钠正电荷脂质体可以增加药物在角膜前的滞留时间，提高角膜渗透性及药物在眼部的生物利用度，减少滴眼次数。     

环孢素脂质体在家兔眼部的吸收与组织分布研究

目的 :以环孢素 (CsA)橄榄油滴眼液为对照制剂 ,考察家兔眼部应用CsA脂质体后 ,CsA在眼部的吸收及组织分布。方法 :2 7只家兔 ,分别多剂量应用 0 5 %CsA橄榄油滴眼液 ,中性脂质体和正电荷脂质体 ,并分别于用药后 0 5 ,1,2h后处死家兔 ,抽取房水 ,分离角膜、虹膜、巩膜、玻璃体和晶体。采用HPLC MS法测定各种组织中CsA的含量。结果 :2种脂质体制剂吸收进入眼组织中的CsA浓度 ,均高于橄榄油滴眼液 ,其中正电荷脂质体均有显著性差异 (P <0 0 5 ) ,而中性脂质体多数有显著性差异 (P <0 0 5 ) ,正电荷脂质体在组织中的平均药物浓度较中性脂质体高 ,但多数无显著性差异。结论 :脂质体可显著改善CsA在眼部吸收 ,提高CsA在眼部各组织的分布浓度     

Ocular bioavailability and tissue distribution of [14C]ketorolac tromethamine in rabbits

The ocular bioavailability of 0.5% [14C]ketorolac tromethamine administered topically (50 microL) to the eye was determined. The ocular bioavailability of ketorolac was 4% in anesthetized rabbits and was determined by comparing drug concentrations in the aqueous humor after topical application with those obtained after intracameral injection of an equivalent dose of 0.25 mg of ketorolac tromethamine per eye. Although ketorolac administered to the eye was completely absorbed systemically, concentrations of ketorolac (AUC) were, on the average, 13 times higher in the aqueous humor than in plasma after topical administration. In a separate ocular distribution study, peak concentrations of radioactivity were achieved in the ocular tissues and in plasma within 1 h post instillation. Concentrations of total radioactivity were highest in the cornea and sclera and lowest in the lens.     

Preparation and ocular pharmacokinetics of ganciclovir liposomes

Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor concentration-time profiles of both liposomes and solution were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aqueous humor concentration-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV solution. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those observed after solution dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.     

In vivo ocular pharmacokinetics of acyclovir dipeptide ester prodrugs by microdialysis in rabbits

In vivo corneal absorption of the dipeptide prodrugs of acyclovir (ACV) was evaluated using microdialysis in rabbits. A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microliters of a 1% solution of L-valine-ACV (VACV), glycine-valine-ACV (GVACV), valine-valine-ACV (VVACV), and valine-tyrosine-ACV (VYACV) was placed in the corneal well and was allowed to diffuse for a period of 2 h, following which the drug solution was aspirated and well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by HPLC to obtain the aqueous humor concentrations. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. GVACV exhibited highest absorption rate (ka) compared with other prodrugs, but all the prodrugs showed similar terminal elimination rate (lambda(z)). The time of maximum absorption (Tmax) of ACV after administration of VACV and the dipeptide prodrugs did not vary significantly (p < 0.05). GVACV exhibited the highest concentration (Cmax) and area under curve (AUC) upon absorption (p < 0.05) compared to VACV, VVACV, and VYACV. Dipeptide prodrugs of ACV were absorbed through the cornea at similar rates but to varying extents. The dipeptide prodrug GVACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections.