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This study investigates the effects of homopolymer additives and kinetic traps on the self-assembly of poly(ethylene glycol)-b-poly(lactide) (PEG-PLA) block copolymer (BCP) nanostructures in aqueous environments. By using non-adsorbing PEG homopolymers to kinetically trap PEG-PLA nanostructures, we demonstrate that varying the concentration and molecular weight of the added PEG induces a reversible micelle-to-vesicle transition. This transition is primarily driven by changes in the molecular geometry of the PEG-PLA BCPs due to excluded volume screening effects. Additionally, the reversible vesicle-to-micelle transition upon PEG’s removal shows time and temperature dependency, highlighting the influence of the system’s kinetic nature. Intermediate structures observed during the transition support a mechanism based on shifts in the molecular geometry of PEG-PLA. As a proof of concept, we show that PEG-PLA vesicles can act as thermoresponsive delivery systems, retaining dye at low temperatures (4 °C) and releasing it upon heating (37 °C). Overall, this work presents a novel approach to controlling BCP nanostructures’ morphology, with implications for drug delivery and material science applications.

Purpose: The objective of this study was to determine the ocular bioavailability of hesperidin and hesperetin, especially with respect to their distribution into the posterior segment of the eye, following systemic and topical administration in rabbits., Methods: Hesperidin and hesperetin were administered either intravenously or topically to male New Zealand white (NZW) rabbits. Vitreous humor and plasma samples were collected after intravenous administration and analyzed to estimate the concentrations of the parent compounds and their metabolites. Ocular tissue concentrations, obtained on topical administration of hesperidin and hesperetin, were also determined., Results: In the systemic circulation, hesperidin and hesperetin were rapidly metabolized into their glucuronides, which are extremely hydrophilic in nature. Vitreal samples did not demonstrate any detectable levels of hesperidin/hesperetin following intravenous administration. Topical administration produced significant concentrations of hesperidin/hesperetin in all the ocular tissues tested at the 1 and 3 hours time points postdosing, with hesperetin showing higher levels compared to hesperidin. However, only low levels were generated in the vitreous humor. Inclusion of a penetration enhancer, benzalkonium chloride (BAK), improved the back-of-the-eye hesperetin levels., Conclusions: Ocular delivery of hesperidin/hesperetin via the systemic route does not seem to be feasible considering the rapid generation of the hydrophilic metabolites. Topical application appears to be more promising and needs to be further developed/refined.

A case of a 41-year-old patient presenting late post-trauma with out any major signs or symptoms is presented herewith. On radiological investigation, a peculiar foreign body was identified in the orbital floor. To our surprise the point of entry of the foreign body was not proportionate with the size of it. Moreover, the trajectory and final location of foreign body did not concur with the symptom less presentation of patient. After what was thought to be adequate investigation, the patient was taken under general anaesthesia to reveal an additional foreign body that put most of the preoperative queries to rest. This case in retrospect emphasises the need for ruling out foreign body in the case of any penetrating injury of orbit with the help of not just radiographs and CT scans but also ultrasonography and MRI.

Hesperidin, a flavanone glycoside, and its aglycone hesperetin are potential candidates for the treatment of diabetic retinopathy and macular edema. The objective of this study was to delineate vitreal pharmacokinetics of hesperidin and hesperetin and the hydrophilic derivative glucosyl hesperidin (hesperidin G) following intravitreal administration in anaesthetized rabbits. Concentration changes in vitreous humor were monitored using microdialysis sampling procedure. All three molecules were administered intravitreally at three dose levels (50 µL injection volume containing 1.5, 4.5, and 15 µg of the drug, resulting in a final vitreal concentration of 1, 3, and 10 µg/mL). Vitreal microdialysis samples were collected every 20 min over a period of 10 h. All three molecules exhibited linear pharmacokinetics within the dose range tested because area under the curve and maximum concentration (C(max) ) increased linearly with increasing dose and a significant difference in the elimination parameters such as clearance or half-life was not observed. The vitreal elimination half-life of these three compounds was observed to correlate with the molecular weight and lipophilicity of the molecules. The findings from this study provide practical information that will be useful in the future design of ocular drug delivery strategies for bioflavonoids., (Copyright © 2012 Wiley Periodicals, Inc.)

The objective of the present study was to investigate the effect of topically coadministered P-glycoprotein (P-gp) substrates/inhibitors on the vitreal kinetics of a systemically administered P-gp substrate. Anesthetized male rabbits were used in these studies. The concentration-time profile of quinidine in the vitreous humor, after intravenous administration, was determined alone and in the presence of topically coadministered verapamil, prednisolone sodium phosphate (PP), and erythromycin. The vitreal pharmacokinetic parameters of quinidine in the presence of verapamil [apparent elimination rate constant (λ(z)), 0.0027 ± 0.0002 min(-1); clearance (CL_F), 131 ± 21 ml/min; area under the curve (AUC(0-∞)), 39 ± 7.0 μg · min/ml; and mean residence time, 435 ± 20 min] were significantly different from those of the control (0.0058 ± 0.0006 min(-1), 296 ± 46 ml/min, 17 ± 3 μg · min/ml, and 232 ± 20 min, respectively). A 1.7-fold decrease in the vitreal λ(z) and a 1.5-fold increase in the vitreal AUC of quinidine were observed in the presence of topical PP. Statistically significant differences between the vitreal profiles of the control and erythromycin-treated group were also observed. Plasma concentration-time profiles of quinidine, alone or in the presence of the topically instilled compounds, remained unchanged, indicating uniform systemic quinidine exposure across groups. This study demonstrates an interaction between topically and systemically coadministered P-gp substrates, probably through the modulation of P-gp on the basolateral membrane of the retinal pigmented epithelium, leading to changes in the vitreal kinetics of the systemically administered agent.

Objectives: Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues., Key Findings: It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration., Summary: The potential therapeutic applications of various bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent bioflavonoids in the ocular tissues and at much lower doses.

Hesperetin, an aglycone of the flavanone hesperidin, is a potential candidate for the treatment of diabetic retinopathy and macular edema. The purpose of this investigation was to determine solubility, stability and in vitro permeability characteristics of hesperetin across excised rabbit corneas. Aqueous and pH dependent solubility was determined using standard shake flask method. Solution stability was evaluated as a function of pH (1.2-9) and temperature (25 and 40 degrees C). Permeability of hesperetin was determined across the isolated rabbit cornea utilizing a side-bi-side diffusion apparatus, in the apical to basolateral (A-B) and basolateral to apical (B-A) directions. Hesperetin displayed asymmetrical transcorneal transport with a 2.3-fold higher apparent permeability in the B-A direction compared to the A-B direction. The transport process was observed to be pH dependent. Surprisingly, however, the involvement of efflux transporters or proton-coupled carrier-systems was not evident in this asymmetric transcorneal diffusion process. The passive and pH dependent corneal transport of hesperetin could probably be attributable to corneal ultrastructure, physicochemical characteristics of hesperetin and the role of transport buffer components., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

In vitro transcorneal permeability studies are an important screening tool in drug development. The objective of this research is to examine the feasibility of using corneas isolated from preserved rabbit eyes as a model for permeability evaluation. Eyes from male New Zealand White rabbits were used immediately or were stored overnight in phosphate-buffered saline (PBS) or Hanks balanced salt solution (HBSS) over wet ice. Integrity of isolated corneas was evaluated by measuring the TEER and by determining the permeability of paracellular and transcellular markers. Active transport was assessed by measuring transcorneal permeability of selected amino acids. Esterase activity was estimated using p-nitrophenyl assay. In all cases, corneas from freshly enucleated eyes were compared to those isolated from the day-old preserved eyes. Transcellular and paracellular passive diffusion was not affected by the storage medium and observed to be similar in the fresh and preserved eye models. However, amino acid transporters demonstrated lower functional activity in corneas excised from eyes preserved in PBS. Moreover, preserved eyes displayed almost 1.5-fold lower esterase activity in the corneal tissue. Thus, corneas isolated from day-old eyes, preserved in HBSS, closely mimics freshly excised rabbit corneas in terms of both active and passive transport characteristics but possesses slightly reduced enzymatic activity., (2009 Wiley-Liss, Inc. and the American Pharmacists Association)

The purpose of this study was to investigate whether topically administered P-glycoprotein (P-gp) substrates/modulators can alter vitreal kinetics of intravitreally administered quinidine. Male New Zealand rabbits were used under anesthesia. Vitreal kinetics of intravitreally administered quinidine (0.75-microg dose) was determined alone and in the presence of verapamil (coadministered topically/intravitreally) or prednisolone hemisuccinate sodium (PHS) (coadministered topically). In the presence of topically instilled verapamil (1% w/v), elimination half-life (t(1/2)) (176 +/- 7 min), apparent elimination rate constant (lambda(z)) (0.0039 +/- 0.0001 min(-1)), and mean retention time (MRT) (143 +/- 30 min) of intravitreally administered quinidine were significantly different from those of the control (105 +/- 11 min, 0.0066 +/- 0.0007 min(-1), and 83 +/- 13 min, respectively). A 2-fold increase in the t(1/2) with a corresponding decrease in lambda(z) and a 1.5-fold increase in the MRT of quinidine were observed in the presence of topically coadministered 2% w/v PHS. Intravitreal coadministration of quinidine and verapamil resulted in a significant increase in t(1/2) (159 +/- 9 min) and a decrease in lambda(z) (0.0043 +/- 0.0002 min(-1)) of quinidine. The vitreal pharmacokinetic parameters of sodium fluorescein, alone or in the presence of topically instilled verapamil, did not show any statistically significant difference, indicating that ocular barrier integrity was not affected by topical verapamil administration. Results from this study suggest that topically applied P-gp substrates/modulators can alter vitreal pharmacokinetics of intravitreally administered P-gp substrates, possibly through the inhibition of P-gp expressed on the basolateral membrane of the retinal pigmented epithelium.

Purpose: The aim of this study was to evaluate the contribution of amino acid transporters in the transcorneal permeation of the aspartate (Asp) ester acyclovir (ACV) prodrug., Methods: Physicochemical characterization, solubility and stability of acyclovir L-aspartate (L-Asp-ACV) and acyclovir D-aspartate (D-Asp-ACV) were studied. Transcorneal permeability was evaluated across excised rabbit cornea., Results: Solubility of L-Asp-ACV and D-Asp-ACV were about twofold higher than that of ACV. The prodrugs demonstrated greater stability under acidic conditions. Calculated pK(a) and logP values for both prodrugs were identical. Transcorneal permeability of L-Asp-ACV (12.1 +/- 1.48 x 10(-6) cm/s) was fourfold higher than D-Asp-ACV (3.12 +/- 0.36 x 10(-6) cm/s) and ACV (3.25 +/- 0.56 x 10(-6) cm/s). ACV generation during the transport process was minimal. L-Asp-ACV transport was sodium and energy dependent but was not inhibited by glutamic acid. Addition of BCH, a specific B(0,+) and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66 +/- 0.21 x 10(-6) cm/s. L-Asp-ACV and D-Asp-ACV did not demonstrate significant difference in stability in ocular tissue homogenates., Conclusion: The results demonstrate that enhanced transport of L-Asp-ACV is as a result of corneal transporter involvement (probably amino acid transporter B(0,+)) and not as a result of changes in physicochemical properties due to prodrug derivatization (permeability of D-Asp-ACV and ACV were not significantly different).

Purpose: Hesperidin holds potential in treating age-related macular degeneration, cataract and diabetic retinopathy. The aim of this study, constituting the first step towards efficient ocular delivery of hesperidin, was to determine its physicochemical properties and in vitro ocular tissue permeability., Methods: pH dependent aqueous solubility and stability were investigated following standard protocols. Permeability of hesperidin across excised rabbit cornea, sclera, and sclera plus retinal pigmented epithelium (RPE) was determined using a side-bi-side diffusion apparatus., Results: Hesperidin demonstrated poor, pH independent, aqueous solubility. Solubility improved dramatically in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and the results supported 1:1 complex formation. Solutions were stable in the pH and temperature (25, 40 degrees C) conditions tested, except for samples stored at pH 9. Transcorneal permeability in the apical-basal and basal-apical directions was 1.11 +/- 0.86 x 10(-6) and 1.16 +/- 0.05 x 10(-6) cm/s, respectively. The scleral tissue was more permeable (10.2 +/- 2.1 x 10(-6) cm/s). However, permeability across sclera/choroid/RPE in the sclera to retina and retina to sclera direction was 0.82 +/- 0.69 x 10(-6), 1.52 +/- 0.78 x 10(-6) cm/s, respectively, demonstrating the barrier properties of the RPE., Conclusion: Our results suggest that stable ophthalmic solutions of hesperidin can be prepared and that hesperidin can efficiently permeate across the corneal tissue. Further investigation into its penetration into the back-of-the eye ocular tissues is warranted.

In today's pharmaceutical arena, it is estimated that more than 40% of new chemical entities produced during drug discovery efforts exhibit poor solubility characteristics. However, over the last decade hot-melt extrusion (HME) has emerged as a powerful processing technology for drug delivery and has opened the door to a host of molecules previously considered unviable as drugs. HME is considered to be an efficient technique in developing solid molecular dispersions and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This article reviews the range of HME applications for pharmaceutical dosage forms, such as tablets, capsules, films and implants for drug delivery through oral, transdermal, transmucosal, transungual, as well as other routes of administration. Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs have made this technique worthy of consideration as a drug delivery solution.