促进剂对复方脚癣灵搽剂中小檗碱和黄芩苷体外经皮吸收及其皮内滞留量的影响

目的研究复方脚癣灵的体外经皮渗透特征,确定最佳促进剂及浓度。方法以自制双室水平扩散池和离体鼠皮进行体外渗透实验,采用HPLC法同时测定盐酸小檗碱和黄芩苷的皮内含量。结果促进剂为丙二醇和薄荷醇,最佳质量分数均为3%时,复方脚癣灵中2种成分的皮内蓄积量有显著的提高。结论应用促进剂后,制剂中小檗碱与黄芩苷在离体鼠皮内有较强的蓄积作用。     

各种吸收促进剂对黄芩苷鼻腔吸收的影响

目的研究黄芩提取物中黄芩苷的鼻腔吸收规律和9种吸收促进剂对黄芩苷鼻腔吸收的促进作用,寻找有效的鼻腔吸收促进剂。方法采用大鼠在体鼻腔循环法考察黄芩苷鼻腔吸收,以鼻腔吸收的一级动力学常数来衡量各种吸收促进剂促吸收作用的强弱。结果黄芩苷鼻腔吸收需加入吸收促进剂,各种不同质量分数吸收促进剂的促进作用为:1%去氧胆酸钠0.5%壳聚糖≈0.5%冰片≈5%甲基化-β-环糊精>5%HP-β-CD>5%β-CD>1%Tween-80≈0.1%EDTA-Na2≈1%磷脂,其中加入最后三者的促吸收效果与不加吸收促进剂时无显著性差异。结论质量分数为1%去氧胆酸钠促吸收效果最好,但鼻黏膜毒性较大,0.5%壳聚糖、0.5%冰片、5%甲基化-β-环糊精和5%HP-β-CD可安全有效地促进黄芩苷的鼻腔吸收。     

氮酮对消炎止痒搽剂中黄芩苷透皮吸收的影响研究

目的研究消炎止痒搽剂中不同氮酮浓度对黄芩苷的离体透皮吸收特性,为该制剂的制备工艺提供依据。方法以离体sD大鼠腹部皮肤为渗透屏障,采用Franz垂直扩散池,以UPLC测定接受液中黄芩苷的含量,考察不同氮酮浓度对黄芩苷累积透皮吸收量的影响。结果与不含氮酮促进剂相比,氮酮可以促进黄芩苷的吸收,且浓度对黄芩苷的透皮吸收有影响,其中氮酮浓度2．5％时,黄芩苷的累积透皮吸收量最大,渗透率为0．4932Ixg·cm-2·h-1。结论氮酮可以促进}肖炎止痒搽剂中黄芩苷的透皮吸收,浓度为2．5％时效果较好。     

黄芩苷泡腾片制备工艺研究

目的优选黄芩苷泡腾片的制备工艺和处方,并进行该制剂的质量考察。方法采用多指标综合评价法和正交实验法筛选黄芩苷泡腾片的制备工艺与处方辅料,并考察了制剂的稳定性。结果最优制备工艺为酸碱分别制粒法;最优处方为PEG6000的质量分数为5%,黄芩苷的质量分数为40%,酸碱总量的质量分数为45%,酸碱比为1∶3,甘露醇的质量分数为10%,黄芩苷泡腾片应避光密封保存在阴凉干燥处。结论制得的黄芩苷泡腾片质量符合《中国药典》规定,具有一定的推广价值。     

壳聚糖对阿昔洛韦滴眼液离体角膜渗透促进作用的考察

目的：考察壳聚糖（CS）对阿昔洛韦（ACV）滴眼液（ACV-CS）离体角膜渗透促进作用,为研制新型ACV滴眼液奠定基础.方法：以CS为增黏剂及吸收促进剂,制备ACV-CS滴眼液;以不加CS的ACV滴眼液为对照,采用Franz扩散池法考察CS对ACV滴眼液离体角膜渗透促进作用.结果：与不加ACV滴眼液相比,ACV-CS滴眼液的黏性显著增加;给药20 min后,ACV-CS滴眼液对离体角膜的累积渗透药量明显大于不加CS的ACV滴眼液（P＆lt;0.05）.结论：CS对ACV滴眼液离体角膜渗透具有明显的促进作用,值得进一步研究.     

黄芩苷脂质体、β-环糊精包合物及磷脂复合物鼻黏膜渗透性及毒性研究

为提高鼻腔给药后脑内药物浓度,本文探讨了以脂质体、β-环糊精包合物和磷脂复合物为黄芩苷载药体系的体外离体动物鼻黏膜渗透性及鼻腔毒性。采用猪、羊、兔鼻黏膜,以体外扩散池装置进行鼻黏膜渗透实验,HPLC法测定接受池中药物累积渗透量,以表观渗透系数为评价标准,考察脂质体、β-环糊精包合物及磷脂复合物载药系统对黄芩苷在离体动物鼻黏膜的透过性,从而筛选出黄芩苷经鼻给药最佳载药形式;采用在体法考察黄芩苷及其磷脂复合物对蟾蜍上颚黏膜纤毛运动的影响和大鼠鼻黏膜长期毒性。3种黄芩苷载药体系的表观渗透系数均明显高于黄芩苷（P<0.05）,滞后时间也比黄芩苷短,提示3种载药载体均可提高黄芩苷的鼻黏膜渗透性,同时磷脂复合物的表观渗透系数明显高于脂质体和环糊精包合物,表明黄芩苷磷脂复合物鼻黏膜渗透性明显优于另外两种载药体系（P<0.05）。黄芩苷磷脂复合物对纤毛运动无影响,对大鼠鼻黏膜也无明显刺激性。结果表明,磷脂复合物为黄芩苷经鼻给药最佳载药形式,能明显提高其鼻黏膜渗透性,对鼻黏膜无毒性,可用于鼻腔给药。

      

黄芩苷单层渗透泵片的制备工艺及体外释药行为研究

目的:制备黄芩苷单层渗透泵片并考察其体外释药行为。方法:以体外累积释放度为评价指标,在将黄芩苷制备成固体分散体以提高其溶解度的基础上,通过单因素及正交试验优化以黄芩苷固体分散体为中间体制备单层渗透泵片的处方制备工艺条件(促渗剂、致孔剂用量及包衣膜增质量);另考察优化工艺所制样品在3种不同释放介质(水、0.1 mol/L盐酸溶液、人工胃液)中的释放速率及释放机制。结果:最优处方制备工艺为促渗剂氯化钠的用量为30 mg、致孔剂聚乙二醇400的用量为辅料醋酸纤维素质量的20%、包衣膜增质量为2%;优化工艺所制3批黄芩苷单层渗透泵片在12 h时的累积释放度的RSD为1.06%(n=3)。其在3种介质中12 h内的累积释放度相似,均达80%以上;释药方程符合零级释药模型(r=0.998 5)。结论:经优化后的工艺制备的黄芩苷单层渗透泵片可在12 h内恒速释药。     

丝裂霉素在兔离体角膜中的渗透特性研究

目的考察丝裂霉素在兔离体角膜中的渗透特性。方法以谷胱甘肽缓冲液为接收液,使用水平式扩散仪考察丝裂霉素在离体兔角膜中的渗透特性;样品使用HPLC测定,采用Agilent Zorbax C18柱(150 mm×4.6 mm,5μm),流动相为甲醇∶水(70∶30,v/v),流速为1 mL/min,检测波长为365 nm。结果建立的丝裂霉素HPLC测定方法专属性、线性、精密度等均良好,丝裂霉素在兔角膜中的渗透按照一级动力学拟合时相关系数最高。结论丝裂霉素在兔离体角膜中的渗透符合一级动力学过程。     

复方积雪草凝胶剂渗透促进剂的研究

目的通过动物离体透皮吸收试验,筛选出最合适复方积雪草苷凝胶剂的渗透促进剂。方法采用改进Franz扩散池装置,以离体小鼠鼠皮为透皮屏障,采用高效液相色谱法测定接收池中积雪草苷的含量,计算积雪草苷累积透皮吸收量与透皮速率。通过比较累积透皮吸收量与透皮速率,筛选出最合适本制剂的渗透促进剂。结果使用渗透促进剂之后,积雪草苷的渗透速率有明显的提高。其中薄荷醇1.0%2.0%0.5%,氮酮1.0%4.0%2.0%。以氮酮1.0%的透皮效果最好。当两种渗透促进剂联用时,效果不佳。结论氮酮(1.0%)是最适合本制剂的渗透促进剂。     

芩榆烧伤液质量控制

目的建立芩榆烧伤液中冰片和关黄柏的鉴别方法及黄芩苷的含量测定方法。方法采用薄层色谱法对芩榆烧伤液中冰片、关黄柏进行定性鉴别;采用高效液相色谱法测定黄芩中黄芩苷的含量。结果冰片、关黄柏薄层色谱斑点清晰,重复性好,专属性强,方法简便;高效液相色谱法测定黄芩苷在8.046～80.46 μg&#8226;mL 1范围内线性关系良好（r＝0.999 5）,平均回收率101.0%,RSD=1.69%。结论所建标准可用于芩榆烧伤液的质量控制     

樟脑对烟酰胺和双氯芬酸钠透皮吸收作用的研究

目的：研究樟脑对烟酰胺和双氯芬酸钠透皮吸收的影响,并与月桂氮苷卓酮的作用进行比较。方法：用两室扩散池体外透皮实验装置,以兔皮为屏障,使用不同浓度的樟脑,分别测定烟酰胺和双氯芬酸钠的透皮百分率。结果：１ ％ 樟脑对烟酰胺没有促皮渗透作用,３ ％ 樟脑对烟酰胺和双氯芬酸钠有促皮渗透作用。结论：樟脑对烟酰胺和双氯芬酸钠均有促皮渗透作用,但作用弱于月桂氮苷卓酮,两药合用时不具有协同作用。     

薄荷醇与樟脑对烟酰胺的促皮渗透作用的研究

目的:研究薄荷醇和樟脑对烟酰胺透皮吸收的影响。方法:用两室扩散池体外透皮实验装置,以兔皮为屏障,使用不同浓度的薄荷醇和樟脑,测定烟酰胺的透皮百分率。结果:含1％薄荷醇组和含1％樟脑组的烟酰胺透皮百分率无显著增加,而含1％薄荷醇和1％樟脑组,含3％薄荷醇组,含3％樟脑组,含3％薄荷醇和3％樟脑组的烟酰胺透皮百分率明显增加。结论:薄荷醇和樟脑均对烟酰胺有促皮渗透作用,两药作用强度相似,两药使用时具有协同作用。     

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.     

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.     

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system.     

Effects of Labrasol on the corneal drug delivery of baicalin

Purpose: To investigate the use of Labrasol in ocular drug delivery system.

Methods: The in vivo ocular irritation of Labrasol was tested by pathological section observation using rabbits. The effects of Labrasol on corneal permeability of baicalin was investigated in vitro, using isolated rabbit corneas. The pharmacokinetics was evaluated by microdialysis in the rabbit aqueous humors.

Results: The results of the ocular irritation studies showed that Labrasol was non-irritant at the concentrations studied (0.5–3.0%(v/v)), while Labrasol produced slight irritation at a concentration of 5.0%(v/v). For the in vitro study, with Labrasol at concentrations of 1.5%, 2.0%, and 3.0%(v/v), the apparent permeability coefficient (P_app) was 1.69-, 3.14-, and 2.23- fold of baicalin solution, respectively. In the pharmacokinetics studies, the AUC value of baicalin solution with 2.0% and 3.0%(v/v) Labrasol were 4.7- and 5.6-fold of that of the control group (p?<?0.01), and the C_max value of baicalin solution with 2.0% and 3.0%(v/v) Labrasol vs the control group were 3.2- and 5.7-fold (p?<?0.01).

Conclusion: Labrasol may have potential clinical benefits in improving the ocular drug delivery of baicalin.     

Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients

The purpose of this study was to investigate the continuous and real-time influence of ophthalmic ingredients on rabbit cornea by monitoring electrophysiological characteristics. The tight junctional permeabilities of FITC-dextran 4,400 (FD-4) was also determined through the cornea in the presence of ophthalmic ingredients. Intact cornea showed approximately one k-ohmxcm(2) of transepithelial electrical resistance (TEER) and extremely low permeability of FD-4. The ophthalmic ingredients used in the present study were benzalkonium chloride (BK; 0.002%, 0.01%, 0.05%), ethylenediaminetetraacetic acid (EDTA; 0.5%), capric acid (C10; 0.25%), saponin (SP; 0.1%), taurocholic acid (TA; 1.0%) and sodium dodecyl sulfate (SDS; 0.01%). They were previously reported to be effective on corneal penetrations of various drugs at those concentrations without severe toxicity. These ingredients decreased TEER and increased corneal permeability of FD-4. BK reduced TEER in a concentration-dependent manner. There was a significant correlation (gamma=0.860) between the permeability coefficient (Papp) of FD-4 and conductance (Gm), which is the reciprocal value of TEER. It was also indicated that Papp and Gm have a relationship with the corneal cytotoxicity of the ingredients. In conclusion, an electrophysiological method using isolated cornea was very useful to determine the continuous and real-time influence of ophthalmic ingredients on the cornea. In this method, electrophysiological conductance must be able to predict corneal tight junction permeability and the corneal cytotoxicity of ingredients.     

Effect of chitosan, benzalkonium chloride and ethylenediaminetetraacetic acid on permeation of acyclovir across isolated rabbit cornea

The overall objective of this study was to evaluate the effect of chitosan, benzalkonium chloride (BAK) and disodium ethylendiaminetetraacetic acid (EDTA), alone and in combination, on permeation of acyclovir (ACV) across excised rabbit cornea. Corneas of male New Zealand White rabbits were used in these studies. Transcorneal permeation studies were conducted at 34 degrees C using a side-bi-side diffusion apparatus. In the presence of 0.01% BAK, transcorneal permeability of ACV was observed to increase almost 10.5-fold, from 3.5x10(-6) to 37.4x10(-6)cm/s. At 0.005% BAK, permeability of ACV was almost 3-fold higher than control. Combination of BAK 0.005% and EDTA 0.01% increased transcorneal penetration of ACV by 2.5-fold. Chitosan 0.2 and 0.1% increased corneal permeability of ACV by 5.8- and 3.1-fold, respectively, whereas, at 0.02%, chitosan did not exhibit a statistically significant effect. BAK at 0.005%, in combination with 0.01% EDTA and 0.1% chitosan, increased transcorneal ACV permeation by 5.5-fold. This study suggests that a judicious combination of chitosan, BAK and EDTA can lead to a significant increase in ACV's transcorneal permeability and that chitosan can enhance diffusion of hydrophilic agents across the corneal membrane. Further in vivo evaluation is warranted.     

Transcorneal permeation of ciprofloxacin and diclofenac from marketed eye drops

The purpose of this research was to evaluate the in vitro permeation characteristics of various marketed eye drops of ciprofloxacin (0.3% w/v aqueous solution) and diclofenac (0.1% w/v aqueous solution) through isolated goat cornea. Effect of these drugs on isolated goat eye lenses was also evaluated. Permeation studies were conducted by putting 1 ml of formulation on the cornea fixed between the donor and receptor compartments of an all glass modified Franz diffusion cell and monitoring ciprofloxacin and diclofenac concentration in the receptor (containing normal saline or bicarbonate ringer solution under continuous stirring at 37±2°) spectrophotometrically at their respective absorption maxima, after 120 min. Paired isolated goat lenses (i.e. of same animal) were used to evaluate the effect of these drugs at selected concentrations against oxidative stress (1 mM hydrogen peroxide solution). After 24 h of incubation at 37°, the lens treated with test solution (hydrogen peroxide+drug in bicarbonate ringer solution) was estimated for soluble protein content and compared with control (only hydrogen peroxide). Among marketed eye drops of ciprofloxacin, Joxin (Jawa Pharmaceuticals) showed maximum in vitro transcorneal permeation (0.558%) while I-Gesic (Centaur Pharmaceuticals) showed maximum % in vitro permeation or in vitro ocular availability among diclofenac eye drops after 120 min of permeation. The soluble protein content estimation studies revealed that these drugs at selected concentrations (permeated after 120 min.) had no deleterious effect on eye lenses rather possessed protective effect, since all formulation showed more soluble protein content when compared with control.     

Ophthalmic bioequivalence of steroid/antibiotic combination formulations

This study compared the relative ocular bioavailability in rabbits of the antibiotic/steroid combination of 0.3 per cent tobramycin and 0.1 per cent fluorometholone acetate to each of the two single-entity products. Two separate studies were conducted, one measuring fluorometholone acetate in cornea and aqueous humour through 240 min and the other measuring tobramycin in the cornea through 120 min. The results for fluorometholone acetate show that the combination product is 15 per cent higher in AUC for the cornea than the single-entity product (0.05 less than p less than 0.1). However, the combination product is only 4.4 per cent higher in AUC when aqueous humour levels are compared (N.S.). The single-entity fluorometholone acetate ointment yielded cornea and aqueous humour levels which were 20 per cent (p less than 0.01) and 6 per cent (N.S.) higher in AUC than the same tissues measured after topical instillation of the suspension. Statistical treatment of the data indicated that the suspension and ointment products, were bioequivalent with respect to fluorometholone acetate in aqueous humour, but not with respect to corneal concentrations. Tobramycin was measured in the cornea following instillation of either the single-entity solution or the combination suspension. Per cent bound (tobramycin to rabbit antibodies determined in vitro from the radioimmunoassay results) was used for statistical analyses of all group means and standard errors. The results indicated that the products were bioinequivalent.