Transscleral and transcorneal iontophoresis of ketoconazole in the rabbit eye

The authors assessed the efficacy of transscleral and transcorneal iontophoresis of ketoconazole as a method of drug delivery to the aqueous humor, vitreous, and cornea of the rabbit eye. Transscleral iontophoresis (4-6 mAmps for 15 minutes) achieved peak ketoconazole concentrations in the aqueous 1 hour after treatment (10.2 micrograms/ml) and remained at fungicidal therapeutic concentrations for 8 hours; in the vitreous, a peak concentration of 0.1 microgram/ml occurred between 1 and 2 hours posttreatment. Transcorneal iontophoresis (1.5 mAmps for 15 minutes) achieved peak corneal concentration of 27.6 micrograms/ml and peak aqueous concentrations of 1.4 micrograms/ml, both 1 hour after iontophoresis. Fungicidal therapeutic drug concentrations were sustained for 2 hours both in the cornea and in the aqueous. These concentrations were compared with those obtained after subconjunctival injection (peak values): 0.8 microgram/ml in aqueous, 5.9 micrograms/ml in cornea, and 0.7 microgram/ml in vitreous, all within 1 hour of injection. Aqueous and corneal concentrations were significantly higher after transscleral and transcorneal iontophoresis than subconjunctival injection (P less than 0.05). Iontophoresis is proposed as an effective means of delivering high concentrations of ketoconazole to the anterior segment of the eye.     

Regional ocular gentamicin levels after transcorneal and transscleral iontophoresis

Transcorneal and transscleral iontophoresis were compared to subconjunctival injection (control) in the delivery of gentamicin into rabbit eyes. Gentamicin levels in the corena, aqueous, and vitreous were measured by a fluorescence polarization assay at various time intervals after treatment. A mean peak corneal concentration of 376.1 micrograms/ml was achieved 2 hr after transcorneal iontophoresis. This was significantly higher than the level obtained in control eyes (P = 0.016). A mean peak aqueous humor concentration of 54.8 micrograms/ml occurred 2 hr after transcorneal iontophoresis. This was significantly higher than the peak level of 14.2 micrograms/ml after subconjunctival injection (P = 0.003). Inhibitory levels (approximately 5 micrograms/ml) were maintained in both aqueous and cornea for 8 hr after transcorneal iontophoresis. After transscleral iontophoresis, the mean peak vitreous humor concentration was 53.4 micrograms/ml at 16 hr and remained inhibitory through 24 hr; the peak aqueous level was 23.2 micrograms/ml and remained inhibitory for 24 hr. Peak drug concentrations in the vitreous were significantly higher than control (P = 0.026). Therapeutic vitreous humor levels were not achievable after transcorneal iontophoresis or subconjunctival injection. Potential corneal toxicity of transcorneal iontophoresis was demonstrated by measuring corneal thickness and endothelial cell counts prior to and 3 days after transcorneal iontophoresis of gentamicin and balanced saline solution (BSS) (control). No significant differences existed between eyes treated with gentamicin compared to those treated with BSS or when pre- versus postiontophoresis of gentamicin in the same eyes were compared. Transcorneal and transscleral iontophoresis may be an effective noninvasive method of delivering inhibitory levels of gentamicin to the cornea, aqueous humor, and vitreous for the treatment of intraocular infections.     

Corneal and intraocular penetration of topical and subconjunctival fusidic acid.

Corneal tissue absorption and intraocular penetration of fusidic acid were assessed in the rabbit after topical or subconjunctival application. Corneal tissue levels of fusidic acid one hour after the last topical application of the drug were well above the minimum inhibitory concentrations (MICs) for most Gram-positive and many Gram-negative organisms. Adequate levels were achieved in the aqueous at one hour following the last topical application, but no significant levels were detected in the vitreous. The corneal tissue and aqueous levels declined at 12 and 24 hours following the last drug application, however, corneal tissue levels at 24 hours were considered to be above the MICs for most Gram-positive organisms. A single subconjunctival injection of 100 mg of fusidic acid produced levels above the MICs of most organisms in the cornea, aqueous, and vitreous which persisted over 24 hours, but subconjunctival injection of fusidic acid at this concentration resulted in conjunctival necrosis and corneal decompensation. Fusidic acid penetrates well into avascular tissue and fully penetrates corneas with both intact and debrided epithelium, as evidenced by the intracameral drug levels. Good corneal penetration and absence of known topical toxicity make fusidic acid suitable for the treatment of microbial keratitis caused by susceptible organisms.     

Intraocular penetration of gentamicin after subconjunctibal and retrobulbar injection .

We compared the ocular penetration of labeled with radioactive carbon gentamicin in squirrel monkeys after subconjunctival and retrobulbar administration. In both normal and infected (Staphylococcus aureus endophthalmitis) eyes, high concentrations of drug were achieved in the sclera and choroid-retina by both routes, while corneal levels were markedly higher after subconjunctival injection than after retrobulbar injection. Regional variations in concentration were evident in these tissues; the highest levels were clustered about the site of injection. Aqueous humor concentrations were lowest in the group with normal eyes treated by the retrobulbar route; vitreous humor levels were extremely low in normal eyes injected subconjunctivally. These data differ from those in rabbits, especially with regard to penetration of the vitreous humor of normal eyes. Interspecies differences were less marked in inflamed eyes. The two species were similar in demonstrating maximum access to the cornea and aqueous humor with subconjunctival injection, and equivalence of the two routes in penetrating the vitreous humor of the inflamed eyes.     

Aqueous and vitreous penetration of levofloxacin after topical and/or oral administration

PURPOSE: To investigate the aqueous and vitreous penetration of levofloxacin, the drug was administered topically and/or orally to patients undergoing vitrectomy. METHODS: Thirty-six patients undergoing initial vitrectomy with phacoemulsification and aspiration (PEA) were enrolled, and were divided randomly into three groups. Group 1 was treated with topical application of levofloxacin (three times on the day before surgery and seven times on the day of surgery), Group 2 received oral administration of levofloxacin (200 mg twice on the day before surgery and 200 mg at 3 hours before surgery), and Group 3 received both topical and oral levofloxacin according to the above schedules. The concentration of levofloxacin was measured in aqueous humor and vitreous fluid samples obtained during surgery. RESULTS: In Groups 1, 2, and 3, the mean levofloxacin concentration in aqueous humor was 0.765+/-0.624 micro g/mL, 1.279+/-0.440 micro g/mL, and 1.823+/-0.490 micro g/mL, respectively, while the mean levofloxacin concentration in vitreous fluid was <0.02 micro g/mL, 1.455+/-0.445 micro g/mL, and 1.369+/-0.530 micro g/mL, respectively. CONCLUSIONS: Oral administration of levofloxacin at a dose of 400 mg/day was sufficient for the prophylaxis of ocular infections, because the drug concentrations in both aqueous humor and vitreous fluid were higher than the MIC90 values for major ocular pathogens. Topical application of levofloxacin achieved adequate drug levels in aqueous humor, but not in vitreous fluid, while combined topical and oral administration had an additive effect on the drug concentration in aqueous humor.     

Intraocular penetration kinetics of prednisolone after subconjunctival injection in rabbits

Prednisolone concentrations in cornea, aqueous humor, and vitreous humor and the residual amount in conjunctival tissue were assayed by high-performance liquid chromatography during a 14-hour period after subconjunctival injection of prednisolone sodium succinate in rabbits. Prednisolone was concentrated in the corneal epithelium and reached a peak within 5 min, whereas the peak level of prednisolone in stroma-endothelium was achieved 1 h after the injection. There was an apparent linear binding of prednisolone with the ocular tissue homogenates and fluids except for the vitreous humor. However, the protein binding of prednisolone with vitreous humor showed marked concentration dependency. A pharmacokinetic model involving a rapid conversion to prednisolone from its ester prodrug, first-order transfer to various tissues, and first-order elimination of unbound prednisolone from vitreous humor succeeded in predicting the observed concentration-time profiles of prednisolone in various ocular tissues and fluids after subconjunctival injection at three different doses: 0.1, 1.0, and 10.0 mg/kg. The present model predicted that absorption into precorneal area and epithelium and direct penetration into aqueous humor and vitreous humor are 1.7, 0.1, and 0.2% of the applied dose, respectively, and that almost the entire dose (98%) is absorbed into the systemic circulation, with a half-life of 38 min.     

Penetration of amikacin into the anterior chamber of the human eye

The authors compared amikacin penetration into the aqueous humor after intraveinous and subconjunctival administration, by samples taken at cataract surgery. Of 12 patients divided into 4 groups, given 500 mg of intraveinous amikacin at one to four hours before surgery, none showed detectable aqueous levels; whereas, the plasma level was maximum at one hour (25.5 +/- 4.5 micrograms/ml). Of 18 cases similarly divided into 4 groups given 30 mg of subconjunctival amikacin, aqueous levels of the drug were detectable at 24 minutes (6.2 +/- 5.2 micrograms/ml) and increased thereafter to 177.5 +/- 11.45 micrograms/ml at the maximum time allowed of 3 hours. No plasma levels were detected at time. Based on prior reports of the minimum inhibiting concentration of amikacin, subconjunctival administration would appear to provide effective aqueous levels for the prophylaxis and treatment of susceptable bacterial infections.     

两性霉素B经三种途径给药后在角膜和房水中药物浓度的实验研究

背景角膜基质内注射或前房内注射两性霉素B治疗顽固的真菌性角膜炎取得较好疗效，但通过这2种途径给药后，药物在角膜和房水的浓度变化尚不清楚。目的探讨质量分数0．25％两性霉素B滴眼液点眼、1％两性霉素B注射液角膜基质内注射及1％两性霉素B注射液前房内注射3种途径给药后兔眼角膜和房水中的药物质量浓度变化。方法健康家兔45只按随机数字表法分为A、B、C3组，每组15只。A组、B组分别在角膜基质内和前房内单次注射10¨g两性霉素B注射液，C组兔眼机械法去除角膜上皮后用0．25％两性霉素B滴眼液点眼，每次50仙l，共6次，每次间隔5rain。分别于用药后30min、6h、1d、3d、7d各处死3只实验兔，获取房水和角膜组织，采用高效液相色谱法进行两性霉素B质量浓度的定量检测。结果在质量浓度0．10～100．00mtg／L范围内，两性霉素B的峰面积与吸收度之间具有良好的线性关系；0．10mg／L为其定量限质量浓度；药物在房水的回收率为89．1％～95．7％，在角膜中为81．4％～83．6％。用药后30rain、6h、1dA组角膜中的药物质量分数高于B组及C组，差异均有统计学意义（P〈0．05），高药物质量浓度可持续7d，超出绝大多数敏感真菌的MIC。。。用药后30min、6h、1dB组兔眼房水中的药物质量浓度高于A组及C组，差异均有统计学意义（P〈0．05）。C组1d内角膜和房水中均检测到明显药物浓度。结论兔眼角膜基质内注射及前房内注射两性霉素B可以提高药物在角膜及房水中的质量浓度，清除角膜上皮可以提高两性霉素B的角膜穿透力。     

Penetration of topically applied ciprofloxacin and ofloxacin into the aqueous humor and vitreous

PURPOSE: To determine the intraocular penetration of topical drops of 2 antibiotics, ciprofloxacin 0.3% and ofloxacin 0.3%, into the aqueous humor and vitreous and to relate these levels to the miminum inhibitory concentration (MIC(90)) for organisms associated with ocular bacterial infections. SETTING: Department of Ophthalmology, Ankara Hospital, and Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. METHODS: This prospective randomized clinical trial comprised 18 patients having cataract surgery, all with an intact corneal epithelium. The patients were randomly assigned to receive topical ciprofloxacin 0.3% (n = 10) or topical ofloxacin 0.3% (n = 8) 1 drop every 15 minutes 5 times and every 30 minutes 3 times before surgery. Aqueous and vitreous samples (if vitreous loss occurred during the cataract surgery) were collected 30 minutes after the administration of the last dose. Drug concentrations were determined by high-performance liquid chromatography (HPLC) fluorescence. RESULTS: All patients had detectable drug concentrations in the aqueous humor and vitreous measurable by HPLC. The mean aqueous humor concentration of ciprofloxacin was 1.13 microg/mL +/- 1.90 (SD) and the mean vitreous concentration, 0.23 +/- 0.06 microg/mL. Topical administration of ciprofloxacin yielded 4.9 times more drug concentration in the anterior chamber than in the vitreous. The mean aqueous concentration of ofloxacin was 2.06 +/- 1.06 microg/mL and the mean vitreous concentration, 0.46 +/- 0.10 microg/mL. Topical administration of ofloxacin yielded 4.7 times more drug concentration in the anterior chamber than in the vitreous. Aqueous humor concentrations of ofloxacin and ciprofloxacin were not statistically significantly different (P =.353). Intravitreal concentrations of ofloxacin were statistically significantly higher than those of ciprofloxacin (P =.001). CONCLUSIONS: Topical ofloxacin 0.3% penetrated better than topical ciprofloxacin 0.3% into the anterior chamber and vitreous in noninflamed eyes. Both drugs were above the MIC(90) for most ocular pathogens in the anterior chamber. The mean concentration in the vitreous of topically applied ofloxacin 0.3% was statistically significantly higher than that of ciprofloxacin 0.3%, but it was not sufficiently above the MIC(90) for most ocular pathogens in terms of empirical endopthalmitis therapy.     

氟康唑眼液滴眼的眼内药代动力学实验研究

目的　研究 0 5 %氟康唑滴眼液在兔角膜的渗透性及其在角膜和房水中的药代动力学行为。方法　将新西兰大白兔双眼滴入 0 5 %氟康唑眼液后 ,分别于不同时间处死家兔 ,将获取的房水和角膜组织用反相高效液相色谱法 (highperformanceliquidchromatography ,HPLC)进行定量测定。色谱条件 :色谱柱为SpherisorbC18,粒径为 5 μm ,色谱柱长度和直径为 2 0 0 0mm× 4 6mm ,柱温为 4 5℃ ,流动相为 0 0 5mol/L磷酸二氢钾 甲醇 (6 5∶35 ) ,流速为 1ml/min ,检测波长为 2 6 5nm。采用非线性最小二乘法进行计算机拟合求得药代动学参数。结果　采用反相HPLC法可以将氟康唑同其他杂质很好分离 ,最低定量浓度为 0 1mg/L ,氟康唑在组织中的回收率平均为 90 6 %。 0 5 %氟康唑滴眼后的各时间点角膜组织及房水中均可检测出氟康唑的含量 ,其中角膜组织中于滴药后 2min时含量最高为 (15 2 0± 1 95 ) μg/g ,房水中 15min时的含量最高为 (2 39± 0 92 )mg/L。角膜上皮渗透系数为1 0 6× 10 -5。角膜组织中药物浓度半衰期为 6 3 96min ,房水中为 4 2 14min。结论　氟康唑可用于真菌性角膜炎的局部抗真菌治疗 ,是否用于治疗真菌性眼内炎尚待研究     

Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate

PURPOSE: To study the dexamethasone concentration in aqueous humor, vitreous, and serum of patients after repeated topical application of dexamethasone disodium phosphate. DESIGN: Prospective nonrandomized comparative trial. PARTICIPANTS: Twenty phakic patients scheduled for a first vitrectomy. METHODS: All participants received dexamethasone disodium phosphate drops according to an application schedule intended to result in steady-state drug concentrations. Starting on the preoperative day, they received 1 drop of dexamethasone disodium phosphate (0.1%) every 1 hours until the time of vitrectomy (total, 10 or 11 drops). At night, ointment containing dexamethasone (0.3 mg/g) and gentamicin (5 mg/g) was administered once. From 7 AM on, the drop application schedule was resumed. At the start of the vitrectomy, samples were taken from the aqueous humor, vitreous, and blood. MAIN OUTCOME MEASURES: The dexamethasone concentrations in the aqueous humor, vitreous, and serum measured by radioimmunoassay. RESULTS: The mean dexamethasone concentrations in the aqueous humor, vitreous, and serum were 30.5 ng/ml (range, 7.1-57.7; standard deviation [SD] 15.0), 1.1 ng/ml (range, 0.0-1.6; SD 0.4), and 0.7 ng/ml (range, 0.0-1.2; SD 0.4), respectively. CONCLUSIONS: Compared with previously tested administration routes (peribulbar or subconjunctival injection or oral administration), the penetration of dexamethasone into the vitreous after repeated drop application is negligible. Despite the frequent dosing schedule, the dexamethasone concentration in the aqueous humor is far lower than after a subconjunctival injection with dexamethasone disodium phosphate. Systemic uptake is low.     

Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis

PURPOSE: To assess the corneal iontophoretic delivery of gentamicin by drug-loaded hydrogel probe, and to determine the resultant ocular disposition and elimination of the drug from the cornea and anterior chamber. METHODS: Corneal iontophoresis of gentamicin sulfate was studied in healthy white rabbits by using drug-loaded disposable hydroxyethyl methacrylate (HEMA) hydrogel disk probes and a portable mini-ion device designed in the authors' laboratory. The iontophoretic treatment was performed with a current intensity of 1 mA for 60 seconds only. Three control groups were used: mock iontophoresis (no current) for 60 seconds, topical eye drops of fortified gentamicin (1.4%) every 5 minutes for 1 hour, and subconjunctival injection of 0.25 mL of 40 mg/mL gentamicin solution. The animals in the iontophoretic experimental groups were killed at predetermined time points. The gentamicin concentrations in the cornea and aqueous humor were assayed with a fluorescence polarization immunoassay. Analysis of the gentamicin eye pharmacokinetics was performed with a modeling approach. RESULTS: Peak gentamicin concentrations in the cornea (363.1 +/- 127.3 microg/g) and in the aqueous humor (29.4 +/- 17.4 microg/mL) were reached at 0 and 2 hours after the iontophoretic treatment, respectively. The peak gentamicin concentrations after a single iontophoresis treatment were 12 to 15 times higher than those obtained after gentamicin injection or after topical eye drop instillation, and much higher than in mock iontophoresis. The concentration versus time profile of gentamicin in the cornea and the anterior chamber after iontophoresis was appropriately described by applying a two-compartment pharmacokinetic model. CONCLUSIONS: A short iontophoretic treatment using gentamicin-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior segments of the eye and maintaining therapeutic drug levels in the cornea for more than 8 hours.     

Concentrations of levofloxacin, ofloxacin, and ciprofloxacin in human corneal stromal tissue and aqueous humor after topical administration

OBJECTIVE: To evaluate the penetration of commercially available levofloxacin 0.5%, ofloxacin 0.3%, and ciprofloxacin 0.3% topical ophthalmic solutions in human corneal stromal and aqueous humor tissues. METHODS: A total of 67 patients scheduled to undergo penetrating keratoplasty for treatment of stromal scar or dystrophy, keratoconus, pellucid marginal degeneration, or endothelial disease were enrolled in this prospective, double-blind, 3-center study. To be considered for inclusion, patients had to have an intact corneal epithelium and minimal or no corneal edema (pachymetry < 650 microm). After informed consent was obtained, patients were randomized to receive 1 drop of levofloxacin 0.5%, ofloxacin 0.3%, or ciprofloxacin 0.3% topical ophthalmic solution at approximately 15 and 10 minutes before surgery. Approximately 0.1 mL of aqueous fluid was aspirated by paracentesis through the trephination wound at the onset of surgery, followed by excision of the affected cornea and removal of its epithelium. Specimens were stored frozen at -70 degrees C until assayed by high-performance liquid chromatography. RESULTS: All 3 fluoroquinolones were well tolerated. A total of 65 corneas and 59 aqueous fluid samples were obtained and assayed. The mean +/- standard deviation corneal concentrations of ciprofloxacin, ofloxacin, and levofloxacin following a 2-drop administration were 9.92 +/- 10.99 microg/g (n = 18), 10.77 +/- 5.90 microg/g (n = 23), and 18.23 +/- 20.51 microg/g (n = 24), respectively. Although corneal stromal levels were highest in the levofloxacin group, the high degree of interpatient variability prevented demonstration of statistically significant differences when compared with ofloxacin (P = 0.377). In contrast, levofloxacin concentrations were approximately twice as high as ciprofloxacin, and this difference reached statistical significance (P = 0.014). The corresponding aqueous humor concentrations of ciprofloxacin, ofloxacin, and levofloxacin were 0.135 +/- 0.231 microg/mL (n = 15), 0.135 +/- 0.111 microg/mL (n = 20), and 0.372 +/- 0.546 microg/mL (n = 24, P < 0.001 versus ciprofloxacin and ofloxacin). CONCLUSION: The topical administration of all 3 agents was well tolerated in patients undergoing penetrating keratoplasty. Two drops of levofloxacin 0.5% solution results in a 1.7- to 2.7-fold greater penetration into human corneal stromal and aqueous humor tissues than ofloxacin 0.3% or ciprofloxacin 0.3%. The mean intracorneal concentrations of all three agents following 2 drops exceeds the MIC90 for the majority of pathogens causing bacterial keratitis. Topical levofloxacin appears to offer pharmacokinetic and pharmacodynamic advantages over ofloxacin and ciprofloxacin in terms of enhanced transcorneal penetration; however, clinical comparative trials are needed to confirm these relative advantages.     

Intraocular absorption of cyclosporin A eyedrops]

A study was carried out on ocular and systemic absorption after topical application of 2% cyclosporin A in patients requiring corneal transplants, determining by polarized light immunofluorescence the levels of this drug in the cornea, aqueous humor and blood. Between 30 and 85 minutes after the last application, considerable levels of cyclosporin A were found in the explanted cornea (236 +/- 42 ng/mL). Relatively lower levels were found in the aqueous humor although there were significant differences between the patients who received a total topical dosage of 5 mg (16.92 +/- 6.86 ng/mL) and those who received 10 mg (25.06 +/- 9.13 ng/mL) over the same period of time. No analytically detectable levels were found in the plasma. We consider that topically administered cyclosporin A can reach immunosuppressive levels of activity in some ocular compartments thus eliminating the potential systemic effects resulting from its utilization by general administration.     

Toxicity and pharmacokinetics of subconjunctival amphotericin B. An experimental study

The pharmacokinetics and toxicity of subconjunctival (S/C) amphotericin B (AmB) were evaluated in Dutch-belted rabbits. Following the S/C injection of 1,500 micrograms of AmB, corneal and aqueous levels were determined by bioassay. The highest levels were present in the periphery of debrided corneas at 1 h (90.12 +/- 2.4 micrograms/g). The debrided central cornea contained 30.84 micrograms/g, almost double the amount present in the intact central cornea. These levels were transient; in the central intact cornea only 2.08 micrograms/g could be detected at 2 h. Peak aqueous levels were low (0.95 +/- .24 micrograms/mL in debrided corneas at 1 h). The S/C injection of 1,500 micrograms of AmB in sodium deoxycholate produced a severe inflammatory response in the conjunctiva, episclera, iris, anterior chamber, and superior rectus muscle that persisted 10 days. Injection of sodium deoxycholate alone produced a similar but less severe response.     

Comparison of intraocular penetration level of cefuzonam sodium and cefotiam after intravenous and subconjunctival injection

We investigated the intraocular penetration of a new Cephem type antibiotic: Cefuzonam sodium (CZON) following intravenous and subconjunctival injection. CZON was administered to 28 eyes in 26 patients by 1 g intravenous injection (IV) and to 11 eyes in 10 patients by 20 mg/0.2 ml subconjunctival injection (SCI). The penetration level of CZON by the IV method was from less than 0.0025-3.35 micrograms/ml into aqueous humor, from less than 0.0025-0.315 microgram/mg into iris tissue and 2.7-157.5 micrograms/ml into serum. The penetration level of CZON by the SCI method was from less than 0.0025-12.8 micrograms/ml into aqueous humor, from less than 0.0025-0.0426 microgram/mg into iris tissue and 1.03-18.5 micrograms/ml into serum. The penetration level of CZON into aqueous humor by SCI was higher than by IV administration. In comparison with the penetration level of CZON and Cefotiam (CTM), both aqueous humor and serum levels of CTM were higher than those of CZON. These results suggested that therapeutic levels in aqueous humor effective against gram-positive and gram-negative pathogens were achieved with the 1 g IV and 20 mg SCI of CZON. However levels effective against Staphylococcus epidermidis were only erratically attained.     

Penetration of amikacin into aqueous humor of rabbits

Amikacin is an aminoglycoside antibiotic that has poor corneal penetration due to its hydrophilic properties. The purpose of this study was to compare and evaluate the penetration of amikacin sulfate into aqueous humor of the rabbit eye when applied by different routes and concentrations, namely 100 or 250 mg/ml topical fortified amikacin eye drops, 100 or 250 mg/ml amikacin-embedded soft contact lenses and 25 mg subconjunctival amikacin injection. One hour after application, amikacin was not detectable in any of the 100 mg/ml concentration groups. High levels of amikacin above the minimum inhibitory concentration for susceptible bacteria were detected when applied subconjunctivally and by 250 mg/ml topical fortified routes. Topical fortified amikacin 250 mg/ml reached the highest value in the aqueous (p < 0.05). Our results point out the poor corneal penetration of amikacin in standard concentrations from the intact rabbit cornea and that subconjunctival injections might provide satisfactory penetration.     

Iontophoresis of vidarabine monophosphate into rabbit eyes

In order to investigate the efficacy of iontophoresis for increasing the penetration of vidarabine monophosphate into the eye, tritium-labeled vidarabine monophosphate was applied to rabbit eyes by topical and iontophoretic application, and the penetration of the compound into the eye, and its subsequent metabolism, were studied. At 20 min after treatment, the ratios of radioactivity for cathodal iontophoresis compared to topical application alone were cornea 8.6, aqueous humor 4.8, and iris 2.4; for 60 min the ratios were cornea 12.2 aqueous humor 17.5 and iris 2.5. In addition, the acid-soluble components were extracted from the cornea and aqueous humor. Vidarabine monophosphate, vidarabine, hypoxanthine arabinoside, adenosine, hypoxanthine, and adenine from the acid-soluble fraction were separated by thin-layer chromatography. The amount of vidarabine monophosphate and vidarabine in the cornea and aqueous humor from the iontophoretically treated group was six to 15 times higher than from the group that received topical application of the drug. It was concluded that cathodal iontophoresis resulted in significantly increased penetration of the antiviral drug vidarabine monophosphate into the anterior chamber of the eye. The effects of iontophoresis of vidarabine monophosphate on corneal epithelium, as observed by scanning electron micrographs, were equal to or less than those seen with the topical application of widely used preservatives in ophthalmic preparations.     

Ocular bioavailability of ciprofloxacin in sustained release formulations.

A novel sustained release delivery system of ciprofloxacin for the eye was developed. The system consists of a viscosity enhancer (carbopol gel or hydroxypropylmethylcellulose solution) plus a penetration enhancer (dodecylmaltoside) to overcome penetration barriers and loss due to wash-out and thus achieve the desired ciprofloxacin ocular absorption. The present studies were designed to assess the ocular penetration and bioavailability of ciprofloxacin in sustained release formulations. In vitro studies in rabbits indicated an approximate 10-fold increase in drug penetration through the rabbit cornea using the penetration enhancer, dodecylmaltoside. In vivo bioavailability studies demonstrate that these formulations provided a long drug duration in the cornea. After administration of a single topical dose of ciprofloxacin (0.3%/30 microL), corneal levels greater than the Minimum Inhibitory Concentration (MIC90) (0.5 microg/g) were observed through eight hours. These sustained release formulations delivered 10-fold more drug into the aqueous humor than the standard solution formulation. Maximum ciprofloxacin concentrations in the aqueous humor (0.5-0.7 microg/mL) were attained between one and two hours after dosing. Using these sustained release formulations, ciprofloxacin can penetrate to the anterior chamber of the eye in concentrations that are inhibitory for most gram-negative and gram-positive organisms. These topical ocular formulations have prophylactic utility for prevention of post-surgical infection, offering greater efficacy and safety than currently available treatments.     

Intraocular availability of topically applied mycophenolate mofetil in rabbits.

The efficacy of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), in high risk keratoplasties and ocular immune-mediated diseases has been shown in recent years. As peroral administration of MMF can cause various side effects, topical application should be considered. This study investigates the intraocular availability of MMF and MPA in the rabbit eye. An eye drop solution (MMF-CD; 1% MMF/10% hydroxypropyl-beta-cyclodextrin (HP-beta-CD)) or a 1% aqueous suspension (MMF-SP) was instilled into the lower cul-de-sac of the right eye of each rabbit. Rabbits (each group: n = 4) were put down after 30, 60 and 240 min. Aqueous humor, vitreous, cornea, sclera, conjunctiva, iris-ciliary-body, and plasma were isolated. Several extraction procedures were performed in order to quantify the drug by HPLC. The aqueous humor concentration of the active metabolite MPA was 24 microg/mL after 30 min for both preparations. The ratio of the MPA concentrations after 30, 60, and 240 min was 1 : 2 : 0.07 for MMF-CD and 1 : 0.6 : 0.04 for MMF-SP, respectively. MPA levels in the cornea were 90.78 / 56.90 / 4.08 x 10(-6) microg/microg for MMF-CD, whereas MMF-SP resulted in MPA levels of 102.65 / 31.18 / 2.59 x 10(-6) microg/microg at the three time points. As a high concentration of the active drug MPA in cornea and aqueous humor is desired, e.g. following corneal transplantation, the MMF/HP-beta-CD formulation could be an useful topical treatment. Furthermore, the present study shows that MMF-CD is superior to MMF-SP by increasing intraocular availability.