Ocular and systemic bioavailability of ophthalmic flurbiprofen

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-g intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of fluobiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 l of 0.3% flurbiprofen in saline (dose = 150 g), and left eyes were instilled with 50 l of 0.15% flurbiprofen in saline (dose=75 g). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administered dose, the 75-g dose was 30% more available to ocular tissues than was the 150-g dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-g and 150-g topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 g of flurbiprofen was 74%.     

Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability

Aim:

To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.

Methods:

FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.

Results:

The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P_app compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36±38.93 ng·mL⁻¹·min·μg⁻¹, which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T_max of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).

Conclusion:

This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.     

氟比洛芬滴眼液中氟比洛芬与防腐剂的含量测定及稳定性考察

目的制定氟比洛芬滴眼液中主药及防腐剂的含量测定方法并进行稳定性考察,预测室温存放的有效期。方法采用RP-HPLC法测定主药及防腐剂的含量,用恒温加速法预测其有效期。结果氟比洛芬质量浓度在6.0~72 mg.L-1内、羟基苯甲酸乙酯质量浓度在7.5~90 mg.L-1内与吸光度呈良好的线性关系;氟比洛芬平均回收率为100.0%,RSD为0.62%;羟基苯甲酸乙酯平均回收率为99.9%,RSD为0.70%。氟比洛芬在室温25℃下的有效期(t0.9)为3.7年,羟基苯甲酸乙酯在室温25℃下的有效期为1.9年。结论建立的含量测定及贮存期预测的方法简便、快速、准确、可靠,适用于制剂的质量控制。     

Enhanced solubility and bioavailability of flurbiprofen by cycloamylose

The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C_max values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure.     

氟比洛芬口服混悬剂的兔药物动力学及其生物利用度

目的:研究氟比洛芬口服给药的药物动力学及生物利用度。方法:利用HPLC法测定氟比洛芬的血药浓度,以交叉给药方式分别给予家兔注射剂和口服混悬剂并且对其药物动力学和生物利用度进行研究。结果:氟比洛芬在家兔体内药动学静脉注射符合二室开放模型,口服符合一室开放模型,氟比洛芬口服混悬剂的绝对生物利用度为61.9%。结论:在进行氟比洛芬剂型研究时应注重提高其口服制剂的生物利用度。     

Ocular tolerance of absorption enhancers in ophthalmic preparations

The use of absorption promoters is a way to improve the bioavailability and therapeutic response of topically applied ophthalmic drugs. The ocular tolerance of 9 potential absorption promoters was investigated as well as the influence of the enhancers' concentration on the ocular tolerance. The substances tested were instillated repetitively (4 times per day, during 3 days, and once just before examination) as aqueous solutions onto rabbit corneas. Fluorescein dyeing enabled us to specifically mark corneal damage that was observed by confocal microscopy. The degree of corneal injury was assessed with an image-processing system that calculated the total fluorescent areas. Confocal microscopy results showed the relatively good tolerance of permeation enhancers like dimethyl sulfoxide (DMSO), decamethonium, edetate, glycocholate, and cholate in contrast to the poorly tolerated saponin and fusidate. Increasing the promoters' concentration led generally to an increase in corneal lesions.     

氟比洛芬酯眼用纳米乳-离子敏型原位凝胶的研究

设计新型纳米乳-离子敏感型原位凝胶 (nanoemulsion-in situ gel, NE-ISG), 以氟比洛芬酯 (flurbiprofen axetil, FBA) 为模型药物, 研究药物在家兔眼部的房水药动学特征, 并对其流变学特征、微观形态、角膜损伤效果和角膜滞留特性等进行了评价。采用剪切均质工艺制备氟比洛芬酯纳米乳 (flurbiprofen axetil nanoemulsion, FBA/NE), 与离子敏感型凝胶材料 (结冷胶) 混合后制得氟比洛芬酯纳米乳-原位凝胶 (flurbiprofen axetil  nanoemulsion-in situ gel, FBA/NE-ISG)。流变学结果显示, FBA/NE-ISG发生胶凝后, 黏度和弹性模量分别增加2 Pa·s和5 Pa, 胶凝能力强。透射电镜结果表明, FBA/NE-ISG中乳滴粒度分布均匀, 胶凝前后无明显变化。角膜损伤评价显示, FBA/NE-ISG无角膜刺激性。角膜滞留特性评价结果显示, NE-ISG角膜滞留时间显著延长, NE-ISG和溶液组的消除速率常数分别为0.008 5 min⁻¹和0.105 2 min⁻¹。房水药动学结果显示, FBA/NE-ISG组AUC_{0→12 h} (126.8 µg·min·mL⁻¹) 和MRT (12.3 h) 分别是氟比洛芬钠滴眼液组 (flurbiprofen sodium eye drop, FB-Na) 的2.9倍和2.7倍, 眼部生物利用度显著提高。FBA/NE-ISG能够显著延长药物的眼表滞留时间, 发挥缓释作用, 提高药物的眼部生物利用度, 并有效降低原形药物氟比洛芬 (flurbiprofen, FB) 的眼部刺激性。     

Comparative bioavailability of two flurbiprofen products: stereospecific versus conventional approach

In this randomized, crossover study comparing the bioavailability of a film-coated (Ansaid) with a sugar-coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 healthy young men, no significant differences were found for Cmax, tmax or AUC, using a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30-min post-dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7.8 per cent) but significant difference in AUC of the active S-configuration (Froben greater than Ansaid). No significant differences between Ansaid and Froben were found for tmax or Cmax for the S-flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products.     

Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and β-cyclodextrin (β-CD) on the solubility and bioavailability of a poorly watersoluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, β-CD or mixture of surfactant and β-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of β-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to β-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and β-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM β-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 μg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or β-CD, with surfactant alone, or with β-CD alone. Therefore, the mixed system consists of surfactant and β-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.     

Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle-formulated ophthalmic drugs

Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunctival penetration, prolonged precorneal residence time, easy instillation, non-irritative and comfortable to minimize lachrymation and reflex blinking, and appropriate rheological properties. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. To improve ocular bioavailability of topically dosed ophthalmic drugs, a variety of ocular drug delivery systems, such as hydrogels, microparticles, nanoparticles, microemulsions, liposomes and collagen shields, have been designed and investigated. These newer systems may, to some extent, control drug release and maintain therapeutic levels in ocular tissues over a prolonged period of time. This review focuses on the in vitro, ex vivo and in vivo studies of ophthalmic drugs formulated in nanoparticles published over the past two decades. The progress and development issues relating to ocular disposition, pharmacokinetics, efficacy and safety of the nanoparticle-formulated ophthalmic drugs are specifically addressed. Information and discussions summarized in this review are helpful for pharmaceutical scientists to develop better ophthalmic therapeutics.     

Improvement of oral bioavailability of flurbiprofen from flurbiprofen/β-cyclodextrin inclusion complex by action of cinnarizine

Improvement of the oral bioavailability of flurbiprofen (Flu) after oral administration of flurbiprofen/β-cyclodextrin inclusion complex (Flu/β-CD) by the action of cinnarizine (CN) was investigated. Flu and Flu/β-CD were administered orally to fasted rats at a dose of 20 mg/kg as Flu. Thirty minutes after drug administration, CN dissolved in pH 4.0 buffer solution or pH 4.0 buffer solution alone was administered to the rats. The dose of CN was 0.17 mg/kg. Blood samples were taken from rats and Flu concentrations in plasma samples were determined by HPLC. It was found from the comparison of Flu and Flu with CN (Flu + CN) that CN had no effect on plasma concentrations of Flu after oral administration of Flu. The mean plasma levels after oral administration of Flu/β-CD with CN (Flu/β-CD + CN) were larger not only than those of Flu and Flu + CN but also than those of Flu/β-CD. The value of C_max in Flu/β-CD + CN was significantly larger than that of Flu/β-CD. This is considered to be caused by the action of CN as a competing agent. This mechanism was supported by the result of solubility study in which Flu solubility in β-CD solution decreased with the addition of CN. It was found from these results that CN had strong ability as a competing agent in vivo.     

Skin microdialysis-based estimation of systemic bioavailability fraction

Systemic bioavailability is usually determined from plasma data. However, when plasma is difficult to access, as in young children, alternative methods would be particularly beneficial. The present study investigates the possibility of calculating systemic bioavailability fraction (F) from skin concentrations measured by two microdialysis (MD) sampling methods: continuous microdialysis and intermittent microdialysis. When the drug concentration in skin is a linear and time-invariant function of plasma concentration, the area under the drug concentration curve in skin is directly proportional to the drug absorbed systemically. To verify this theory, we compared the F estimated from MD concentrations in the skin with that obtained from the plasma data in the same experiment. Two model drugs were selected for the study: amoxicillin and ketoprofen. Drugs were administered to rabbits as intravenous infusion or oral suspension according to a randomized crossover design. F estimated by either MD method was not significantly different from that obtained from the plasma for both drugs tested. However, the skin data exhibited a larger variability. These results confirm that skin MD could be an alternative way to obtain data for the calculation of systemic fraction of drug absorbed.     

硫普罗宁眼用凝胶的生物利用度及抗白内障作用

目的考察硫普罗宁眼用原位凝胶生物利用度及抗白内障效果。方法采用连续取样技术,通过柱前衍生化方法考察药物在兔眼房水中的动力学行为。利用硒性白内障大鼠晶状体混浊度的裂隙灯图像分析,动态考察硫普罗宁眼用原位凝胶的抗白内障作用。结果高剂量组硫普罗宁原位凝胶药物-时间曲线下面积为水溶液组的1.58倍。硫普罗宁原位凝胶和水溶液均延缓白内障的发生时间,前者作用尤佳,晶状体混浊度仅达到12%。结论与水溶液相比,硫普罗宁原位凝胶可提高眼内生物利用度,明显延缓白内障形成。     

微渗析技术研究依诺沙星眼用缓释凝胶剂兔眼内药动学

目的:研究依诺沙星家兔眼内药动学.方法:采用微渗析技术进行依诺沙星眼用缓释凝胶剂在体药动学的研究,数据经非隔室模型处理,以方差分析和双单侧t检验评价各参数.结果:眼用缓释凝胶剂的药动学参数为:AUC=(1.615±0.900)μg·h·mL-1,Cmax=(2.726±1.790)μg·mL-1,Tmax=(0.33±0.24)h,Ke=(0.270±0.140);滴眼液的药动学参数为:AUC=(0.414±0.210)μg·h·mL-1,Cmax=(0.689±0.890)μg·mL-1,Tmax=(0.25±0.10)h,Ke=(0.548±0.500).结论:眼用缓释凝胶剂明显提高了药物在眼内的生物利用度,并且延长了作用时间,达到了缓释制剂的设计要求.