Buprenorphine is a well-established μ-opioid receptor partial agonist that shows robust analgesic efficacy. Endo Pharmaceuticals is developing a soluble buccal film formulation (utilizing a BioErodible MucoAdhesive [BEMA®] drug delivery system) with improved bioavailability. As with all buccal dose forms, there is the potential for absorption to be influenced by buccal pH or by any fluids consumed at the time of administration. To that end, two clinical studies were undertaken to evaluate the effects of co-administration of liquids on the pharmacokinetics and tolerability of a single oral dose of buprenorphine buccal film (900 μg) in healthy subjects. Buprenorphine buccal film was administered without any liquids or just prior to hot, cold, or room temperature water, or low vs. high pH liquids. Sublingual Buprenorphine (8 mg) was included as a comparator. Subjects assigned to a treatment with a co-administered beverage were instructed to begin sipping the beverage 5 minutes after administration of buccal buprenorphine and to complete within 15 minutes. Plasma levels of buprenorphine and the active metabolite, norbuprenorphine, were measured. A total of 57 subjects completed the trials. High pH liquid had no significant impact, whereas low pH decreased systemic exposure (AUCinf) to buprenorphine by approximately 37%. Co-administered water, regardless of temperature, decreased the rate (Cmax) and extent (AUC) of buprenorphine absorption by 23-27%. Norbuprenorphine levels were similar across all study arms. The relative bioavailability of buccal buprenorphine relative to sublingual buprenorphine HCl was 187.10% and 191.53% based on AUCt and AUCinf, respectively. In conclusion, ingestion of liquids shortly after application of a BEMA® buprenorphine buccal film had variable, generally modest effects on buprenorphine plasma levels, optimal exposure is achieved when the film is applied without ingested liquids. This study was funded by Endo Pharmaceuticals Inc.

Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent, is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Three hydrophilic amide prodrugs of celecoxib, celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity were significantly lower than for celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10-20% conversion to parent celecoxib in 30 min. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5-fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 μM. Celecoxib succinamidic acid, a soluble prodrug of celecoxib with reduced melanin binding, enhances transscleral retinal delivery of celecoxib.

MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) formulation of 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen (HB/APAP ER) being developed for management of moderate to moderately severe acute pain. The product utilizes AcuForm™ gastroretentive drug delivery technology. This study evaluated single- and multiple-dose pharmacokinetics and bioavailability following administration of MNK-155 (7.5 mg HB/325 mg APAP) given as 1 or 2 tablets every 12 hours (q12h) compared with 1 tablet of IR 7.5 mg HB/325 mg APAP administered every 6 hours (q6h) in 44 healthy subjects under fasted conditions. For the single-dose portion of the study, subjects received 1 dose of MNK-155 or IR product q6h for 2 doses. For the multiple-dose portion, MNK-155 was administered q12h, and the IR product q6h for 4.5 days. The most common treatment-emergent adverse events (AEs) included nausea, headache, fatigue, pruritus, vomiting, and dizziness. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly following administration of a single dose of MNK-155, with hydrocodone concentrations sustained above pre-dose levels over the 12-hour dosing interval. APAP concentrations approximated baseline levels by 10-12 hours after dosing. Steady-state conditions for hydrocodone were observed in 5-6 days and in 4-7 days for APAP. Total exposure (dose-normalized area under the concentration–time curve [AUC]) to hydrocodone and APAP for both single dose and steady state were equivalent to the IR product. As expected, single-dose peak hydrocodone exposure (dose-normalized maximum plasma concentration [Cmax]) for MNK-155 was 26% (1 tablet) and 28% (2 tablets) lower than the IR drug. However, single-dose peak exposure (dose-normalized Cmax) for APAP and multiple-dose Cmaxss for both hydrocodone and APAP for MNK-155 were equivalent to the IR product. Supported by funding from Mallinckrodt Inc. MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) formulation of 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen (HB/APAP ER) being developed for management of moderate to moderately severe acute pain. The product utilizes AcuForm™ gastroretentive drug delivery technology. This study evaluated single- and multiple-dose pharmacokinetics and bioavailability following administration of MNK-155 (7.5 mg HB/325 mg APAP) given as 1 or 2 tablets every 12 hours (q12h) compared with 1 tablet of IR 7.5 mg HB/325 mg APAP administered every 6 hours (q6h) in 44 healthy subjects under fasted conditions. For the single-dose portion of the study, subjects received 1 dose of MNK-155 or IR product q6h for 2 doses. For the multiple-dose portion, MNK-155 was administered q12h, and the IR product q6h for 4.5 days. The most common treatment-emergent adverse events (AEs) included nausea, headache, fatigue, pruritus, vomiting, and dizziness. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly following administration of a single dose of MNK-155, with hydrocodone concentrations sustained above pre-dose levels over the 12-hour dosing interval. APAP concentrations approximated baseline levels by 10-12 hours after dosing. Steady-state conditions for hydrocodone were observed in 5-6 days and in 4-7 days for APAP. Total exposure (dose-normalized area under the concentration–time curve [AUC]) to hydrocodone and APAP for both single dose and steady state were equivalent to the IR product. As expected, single-dose peak hydrocodone exposure (dose-normalized maximum plasma concentration [Cmax]) for MNK-155 was 26% (1 tablet) and 28% (2 tablets) lower than the IR drug. However, single-dose peak exposure (dose-normalized Cmax) for APAP and multiple-dose Cmaxss for both hydrocodone and APAP for MNK-155 were equivalent to the IR product. Supported by funding from Mallinckrodt Inc.

Two similar crossover studies characterized the pharmacokinetics and tolerability of diclofenac sodium 2% topical solution in relation to diclofenac sodium 1.5% topical solution. One study utilized an additional arm of oral diclofenac sodium 75 mg as a comparator. During separate 7.5-day study periods, healthy subjects administered diclofenac sodium 2% topical solution twice daily (40.4 mg/knee; total daily dose, 162 mg), diclofenac sodium 1.5% topical solution 4 times daily (19.3 mg/knee; total daily dose, 154 mg), or 1 diclofenac sodium 75-mg tablet orally twice daily (study 1 only; total daily dose, 150 mg). The primary pharmacokinetic outcomes were steady-state (day 8) mean (SD) 0- to 24-hour area under the plasma diclofenac concentration curve (AUC0-24ss) and steady-state peak plasma diclofenac concentrations (Cmaxss). Tolerability was assessed by collecting adverse event (AE) data, including skin irritation. Of the 62 subjects enrolled in both studies to receive topical diclofenac, 51 completed all study phases. A pooled analysis demonstrated that diclofenac sodium 2% topical solution produced higher diclofenac plasma concentrations than the 1.5% formulation on day 1; however, the peak (Cmaxss ) and extent (AUC0-24ss) of systemic exposure at steady-state (day 8) for diclofenac sodium 2% topical solution (AUC0-24ss, 319.5 [162.4] ng•h/mL; Cmaxss, 19.8 [10.1] ng/mL) and diclofenac sodium 1.5% topical solution (AUC0-24ss, 295.5 [168.9] ng•h/mL; Cmaxss, 16.1 [9.2] ng/mL) were comparable. Orally administered diclofenac produced substantially greater systemic exposure (day 8, AUC0-24ss, 4426.0 [2793.7] ng•h/mL; Cmaxss, 1348.4 [1073.8] ng/mL) than the topical formulations. Mild application site reactions (ie, dryness, erythema, and pruritus) were the most common AEs for both topical diclofenac formulations. The observed pharmacokinetic profile for diclofenac sodium 2% topical solution was similar to the 1.5% formulation, despite different dosing schedules and diclofenac concentrations; both formulations resulted in substantially lower systemic exposure relative to orally administered diclofenac. Supported by funding from Mallinckrodt Inc. Two similar crossover studies characterized the pharmacokinetics and tolerability of diclofenac sodium 2% topical solution in relation to diclofenac sodium 1.5% topical solution. One study utilized an additional arm of oral diclofenac sodium 75 mg as a comparator. During separate 7.5-day study periods, healthy subjects administered diclofenac sodium 2% topical solution twice daily (40.4 mg/knee; total daily dose, 162 mg), diclofenac sodium 1.5% topical solution 4 times daily (19.3 mg/knee; total daily dose, 154 mg), or 1 diclofenac sodium 75-mg tablet orally twice daily (study 1 only; total daily dose, 150 mg). The primary pharmacokinetic outcomes were steady-state (day 8) mean (SD) 0- to 24-hour area under the plasma diclofenac concentration curve (AUC0-24ss) and steady-state peak plasma diclofenac concentrations (Cmaxss). Tolerability was assessed by collecting adverse event (AE) data, including skin irritation. Of the 62 subjects enrolled in both studies to receive topical diclofenac, 51 completed all study phases. A pooled analysis demonstrated that diclofenac sodium 2% topical solution produced higher diclofenac plasma concentrations than the 1.5% formulation on day 1; however, the peak (Cmaxss ) and extent (AUC0-24ss) of systemic exposure at steady-state (day 8) for diclofenac sodium 2% topical solution (AUC0-24ss, 319.5 [162.4] ng•h/mL; Cmaxss, 19.8 [10.1] ng/mL) and diclofenac sodium 1.5% topical solution (AUC0-24ss, 295.5 [168.9] ng•h/mL; Cmaxss, 16.1 [9.2] ng/mL) were comparable. Orally administered diclofenac produced substantially greater systemic exposure (day 8, AUC0-24ss, 4426.0 [2793.7] ng•h/mL; Cmaxss, 1348.4 [1073.8] ng/mL) than the topical formulations. Mild application site reactions (ie, dryness, erythema, and pruritus) were the most common AEs for both topical diclofenac formulations. The observed pharmacokinetic profile for diclofenac sodium 2% topical solution was similar to the 1.5% formulation, despite different dosing schedules and diclofenac concentrations; both formulations resulted in substantially lower systemic exposure relative to orally administered diclofenac. Supported by funding from Mallinckrodt Inc.

MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) tablet formulation containing 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen (HB/APAP ER). This study evaluated single- and multiple-dose pharmacokinetics and bioavailability of MNK-155 administered as 2 or 3 tablets every 12 hours (q12h) compared with 1 tablet IR 7.5 mg HB/325 mg APAP every 6 hours (q6h) in healthy subjects under fasted conditions. For the single-dose portion, subjects (n=30) received one single dose of MNK-155, and IR product q6h for two doses (hydrocodone/ibuprofen [Vicoprofen®] or tramadol/APAP [Ultracet®]). For the multiple-dose portion, subjects (n=29) received 2 tablets MNK-155 q12h with or without a 3-tablet loading dose, and the IR product q6h for 4.5 days. The most common adverse events (AEs) included nausea, pruritus, vomiting, somnolence, constipation, headache, euphoric mood, and dizziness. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly after MNK-155 administration. Hydrocodone concentrations were sustained above pre-dose levels over the 12-hour dosing interval. By 10-12 hours after administration, APAP concentrations approximated baseline levels. Steady-state was achieved in 2 days for hydrocodone and 1-2 days for APAP. Total exposure (dose-normalized area under the concentration–time curve [AUC]) to hydrocodone and APAP after MNK-155 administration, with and without the loading dose, were equivalent to marketed IR products in single-dose and steady-state conditions. Single-dose peak hydrocodone exposure (dose-normalized maximum plasma concentration [Cmax]) for MNK-155 was approximately 30% lower than for IR hydrocodone/ibuprofen. However, single-dose peak exposure (dose-normalized Cmax) for APAP and multiple-dose Cmaxss for hydrocodone and APAP were equivalent to marketed IR products, with less fluctuation in hydrocodone versus IR hydrocodone/ibuprofen and lower trough plasma concentrations of APAP versus IR tramadol/APAP. These findings support a proposed dosing interval of MNK-155 every 12 hours. Supported by funding from Mallinckrodt Inc.

MNK-155 contains 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen in an immediate-release (IR)/extended-release (ER) tablet formulation utilizing AcuForm™ gastroretentive drug delivery technology. MNK-155 (HB/APAP ER) is under development for the management of moderate to moderately severe acute pain with 12-hour dosing. This study evaluated the extent to which MNK-155 intact, MNK-155 crushed, and IR HB/APAP (Norco®) produce certain subjective effects that have been associated with drug abuse in recreational opioid users, such as drug liking, high, and good drug effects. Subjects received a single dose of one of 7 study treatments: MNK-155 intact high-dose (45 mg HB/1950 mg APAP, 6 tablets) or low-dose (22.5 mg HB/975 mg APAP, 3 tablets); IR HB/APAP intact high-dose (45 mg HB/1950 mg APAP, 6 tablets) or low-dose (22.5 mg HB/975 mg APAP, 3 tablets); MNK-155 HB/APAP crushed (encapsulated) high-dose (45 mg HB/1950 mg APAP, 12 capsules); IR HB/APAP crushed (encapsulated) high-dose (45 mg HB/1950 mg APAP, 6 capsules) and placebo. Primary comparisons were between (1) intact high-dose MNK-155 and intact high-dose IR HB/APAP; (2) crushed high-dose MNK-155 and intact high-dose IR HB/APAP; and (3) high-dose IR HB/APAP and placebo. Study validity was confirmed by higher scores for drug liking, high, and good drug effects for low-dose, high-dose, and crushed IR HB/APAP versus placebo. Least-squares (LS) median values for all 9 primary endpoint comparisons were significantly lower (P<0.001) for both high-dose intact and crushed MNK-155 than intact high-dose IR HB/APAP for drug liking, high, and good drug effects. In this population of recreational prescription opioid users, intact and crushed MNK-155 produced less drug liking, high, and good drug effects compared with IR HB/APAP, representing a positive result in studies necessary to determine if MNK-155 is associated with lower potential for abuse when tampered and administered orally. Supported by funding from Mallinckrodt Inc.

MNK-155 is a bilayer tablet formulation of immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB) 7.5 mg and acetaminophen (APAP) 325 mg (HB/APAP ER) being developed for the management of moderate to moderately severe acute pain. This study evaluated single-dose pharmacokinetics and bioavailability following administration of 3 tablets of MNK-155 (HB 7.5 mg/APAP 325 mg) under fed conditions (high- and low-fat meals) compared with fasted conditions. Healthy volunteers (n=21) received a single dose (3 tablets) of MNK-155 after a high-fat meal, after a low-fat meal, and under fasted conditions. Nausea, pruritus, vomiting, somnolence, and dizziness were the most frequently reported treatment-emergent adverse events (AEs) in this population. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly after MNK-155 administration, with plasma hydrocodone concentrations sustained above pre-dose levels over the proposed 12-hour dosing interval. APAP concentrations approximated baseline levels by 10-12 hours after dosing. The confidence intervals for the total exposure (area under the concentration–time curve [AUC]) after administration of 3 tablets of MNK-155 under fed conditions (low-fat and high-fat meal) were within the no-effect range for both hydrocodone and APAP. Peak exposure (maximum plasma concentration [Cmax]) for hydrocodone following administration of MNK-155 after a high-fat meal did not differ from that under the fasted condition. The lower peak exposure for APAP under both fed conditions and the slight increase in mean peak exposure for hydrocodone after a low-fat meal are consistent with food effects on peak exposure that have been reported for other hydrocodone- and APAP-containing products. These findings support the appropriate administration of MNK-155 without regard to food. Supported by funding from Mallinckrodt Inc.

MNK-155 contains 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen in an immediate-release (IR)/extended-release (ER) tablet formulation utilizing AcuForm™ gastroretentive drug delivery technology. MNK-155 (HB/APAP ER) is under development for the management of moderate to moderately severe acute pain with 12-hour dosing. This study evaluated the extent to which MNK-155 intact, MNK-155 crushed, and IR HB/APAP (Norco®) produce certain subjective effects that have been associated with drug abuse in recreational opioid users, such as drug liking, high, and good drug effects. Subjects received a single dose of one of 7 study treatments: MNK-155 intact high-dose (45 mg HB/1950 mg APAP, 6 tablets) or low-dose (22.5 mg HB/975 mg APAP, 3 tablets); IR HB/APAP intact high-dose (45 mg HB/1950 mg APAP, 6 tablets) or low-dose (22.5 mg HB/975 mg APAP, 3 tablets); MNK-155 HB/APAP crushed (encapsulated) high-dose (45 mg HB/1950 mg APAP, 12 capsules); IR HB/APAP crushed (encapsulated) high-dose (45 mg HB/1950 mg APAP, 6 capsules) and placebo. Primary comparisons were between (1) intact high-dose MNK-155 and intact high-dose IR HB/APAP; (2) crushed high-dose MNK-155 and intact high-dose IR HB/APAP; and (3) high-dose IR HB/APAP and placebo. Study validity was confirmed by higher scores for drug liking, high, and good drug effects for low-dose, high-dose, and crushed IR HB/APAP versus placebo. Least-squares (LS) median values for all 9 primary endpoint comparisons were significantly lower (P<0.001) for both high-dose intact and crushed MNK-155 than intact high-dose IR HB/APAP for drug liking, high, and good drug effects. In this population of recreational prescription opioid users, intact and crushed MNK-155 produced less drug liking, high, and good drug effects compared with IR HB/APAP, representing a positive result in studies necessary to determine if MNK-155 is associated with lower potential for abuse when tampered and administered orally. Supported by funding from Mallinckrodt Inc.

s The Journal of Pain S97 (484) An assessment of the efficacy and tolerability of diclofenac sodium 2% topical solution for treating osteoarthritis of the knee T Barrett, R Franke, N Cheruvu, M Giuliani, J Ward, and K Devarakonda; Mallinckrodt Inc., Hazelwood, MO This double-blind, randomized, controlled, parallel-group study assessed the efficacy and tolerability of diclofenac sodium 2% topical solution in patients with primary osteoarthritis of the knee. Patients were randomly assigned to receive diclofenac sodium 2% topical solution or vehicle, applied twice daily for 4 weeks on an outpatient basis. The primary efficacy outcome was change from baseline to final visit in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale, expressed as least square means (LSM) with standard errors (SE). Secondary outcomes included WOMAC physical function and stiffness subscales; patient global assessment (PGA) of osteoarthritis status; knee pain intensity measured at midday, evening, and over the previous 24 hours with a numeric rating scale (NRS); and use of supplemental analgesics. Between-group statistical comparisons were made using analysis of covariance at an a=0.10. Adverse event (AE) occurrence was also assessed. Two hundred fifty-nine patients were enrolled and received $1 dose of diclofenac sodium 2% topical solution (n=130) or vehicle (n=129). Significantly greater reductions in LSM (SE) WOMAC pain scores were observed for patients receiving diclofenac sodium 2% topical solution (-4.4 [0.4]) compared with vehicle (-3.4 [0.4]; P=0.040) at the final visit. Similar results were observed for WOMAC physical function (-13.9 [1.2] vs -10.7 [1.3]; P=0.061) and stiffness (-1.7 [0.2] vs -1.3 [0.2]; P=0.097) and PGA (-1.1 [0.1] vs -0.8 [0.1]; P=0.085). The vehicle control group experienced slightly more AEs than active treatment (38.8% vs 31.5%), which primarily involved application site reactions. Regardless of missing data imputationmethod used, diclofenac sodium 2% topical solution using a twice daily dosing regimen produced significantly greater improvements in pain reduction associated with osteoarthritis of the knee compared to vehicle control and was generally well tolerated. Supported by funding from Mallinckrodt Inc. (485) A comparison of the pharmacokinetics and tolerability of diclofenac sodium 2% and 1.5% topical solutions R Franke, T Barrett, N Cheruvu, M Giuliani, and K Devarakonda; Mallinckrodt

MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) tablet formulation of hydrocodone bitartrate 7.5 mg/acetaminophen 325 mg (HB/APAP ER), utilizing gastroretentive drug delivery technology. MNK-155 is currently under development for the management of moderate to moderately severe acute pain. The purpose of this study was to evaluate the effect of fed (high- and low-fat meals) versus fasted conditions on single-dose pharmacokinetics and bioavailability following administration of MNK-155 (HB 7.5 mg/APAP 325 mg) given as 2 tablets. Healthy subjects (n=40) received a single dose of 2 tablets MNK-155 under fed conditions after a high-fat meal and after a low-fat meal, and under fasted conditions. The most commonly reported treatment-emergent adverse events (AEs) included nausea, vomiting, and dizziness. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly following administration of a single dose of MNK-155. In addition, hydrocodone concentrations were sustained above pre-dose levels over the 12-hour dosing interval. APAP levels approximated baseline levels by 10-12 hours after dosing. Confidence intervals for the total exposure (area under the concentration–time curve [AUC]) for both hydrocodone and APAP after administration of 2 tablets of MNK-155 under fed conditions (both low-fat and high-fat meal) were within the no-effect range. In addition, peak exposure (maximum plasma concentration [Cmax]) for hydrocodone under both fed conditions did not differ from the fasted condition. The finding of lower peak exposure for APAP under both fed conditions is consistent with effects that have been reported for other APAP-containing products. The results of this study support the appropriate administration of MNK-155 without regard to food. Supported by funding from Mallinckrodt Inc.

Today’s revolution in imaging technologies in the biomedical sciences has raised much needed hope for improved diagnostics, therapeutics, and the eventual cure of many debilitating illnesses. Imaging itself has become the seed technology that has fostered the development of many novel diagnostic approaches as well as helping point the way to witnessing the mechanism of action of drugs and biologics. The advancement of new drugs and biologics will be undertaken in the future with surrogate biomarkers, and many of these will be in the form of imaging. Imaging of pharmacodynamic responses to therapies such as changes in RECIST, cerebral glucose utilization, MRI BOLD changes reflecting neurologic activity, and many other novel approaches are opportunities for the imaging community to work with the regulatory community to contribute to the advancement of novel agents. As stated by Dr Steven Larson (2007) “We are experiencing a paradigm shift from anatomic towards biomarker (molecular imaging) as the primary means for assessing treatment response in oncology” and as such the regulatory environment for this to happen must be considered and developed to maximize the potential which imaging brings to medical diagnosis and to clinical decision making.

PURPOSE To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport. METHODS The transport of eight β-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral β-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis. RESULTS Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R(2) ≥ 0.80). The CRPE impeded the SCRPE transport of all β-blockers (51%-64% resistance in the rabbits; 84%-99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R(2) ≥ 0.85). Bovine (R(2) = 0.84), porcine (R(2) = 0.84), and human (R(2) = 0.71) SCRPE transport was more predictive than that in the rabbit models (R(2) = 0.60-0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ≪ pigmented rabbit < porcine ∼ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport. CONCLUSIONS Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral β-blocker transport, with the barrier being more significant for lipophilic β-blockers. Although different in magnitude between species, sclera/SCRPE transport can be correlated between species. Tissue thickness accounts for the species differences in scleral transport. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport.

PURPOSEThe purpose of this study was to evaluate partitioning into and transport across posterior segment tissues (sclera, retinal pigment epithelium (RPE)-choroid) of AL-4940, the active metabolite of angiostatic cortisene anecortave acetate (AL-3789).METHODSTransport of [(14)C]-AL-4940 was measured through RPE-choroid-sclera (RCS) and sclera, excised from Dutch Belted pigmented rabbits' eyes, in the directions of scleral to vitreal (S-->V) and vitreal to scleral (V-->S) for 3 h at 37 degrees C using Ussing chambers. Tissue integrity was monitored by transepithelial electrical resistance (TEER), potential difference (PD), and biochemical assay (LDH). Partitioning in RPE-choroid and sclera was determined separately for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Mathematical analysis for bilaminate membranes used partitioning and transport data to derive diffusion coefficients for 2 tissue layers sclera and RPE-choroid.RESULTSPartitioning of drug in tissue was comparable for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Partition coefficients of drug in tissue were 2.2 for sclera and about 4 for RPE-choroid. Permeability through sclera alone was about 3 x 10(-5) cm/s and about 1 x 10(-5) cm/s through the RCS tissue, irrespective of the direction of transport (S-->V) or (V-->S). Results from bioelectrical and biochemical evaluation of tissue with modified LDH assay provided evidence that the RCS tissue preparation remained viable during the period of transport study.CONCLUSIONSThe thin RPE-choroid layer contributes significantly to resistance to drug transport, and diffusivity in this layer is 10 times less than in sclera. This experimental scheme is proposed as an important component for the development of a general ocular physiologically based pharmacokinetic model.

Importance of the field: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR.Areas covered in this review: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections.What the reader will gain: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery.Take home message: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders.

Purpose To investigate the effects of diabetes on transscleral retinal delivery of celecoxib in albino and pigmented rats. Methods Albino (Sprague Dawley—SD) and pigmented (Brown Norway—BN) rats were made diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg) following 24 h of fasting and diabetes was confirmed (blood glucose >250 mg/dL). Two months after diabetes induction, the integrity of blood-retinal-barrier in control versus diabetic rats from both strains was compared by using FITC-dextran leakage assay. Fifty microliter suspension of celecoxib (3 mg/rat) was injected periocularly in both the strains in one eye, 2 months following diabetes induction. The animals were euthanized at the end of 0.25, 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing and celecoxib levels in ocular tissues and plasma were estimated using a HPLC assay. Results Diabetes (2-month duration) resulted in 2.4 and 3.5 fold higher blood-retinal barrier leakage in diabetic SD and BN rats, respectively, compared to controls. The area under tissue celecoxib concentration versus time curves (AUC) for sclera, cornea, and lens were not significantly different between control and diabetic animals. However, retinal and vitreal AUCs of celecoxib in treated eyes were approximately 1.5-fold and 2-fold higher in diabetic SD and BN rats, respectively, as compared to the controls. Conclusions Transscleral retinal and vitreal delivery of celecoxib is significantly higher in diabetic animals of both strains. The increase in retinal delivery of celecoxib due to diabetes is higher in pigmented rats compared to albino rats. Higher delivery of celecoxib in diabetic animals compared to control animals can be attributed to the disruption of blood-retinal barrier due to diabetes.